Search "screen flickering windows 10 site:microsoft.com" (2024)

Hepatic encephalopathy describes a spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction and/or portosystemic shunting. Overt hepatic encephalopathy develops in 30 to 45 percent of patients with cirrhosis and in 10 to 50 percent of patients with tr

CloseManual muscle test scales and grading criteriaManual muscle test scales and grading criteria MRC Adaptation A MRC Adaptation B Kendall 10-Point Scale 5 Normal strength. 5 Normal strength. 10 Holds test position against strong pressure. 5– Uncertain muscle weakness. 5– Barely detectable weakness. N/A 4+ Inability to resist against maximal pressure throughout range of motion. 4S Same as 4 but stronger than reference muscle. 9 Holds test position against moderate to strong pressure. 4 Ability to resist against moderate pressure throughout range of motion. 4 Muscle is weak but moves joint against a combination of gravity and some resistance. 8 Holds test position against moderate pressure. 4– Ability to resist against minimal pressure throughout range of motion. 4W Same as 4 but weaker than reference muscle. 7 Holds test position against slight to moderate pressure. 3+ Ability to move through full range of motion against gravity and to resist against minimal pressure through partial range of motion, then contraction breaks abruptly. 3+ The muscle is capable of transient resistance but collapses abruptly. This degree of weakness is difficult to put into words, but it is a muscle that is able to move the joint against gravity and an additional small amount of resistance. It is not to be used for muscles capable of sustained resistance throughout the whole range of movement. 6 Holds test position against slight pressure. 3 Ability to move through full range of motion against gravity. 3 Muscle cannot move against resistance but moves the joint fully against gravity. With the exception of knee extensors, the joint must be moved through the full mechanical range against gravity. If a patient has contractures that limit movement of the joint, the mechanical range will obviously be to the point at which the contractures cause a significant resistance to the movement. 5 Holds test position (no added pressure). 3– Ability to move through greater than one-half range of motion against gravity. 3– Muscle moves the joint against gravity but not through the full extent of the mechanical range of the joint. 4 Gradual release from test position. 2+ Ability to move through less than one-half range of motion against gravity. N/A 3 Moves through partial range of motion against gravity. 2 Ability to move through full range of motion with gravity eliminated. 2 Muscle moves the joint when gravity is eliminated. 2 Moves through complete range of motion on a horizontal plane. 2– Ability to move in any arc of motion with gravity eliminated. N/A 1 Moves through partial range of motion on a horizontal plane. 1 A flicker of movement is seen or felt in the muscle. 1 A flicker of movement is seen or felt in the muscle. T A flicker of movement is seen or felt in the muscle. 0 No contraction palpable. 0 No movement. 0 No visible movement of the part.Grading criteria for all scales have been modified for brevity.MRC: Medical Research Council; N/A: not applicable; T: trace.References:Personius KE, Pandya S, King WM, et al. Facioscapulohumeral dystrophy natural history study: Standardization of testing procedures and reliability of measurements. The FSH DY Group. Phys Ther 1997; 74:253.Fowler WM Jr, Abresch RT, Aitkens S, et al. Profiles of neuromuscular diseases. Design of the protocol. Am J Phys Med Rehabil 1995; 74 Suppl:S62.Kendall FP, McCreary EK, Provance PG. Muscles: Testing and Function, 4th ed, Williams and Wilkins, Baltimore, 1993.Graphic 126332 Version 1.0

CloseHuman papillomavirus 9-valent vaccine (9vHPV): Drug informationHuman papillomavirus 9-valent vaccine (9vHPV): Drug information(For additional information see "Human papillomavirus 9-valent vaccine (9vHPV): Patient drug information" and see "Human papillomavirus 9-valent vaccine (9vHPV): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USGardasil 9Brand Names: CanadaGardasil 9Pharmacologic CategoryVaccine;Vaccine, Inactivated (Viral)Dosing: AdultImmunizationImmunization: IM:Manufacturer's labeling: Adults ≤45 years of age: 3-dose series: 0.5 mL at 0, 2, and 6 months.CDC/ACIP recommended immunization schedule: Adults ≤26 years of age: Catch-up vaccination is recommended in all persons ≤26 years of age if not previously vaccinated or have not completed the 3-dose series (typically administer first dose at age 11 to 12 years). Second and third doses may be given after age 26 years to complete a previously initiated series (Ref). Note: Shared clinical decision-making regarding catch-up human papillomavirus vaccination is recommended for some adults 27 to 45 years of age (Ref). The American Cancer Society does not endorse vaccination in adults 27 to 45 years of age (Ref).Have not received any doses: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months. There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.Partially vaccinated, first dose before 15 years of age:If 2 doses administered at least 5 months apart: No more doses needed.If only a single dose or if doses <5 months apart: IM: Administer one additional 0.5 mL dose.Partially vaccinated, first dose at 15 years of age or later: Complete 3-dose series: IM: There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Pediatric(For additional information see "Human papillomavirus 9-valent vaccine (9vHPV): Pediatric drug information")Note: Consult CDC/ACIP annual immunization schedules for additional information including specific detailed recommendations for catch-up scenarios and/or care of patients with high-risk conditions. According to ACIP, doses administered ≤4 days before minimum interval or age are considered valid; however, local or state mandates may supersede this timeframe (Ref).Primary immunizationPrimary immunization: Children ≥9 years and Adolescents: IM: 0.5 mL per dose for 2 or 3 doses; see the following recommendations for number and timing of doses (Ref).CDC/ACIP recommended immunization schedule: Routine vaccination at 11 to 12 years of age for all persons; may start as early as 9 years of age. AAP and ACS recommend routine vaccination between 9 and 12 years of age (Ref).In a 2-dose schedule, minimum interval between first and second doses is 5 months.In a 3-dose schedule, minimum interval between first and second doses is 4 weeks; the minimum interval between the second and third dose is 12 weeks; the minimum interval between first and third doses is 5 months (Ref).Non-immunocompromised patients and certain specified medical conditions: Asplenia, asthma, chronic granulomatous disease, chronic liver disease, chronic lung disease, chronic renal disease, central nervous system, anatomic barrier defects (eg, cochlear implant), complement deficiency, diabetes, heart disease, or sickle cell disease:Children ≥9 years and Adolescents <15 years: 2-dose series: IM: 0.5 mL at 0, and 6 to 12 months. Administer first dose at age 11 to 12 years. For patients with any history of sexual abuse or assault, vaccination should be started at 9 years.Adolescents ≥15 years: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.Immunocompromised patients: Including those with conditions that might reduce cell-mediated or humoral immunity, such as B lymphocyte antibody deficiencies, T lymphocyte complete or partial defects, HIV infection, malignant neoplasms, transplantation, autoimmune disease, or immunosuppressive therapy:Children ≥9 years and Adolescents: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.Manufacturing labeling: May not reflect current practice:Children ≥9 years and Adolescents <15 years:2-dose series: IM: 0.5 mL per dose; administer the second dose at 6 to 12 months after initial dose. If the second dose is inadvertently administered earlier than 5 months after the first dose, then patient should be converted to a 3-dose series.3-dose series: IM: 0.5 mL per dose; administer the second and third doses at 2 and 6 months after initial dose.Adolescents ≥15 years: IM: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose.Catch-up immunizationCatch-up immunization: CDC/ACIP recommendations (Ref): Note: Do not restart the series. If doses have been given, begin the below schedule at the applicable dose number. Children ≥9 years and Adolescents: IM: 0.5 mL per dose for a total of 2 to 3 doses (See CDC/ACIP recommendations in Primary Immunization for 2-dose vs 3-dose schedule criteria):First dose given on the elected date.Second dose given at least 4 weeks after the first dose (for a 3-dose schedule) or 5 months after the first dose (for a 2-dose schedule).Third dose (for a 3-dose schedule) given at least 12 weeks after the second dose and at least 5 months after the first dose.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension, Intramuscular [preservative free]: Gardasil 9:(0.5 mL) [contains polysorbate 80, yeast extract]Suspension Prefilled Syringe, Intramuscular [preservative free]: Gardasil 9:(0.5 mL) [contains polysorbate 80, yeast extract]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension, Intramuscular [preservative free]:Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract; latex-free]Suspension Prefilled Syringe, Intramuscular [preservative free]:Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract; latex-free]Medication Guide and/or Vaccine Information Statement (VIS)In the US, the appropriate CDC-approvedVaccine Information Statement (VIS) must be provided to the patient prior to administering each dose of this vaccine; VIS is available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-gardasil-9.htmlAdministration: AdultIM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (Ref). To prevent syncope-related injuries, patients should be vaccinated while seated or lying down (Ref). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage following IM injection, the vaccine should be administered IM if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, IM vaccination can be scheduled shortly after such therapy is administered. A fine needle (≤23-gauge) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (Ref).Administration: PediatricIM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (Ref). To prevent syncope related injuries, adolescents should be vaccinated while seated or lying down (Ref). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement (VIS) edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage following intramuscular injection, the vaccine should be administered intramuscularly if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23-gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (Ref).Use: Labeled IndicationsPrevention of human papillomavirus infection:Females 9 to 45 years of age:For the prevention of the following diseases:Cervical, vulvar, vagin*l, anal, oropharyngeal, and other head and neck cancers caused by human papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58.Genital warts (condyloma acuminata) caused by HPV types 6 and 11.For the prevention of the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:Cervical intraepithelial neoplasia grades 1, 2, and 3.Cervical adenocarcinoma in situ.Vulvar intraepithelial neoplasia grades 2 and 3.vagin*l intraepithelial neoplasia grades 2 and 3.Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.Males 9 through 45 years of age:For the prevention of the following diseases:Anal, oropharyngeal, and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58.Genital warts (condyloma acuminata) caused by HPV types 6 and 11.For the prevention of the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:AIN grades 1, 2, and 3.The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for females and males 11 to 12 years of age; for patients with any history of sexual abuse or assault, vaccination should be started at 9 years of age. Catch-up vaccination is recommended for all persons through 26 years of age. Shared clinical decision-making regarding catch-up HPV vaccination is recommended for some adults 27 to 45 years of age (CDC/ACIP [Meites 2019]). The American Academy of Pediatrics and the American Cancer Society (ACS) recommend routine vaccination for individuals 9 to 12 years of age (ACS [Saslow 2020]; Red Book [AAP 2018]). ACS recommends catch-up vaccination only for individuals through 26 years of age (ACS [Saslow 2020]).Medication Safety IssuesSound-alike/look-alike issues:Papillomavirus vaccine 9-valent (Gardasil 9) may be confused with Papillomavirus vaccine types 6, 11, 16, 18 (Gardasil)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with IPV (inactivated poliovirus vaccine)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with HBV (previously used for hepatitis B vaccine; HepB is correct abbreviation)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with Hib (Haemophilus b conjugate vaccine)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Reported incidences are for females 9 to 45 years of age and males 9 to 26 years of age.>10%:Local: Erythema at injection site (7% to 42%; increased with successive doses), pain at injection site (63% to 90%), swelling at injection site (13% to 49%; increased with successive doses)Nervous system: Headache (7% to 20%)1% to 10%:Dermatologic: Injection site pruritus (1% to 8%)Gastrointestinal: Diarrhea (≤1%), nausea (1% to 4%), upper abdominal pain (≤2%)Immunologic: Autoimmune disease (2%)Local: Bleeding at injection site (1%), bruising at injection site (2%), hematoma at injection site ( ≤5%), hypersensitivity reaction at injection site (1%), induration at injection site (≤2%), injection site nodule (1%), injection site reaction (≤1%)Nervous system: Dizziness (≤3%), fatigue (1% to 3%)Neuromuscular & skeletal: Myalgia (≤1%)Respiratory: Oropharyngeal pain (1% to 3%)Miscellaneous: Fever (2% to 10%)<1%:Local: Warm sensation at injection siteRespiratory: Upper respiratory tract infectionFrequency not defined:Hypersensitivity: Hypersensitivity reactionRespiratory: Status asthmaticusPostmarketing:Cardiovascular: SyncopeDermatologic: UrticariaGastrointestinal: VomitingContraindicationsHypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of this vaccine or human papillomavirus (types 6, 11, 16, 18) vaccine (recombinant).Warnings/PrecautionsConcerns related to adverse effects:• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2021]).• Shoulder injury related to vaccine administration: Vaccine administration that is too high on the upper arm may cause shoulder injury (eg, shoulder bursitis or tendinitis) resulting in shoulder pain and reduced range of motion following injection. Use proper injection technique for vaccines administered in the deltoid muscle (eg, injecting in the central, thickest part of the muscle) to reduce the risk of shoulder injury related to vaccine administration (Cross 2016; Foster 2013).• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2021]).Disease-related concerns:• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2021]).• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2021]).• Human papillomavirus infection: There is no evidence that individuals already infected with human papillomavirus (HPV) will be protected; those already infected with 1 or more HPV types were protected from disease caused by the remaining HPV types. Not for the treatment of active disease; will not protect against diseases not caused by HPV vaccine types not included in the vaccine. Does not eliminate the necessity for recommended cervical or anal cancer screenings.Concurrent drug therapy issues:• Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2021]).• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (ACIP [Kroger 2021]).Special populations:• Altered immunocompetence: Consider deferring immunization during periods of severe immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high-dose corticosteroids]); may have a reduced response to vaccination. In general, household and close contacts of persons with altered immunocompetence may receive all age-appropriate vaccines. Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2021]; IDSA [Rubin 2014]). Dosage form specific issues:• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.• Previously vaccinated with Gardasil (quadrivalent): Safety and immunogenicity of Gardasil 9 were assessed in individuals who previously completed a 3-dose vaccination series with Gardasil (quadrivalent). Studies using a mixed regimen of HPV vaccines to assess interchangeability were not performed. Per the ACIP, if the provider does not have available or does not know the HPV product used previously, any gender appropriate product can be used to complete the series (CDC/ACIP [Petrosky 2015]).• Yeast: Product may contain yeast.Other warnings/precautions:• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the annual ACIP Recommended Immunization Schedules (refer to CDC schedule for detailed information). Specific recommendations for vaccination in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the IDSA (Rubin 2014).• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2021]). Vaccination is safe for individuals 27 to 45 years of age; however, consider decreased effectiveness and potential for lower cancer prevention in these older ages (ACS [Saslow 2020]; CDC/ACIP [Meites 2019])).• Maximum efficacy: The entire series should be completed for maximum efficacy.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acetaminophen: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationCladribine: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of cladribine when possible. Patients vaccinated less than 14 days before initiating or during cladribine should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationCorticosteroids (Systemic): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationElivaldogene Autotemcel: May enhance the adverse/toxic effect of Vaccines. Specifically, there may be a greater risk for contracting an infection from any live vaccine. Elivaldogene Autotemcel may diminish the therapeutic effect of Vaccines. Management: Administration of vaccines is not recommended in the 6 weeks before myeloablative conditioning, and until hematologic recovery after elivaldogene autotemcel treatment. Risk X: Avoid combinationFingolimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Risk D: Consider therapy modificationImmunosuppressants (Cytotoxic Chemotherapy): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Miscellaneous Oncologic Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Therapeutic Immunosuppressant Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modificationMethotrexate: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to methotrexate initiation, if possible. If patients are vaccinated less than 14 days prior to or during methotrexate therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationPropacetamol: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of propacetamol before or during vaccine administration when possible. Propacetamol is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationRiTUXimab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of rituximab when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 6 months after therapy is complete. Risk D: Consider therapy modificationSiponimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Risk D: Consider therapy modificationTeplizumab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccination with inactivated or non-replicating vaccines is not recommended in the 2 weeks prior to teplizumab therapy, during treatment, or for 6 weeks following completion of therapy. Risk D: Consider therapy modificationReproductive ConsiderationsPregnancy testing is not required prior to administration of the vaccine (ACOG 2020; CDC/ACIP [Petrosky 2015]).Based on available information, the human papillomavirus vaccine is not expected to decrease female fertility (Christianson 2020; Schmuhl 2020). However, human papillomavirus infection may be associated with infertility in males and females. Vaccination may increase fertility in some patients; however, additional study is needed (Garolla 2018; McInerney 2017; Pereira 2015).Pregnancy ConsiderationsBased on available data, an increased risk of adverse pregnancy outcomes, specifically miscarriage or congenital anomalies, has not been observed following inadvertent administration of the papillomavirus vaccine during pregnancy (ACOG 2020; Kharbanda 2021; Landazabal 2019). However, administration of the vaccine in pregnancy is not recommended. The vaccine series (or completion of the series) should be delayed until pregnancy is completed (ACOG 2020; CDC/ACIP [Petrosky 2015]).Data collection to monitor pregnancy and infant outcomes following exposure to the papillomavirus (9-valent) vaccine is ongoing. A registry has been established for patients exposed to the Gardasil 9 HPV vaccine during pregnancy (1-800-986-8999).Breastfeeding ConsiderationsIt is not known if components of this vaccine are present in breast milk.According to the manufacturer, the decision to breastfeed during following immunization should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. However, maternal vaccination is not a contraindication to breastfeeding; the papillomavirus vaccine may be administered to breastfeeding patients (ACIP [Kroger 2021]; ACOG 2020). Administration of inactivated virus vaccine does not affect the safety of breastfeeding for the mother or the infant (ACIP [Kroger 2021]).Monitoring ParametersScreening for human papillomavirus is not required prior to vaccination. Monitor for anaphylaxis and syncope for 15 minutes following administration (ACIP [Kroger 2021]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion. Continue recommended anal cancer screening.Females: Gynecologic screening exam, papillomavirus test; screening for cervical cancer should continue per current guidelines following vaccination.Mechanism of ActionContains inactive human papillomavirus (HPV) proteins (types 6 L1,11 L1, 16 L1, 18 L1, 31 L1, 33 L1, 45 L1, 52 L1, and 58 L1) which produce neutralizing antibodies to prevent cervical, vulvar, vagin*l, and analcancers, cervical adenocarcinoma, cervical, vagin*l, vulvar, and anal neoplasia, and genital warts caused by HPV. Efficacy of HPV 9-valent vaccine against anogenital diseases related to the vaccine HPV types in humans is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.Brand Names: InternationalGardasil 9 (AT, AU, BE, CZ, DE, DK, EE, HK, HR, KR, LT, LV, MY, NL, NZ, PH, PL, PT, RO, SI, SK)For country code abbreviations (show table)Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.American College of Obstetricians and Gynecologists' Committee on Adolescent Health Care, American College of Obstetricians and Gynecologists' Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group. Human papillomavirus vaccination: ACOG committee opinion, number 809. Obstet Gynecol. 2020;136(2):e15-e21. doi:10.1097/AOG.0000000000004000 [PubMed 32732766]Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm.Centers for Disease Control and Prevention (CDC). Vaccination guidance during a pandemic. Updated October 20, 2020. Available at https://www.cdc.gov/vaccines/pandemic-guidance/index.htmlChristianson MS, Wodi P, Talaat K, Halsey N. Primary ovarian insufficiency and human papilloma virus vaccines: a review of the current evidence. Am J Obstet Gynecol. 2020;222(3):239-244. doi:10.1016/j.ajog.2019.08.045 [PubMed 31479634]Cross GB, Moghaddas J, Buttery J, Ayoub S, Korman TM. Don't aim too high: avoiding shoulder injury related to vaccine administration. Aust Fam Physician. 2016;45(5):303-306. [PubMed 27166466]Einstein MH, Baron M, Levin MJ, et al; HPV-010 Study Group. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009;5(10):705-719. [PubMed 19684472]Foster SL, Davis MV. Vaccine administration: preventing serious shoulder injuries. J Am Pharm Assoc (2003). 2013;53(1):102-103. doi:10.1331/JAPhA.2013.13503 [PubMed 23636163]Gardasil 9 (human papilloma virus 9-valent vaccine) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; June 2020.Gardasil 9 (human papilloma virus 9-valent vaccine) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; August 2021.Garolla A, De Toni L, Bottacin A, et al. Human papillomavirus prophylactic vaccination improves reproductive outcome in infertile patients with HPV sem*n infection: a retrospective study. Sci Rep. 2018;8(1):912. doi:10.1038/s41598-018-19369-z [PubMed 29343824]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):313. [PubMed 12534540]Kharbanda EO, Vazquez-Benitez G, DeSilva MB, et al. Association of inadvertent 9-valent human papillomavirus vaccine in pregnancy with spontaneous abortion and adverse birth outcomes. JAMA Netw Open. 2021;4(4):e214340. doi:10.1001/jamanetworkopen.2021.4340 [PubMed 33818618]Landazabal CS, Moro PL, Lewis P, Omer SB. Safety of 9-valent human papillomavirus vaccine administration among pregnant women: adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014-2017. Vaccine. 2019;37(9):1229-1234. doi:10.1016/j.vaccine.2018.11.077 [PubMed 30660400]Kroger A, Bahta L, Hunter P. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices (ACIP). https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Accessed April 30, 2021.Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Markowitz LE, Dunne EF, Saraiya M, et al; Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2014;63(49):1182]. MMWR Recomm Rep. 2014;63(RR-05):1-30. [PubMed 25167164]McInerney KA, Hatch EE, Wesselink AK, et al. The effect of vaccination against human papillomavirus on fecundability. Paediatr Perinat Epidemiol. 2017;31(6):531-536. doi:10.1111/ppe.12408 [PubMed 28881394]Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination – updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65(49):1405-1408. [PubMed 27977643]Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702. doi: 10.15585/mmwr.mm6832a3. [PubMed 31415491]Pereira N, Kucharczyk KM, Estes JL, et al. Human papillomavirus infection, infertility, and assisted reproductive outcomes. J Pathog. 2015;2015:578423. doi:10.1155/2015/578423 [PubMed 26609434]Petrosky E, Bocchini JA Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64(11):300-304. [PubMed 25811679]Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-e100. [PubMed 24311479]Saslow D, Andrews KS, Manassaram-Baptiste D, Smith RA, Fontham ETH; American Cancer Society Guideline Development Group. Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. CA Cancer J Clin. 2020;70(4):274-280. doi:10.3322/caac.21616 [PubMed 32639044]Schmuhl NB, Mooney KE, Zhang X, Cooney LG, Conway JH, LoConte NK. No association between HPV vaccination and infertility in U.S. females 18-33 years old. Vaccine. 2020;38(24):4038-4043. doi:10.1016/j.vaccine.2020.03.035 [PubMed 32253100]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. [PubMed 7746084]World Health Organization (WHO). Guiding principles for immunization activities during the COVID-19 pandemic: interim guidance, 26 March 2020. Published March 26, 2020. Available at https://apps.who.int/iris/handle/10665/331590Topic 98713 Version 124.0

CloseHuman papillomavirus 9-valent vaccine (9vHPV): Pediatric drug informationHuman papillomavirus 9-valent vaccine (9vHPV): Pediatric drug information(For additional information see "Human papillomavirus 9-valent vaccine (9vHPV): Drug information" and see "Human papillomavirus 9-valent vaccine (9vHPV): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USGardasil 9Brand Names: CanadaGardasil 9Therapeutic CategoryVaccine;Vaccine, Inactivated (Viral)Dosing: PediatricNote: Consult CDC/ACIP annual immunization schedules for additional information including specific detailed recommendations for catch-up scenarios and/or care of patients with high-risk conditions. According to ACIP, doses administered ≤4 days before minimum interval or age are considered valid; however, local or state mandates may supersede this timeframe (Ref).Primary immunizationPrimary immunization: Children ≥9 years and Adolescents: IM: 0.5 mL per dose for 2 or 3 doses; see the following recommendations for number and timing of doses (Ref).CDC/ACIP recommended immunization schedule: Routine vaccination at 11 to 12 years of age for all persons; may start as early as 9 years of age. AAP and ACS recommend routine vaccination between 9 and 12 years of age (Ref).In a 2-dose schedule, minimum interval between first and second doses is 5 months.In a 3-dose schedule, minimum interval between first and second doses is 4 weeks; the minimum interval between the second and third dose is 12 weeks; the minimum interval between first and third doses is 5 months (Ref).Non-immunocompromised patients and certain specified medical conditions: Asplenia, asthma, chronic granulomatous disease, chronic liver disease, chronic lung disease, chronic renal disease, central nervous system, anatomic barrier defects (eg, cochlear implant), complement deficiency, diabetes, heart disease, or sickle cell disease:Children ≥9 years and Adolescents <15 years: 2-dose series: IM: 0.5 mL at 0, and 6 to 12 months. Administer first dose at age 11 to 12 years. For patients with any history of sexual abuse or assault, vaccination should be started at 9 years.Adolescents ≥15 years: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.Immunocompromised patients: Including those with conditions that might reduce cell-mediated or humoral immunity, such as B lymphocyte antibody deficiencies, T lymphocyte complete or partial defects, HIV infection, malignant neoplasms, transplantation, autoimmune disease, or immunosuppressive therapy:Children ≥9 years and Adolescents: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.Manufacturing labeling: May not reflect current practice:Children ≥9 years and Adolescents <15 years:2-dose series: IM: 0.5 mL per dose; administer the second dose at 6 to 12 months after initial dose. If the second dose is inadvertently administered earlier than 5 months after the first dose, then patient should be converted to a 3-dose series.3-dose series: IM: 0.5 mL per dose; administer the second and third doses at 2 and 6 months after initial dose.Adolescents ≥15 years: IM: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose.Catch-up immunizationCatch-up immunization: CDC/ACIP recommendations (Ref): Note: Do not restart the series. If doses have been given, begin the below schedule at the applicable dose number. Children ≥9 years and Adolescents: IM: 0.5 mL per dose for a total of 2 to 3 doses (See CDC/ACIP recommendations in Primary Immunization for 2-dose vs 3-dose schedule criteria):First dose given on the elected date.Second dose given at least 4 weeks after the first dose (for a 3-dose schedule) or 5 months after the first dose (for a 2-dose schedule).Third dose (for a 3-dose schedule) given at least 12 weeks after the second dose and at least 5 months after the first dose.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Human papillomavirus 9-valent vaccine (9vHPV): Drug information")ImmunizationImmunization: IM:Manufacturer's labeling: Adults ≤45 years of age: 3-dose series: 0.5 mL at 0, 2, and 6 months.CDC/ACIP recommended immunization schedule: Adults ≤26 years of age: Catch-up vaccination is recommended in all persons ≤26 years of age if not previously vaccinated or have not completed the 3-dose series (typically administer first dose at age 11 to 12 years). Second and third doses may be given after age 26 years to complete a previously initiated series (Ref). Note: Shared clinical decision-making regarding catch-up human papillomavirus vaccination is recommended for some adults 27 to 45 years of age (Ref). The American Cancer Society does not endorse vaccination in adults 27 to 45 years of age (Ref).Have not received any doses: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months. There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.Partially vaccinated, first dose before 15 years of age:If 2 doses administered at least 5 months apart: No more doses needed.If only a single dose or if doses <5 months apart: IM: Administer one additional 0.5 mL dose.Partially vaccinated, first dose at 15 years of age or later: Complete 3-dose series: IM: There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension, Intramuscular [preservative free]: Gardasil 9:(0.5 mL) [contains polysorbate 80, yeast extract]Suspension Prefilled Syringe, Intramuscular [preservative free]: Gardasil 9:(0.5 mL) [contains polysorbate 80, yeast extract]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension, Intramuscular [preservative free]:Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract; latex-free]Suspension Prefilled Syringe, Intramuscular [preservative free]:Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract; latex-free]Medication Guide and/or Vaccine Information Statement (VIS)In the US, the appropriate CDC-approvedVaccine Information Statement (VIS) must be provided to the patient prior to administering each dose of this vaccine; VIS is available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-gardasil-9.htmlAdministration: PediatricIM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (Ref). To prevent syncope related injuries, adolescents should be vaccinated while seated or lying down (Ref). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement (VIS) edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage following intramuscular injection, the vaccine should be administered intramuscularly if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23-gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (Ref).Administration: AdultIM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (Ref). To prevent syncope-related injuries, patients should be vaccinated while seated or lying down (Ref). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage following IM injection, the vaccine should be administered IM if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, IM vaccination can be scheduled shortly after such therapy is administered. A fine needle (≤23-gauge) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (Ref).Storage/StabilityStore refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light.Administer as soon as possible after being removed from refrigeration. HPV 9-valent vaccine can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.UsePrevention of the following: Cervical, vulvar, vagin*l, anal, oropharyngeal, and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts caused by HPV types 6 and 11; cervical adenocarcinoma in situ; and vulvar, vagin*l, cervical, or anal intraepithelial neoplasia caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 (All indications: FDA approved in females ages 9 to 45 years).Prevention of the following: Genital warts caused by HPV types 6 and 11; anal, oropharyngeal, and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; and anal intraepithelial neoplasia grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 (All indications: FDA approved in males ages 9 to 45 years).The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for females and males 11 to 12 years of age; for patients with any history of sexual abuse or assault, vaccination should be started at 9 years of age. Catch-up vaccination is recommended for all persons through 26 years of age. Shared clinical decision-making regarding catch-up HPV vaccination is recommended for some adults 27 to 45 years of age (CDC/ACIP [Meites 2019]). The American Academy of Pediatrics (AAP) and the American Cancer Society (ACS) recommend routine vaccination for individuals 9 to 12 years of age (ACS [Saslow 2020]; Red Book [AAP 2018]). ACS recommends catch-up vaccination only for individuals through 26 years of age (ACS [Saslow 2020]).Medication Safety IssuesSound-alike/look-alike issues:Papillomavirus vaccine 9-valent (Gardasil 9) may be confused with Papillomavirus vaccine types 6, 11, 16, 18 (Gardasil)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with IPV (inactivated poliovirus vaccine)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with HBV (previously used for hepatitis B vaccine; HepB is correct abbreviation)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with Hib (Haemophilus b conjugate vaccine)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Reported incidences are for females 9 to 45 years of age and males 9 to 26 years of age.>10%:Local: Erythema at injection site (7% to 42%; increased with successive doses), pain at injection site (63% to 90%), swelling at injection site (13% to 49%; increased with successive doses)Nervous system: Headache (7% to 20%)1% to 10%:Dermatologic: Injection site pruritus (1% to 8%)Gastrointestinal: Diarrhea (≤1%), nausea (1% to 4%), upper abdominal pain (≤2%)Immunologic: Autoimmune disease (2%)Local: Bleeding at injection site (1%), bruising at injection site (2%), hematoma at injection site ( ≤5%), hypersensitivity reaction at injection site (1%), induration at injection site (≤2%), injection site nodule (1%), injection site reaction (≤1%)Nervous system: Dizziness (≤3%), fatigue (1% to 3%)Neuromuscular & skeletal: Myalgia (≤1%)Respiratory: Oropharyngeal pain (1% to 3%)Miscellaneous: Fever (2% to 10%)<1%:Local: Warm sensation at injection siteRespiratory: Upper respiratory tract infectionFrequency not defined:Hypersensitivity: Hypersensitivity reactionRespiratory: Status asthmaticusPostmarketing:Cardiovascular: SyncopeDermatologic: UrticariaGastrointestinal: VomitingContraindicationsHypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of this vaccine or human papillomavirus (types 6, 11, 16, 18) vaccine (recombinant).Warnings/PrecautionsConcerns related to adverse effects:• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2021]).• Shoulder injury related to vaccine administration: Vaccine administration that is too high on the upper arm may cause shoulder injury (eg, shoulder bursitis or tendinitis) resulting in shoulder pain and reduced range of motion following injection. Use proper injection technique for vaccines administered in the deltoid muscle (eg, injecting in the central, thickest part of the muscle) to reduce the risk of shoulder injury related to vaccine administration (Cross 2016; Foster 2013).• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2021]).Disease-related concerns:• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2021]).• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2021]).• Human papillomavirus infection: There is no evidence that individuals already infected with human papillomavirus (HPV) will be protected; those already infected with 1 or more HPV types were protected from disease caused by the remaining HPV types. Not for the treatment of active disease; will not protect against diseases not caused by HPV vaccine types not included in the vaccine. Does not eliminate the necessity for recommended cervical or anal cancer screenings.Concurrent drug therapy issues:• Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2021]).• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (ACIP [Kroger 2021]).Special populations:• Altered immunocompetence: Consider deferring immunization during periods of severe immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high-dose corticosteroids]); may have a reduced response to vaccination. In general, household and close contacts of persons with altered immunocompetence may receive all age-appropriate vaccines. Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2021]; IDSA [Rubin 2014]). Dosage form specific issues:• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.• Previously vaccinated with Gardasil (quadrivalent): Safety and immunogenicity of Gardasil 9 were assessed in individuals who previously completed a 3-dose vaccination series with Gardasil (quadrivalent). Studies using a mixed regimen of HPV vaccines to assess interchangeability were not performed. Per the ACIP, if the provider does not have available or does not know the HPV product used previously, any gender appropriate product can be used to complete the series (CDC/ACIP [Petrosky 2015]).• Yeast: Product may contain yeast.Other warnings/precautions:• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the annual ACIP Recommended Immunization Schedules (refer to CDC schedule for detailed information). Specific recommendations for vaccination in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the IDSA (Rubin 2014).• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2021]). Vaccination is safe for individuals 27 to 45 years of age; however, consider decreased effectiveness and potential for lower cancer prevention in these older ages (ACS [Saslow 2020]; CDC/ACIP [Meites 2019])).• Maximum efficacy: The entire series should be completed for maximum efficacy.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAcetaminophen: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationCladribine: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of cladribine when possible. Patients vaccinated less than 14 days before initiating or during cladribine should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationCorticosteroids (Systemic): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationElivaldogene Autotemcel: May enhance the adverse/toxic effect of Vaccines. Specifically, there may be a greater risk for contracting an infection from any live vaccine. Elivaldogene Autotemcel may diminish the therapeutic effect of Vaccines. Management: Administration of vaccines is not recommended in the 6 weeks before myeloablative conditioning, and until hematologic recovery after elivaldogene autotemcel treatment. Risk X: Avoid combinationFingolimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Risk D: Consider therapy modificationImmunosuppressants (Cytotoxic Chemotherapy): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Miscellaneous Oncologic Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Therapeutic Immunosuppressant Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modificationMethotrexate: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to methotrexate initiation, if possible. If patients are vaccinated less than 14 days prior to or during methotrexate therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationPropacetamol: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of propacetamol before or during vaccine administration when possible. Propacetamol is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationRiTUXimab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of rituximab when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 6 months after therapy is complete. Risk D: Consider therapy modificationSiponimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Risk D: Consider therapy modificationTeplizumab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccination with inactivated or non-replicating vaccines is not recommended in the 2 weeks prior to teplizumab therapy, during treatment, or for 6 weeks following completion of therapy. Risk D: Consider therapy modificationReproductive ConsiderationsPregnancy testing is not required prior to administration of the vaccine (ACOG 2020; CDC/ACIP [Petrosky 2015]).Based on available information, the human papillomavirus vaccine is not expected to decrease female fertility (Christianson 2020; Schmuhl 2020). However, human papillomavirus infection may be associated with infertility in males and females. Vaccination may increase fertility in some patients; however, additional study is needed (Garolla 2018; McInerney 2017; Pereira 2015).Pregnancy ConsiderationsBased on available data, an increased risk of adverse pregnancy outcomes, specifically miscarriage or congenital anomalies, has not been observed following inadvertent administration of the papillomavirus vaccine during pregnancy (ACOG 2020; Kharbanda 2021; Landazabal 2019). However, administration of the vaccine in pregnancy is not recommended. The vaccine series (or completion of the series) should be delayed until pregnancy is completed (ACOG 2020; CDC/ACIP [Petrosky 2015]).Data collection to monitor pregnancy and infant outcomes following exposure to the papillomavirus (9-valent) vaccine is ongoing. A registry has been established for patients exposed to the Gardasil 9 HPV vaccine during pregnancy (1-800-986-8999).Monitoring ParametersScreening for HPV is not required prior to vaccination. Monitor for syncope and hypersensitivity for 15 minutes following administration (ACIP [Kroger 2021]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion. Continue recommended anal cancer screening.Females: Gynecologic screening exam, papillomavirus test; screening for cervical cancer should continue per current guidelines following vaccinationMechanism of ActionContains inactive human papillomavirus (HPV) proteins (types 6 L1,11 L1, 16 L1, 18 L1, 31 L1, 33 L1, 45 L1, 52 L1, and 58 L1) which produce neutralizing antibodies to prevent cervical, vulvar, vagin*l, and analcancers, cervical adenocarcinoma, cervical, vagin*l, vulvar, and anal neoplasia, and genital warts caused by HPV. Efficacy of HPV 9-valent vaccine against anogenital diseases related to the vaccine HPV types in humans is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.Brand Names: InternationalGardasil 9 (AT, AU, BE, CZ, DE, DK, EE, HK, HR, KR, LT, LV, MY, NL, NZ, PH, PL, PT, RO, SI, SK)For country code abbreviations (show table)Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.American College of Obstetricians and Gynecologists' Committee on Adolescent Health Care, American College of Obstetricians and Gynecologists' Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group. Human papillomavirus vaccination: ACOG committee opinion, number 809. Obstet Gynecol. 2020;136(2):e15-e21. doi:10.1097/AOG.0000000000004000 [PubMed 32732766]Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm.Centers for Disease Control and Prevention (CDC). Vaccination guidance during a pandemic. Updated October 20, 2020. Available at https://www.cdc.gov/vaccines/pandemic-guidance/index.htmlChristianson MS, Wodi P, Talaat K, Halsey N. Primary ovarian insufficiency and human papilloma virus vaccines: a review of the current evidence. Am J Obstet Gynecol. 2020;222(3):239-244. doi:10.1016/j.ajog.2019.08.045 [PubMed 31479634]Cross GB, Moghaddas J, Buttery J, Ayoub S, Korman TM. Don't aim too high: avoiding shoulder injury related to vaccine administration. Aust Fam Physician. 2016;45(5):303-306. [PubMed 27166466]Einstein MH, Baron M, Levin MJ, et al; HPV-010 Study Group. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009;5(10):705-719. [PubMed 19684472]Foster SL, Davis MV. Vaccine administration: preventing serious shoulder injuries. J Am Pharm Assoc (2003). 2013;53(1):102-103. doi:10.1331/JAPhA.2013.13503 [PubMed 23636163]Gardasil 9 (human papilloma virus 9-valent vaccine) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; June 2020.Gardasil 9 (human papilloma virus 9-valent vaccine) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; August 2021.Garolla A, De Toni L, Bottacin A, et al. Human papillomavirus prophylactic vaccination improves reproductive outcome in infertile patients with HPV sem*n infection: a retrospective study. Sci Rep. 2018;8(1):912. doi:10.1038/s41598-018-19369-z [PubMed 29343824]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):313. [PubMed 12534540]Kharbanda EO, Vazquez-Benitez G, DeSilva MB, et al. Association of inadvertent 9-valent human papillomavirus vaccine in pregnancy with spontaneous abortion and adverse birth outcomes. JAMA Netw Open. 2021;4(4):e214340. doi:10.1001/jamanetworkopen.2021.4340 [PubMed 33818618]Landazabal CS, Moro PL, Lewis P, Omer SB. Safety of 9-valent human papillomavirus vaccine administration among pregnant women: adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014-2017. Vaccine. 2019;37(9):1229-1234. doi:10.1016/j.vaccine.2018.11.077 [PubMed 30660400]Kroger A, Bahta L, Hunter P. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices (ACIP). https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Accessed April 30, 2021.Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Markowitz LE, Dunne EF, Saraiya M, et al; Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2014;63(49):1182]. MMWR Recomm Rep. 2014;63(RR-05):1-30. [PubMed 25167164]McInerney KA, Hatch EE, Wesselink AK, et al. The effect of vaccination against human papillomavirus on fecundability. Paediatr Perinat Epidemiol. 2017;31(6):531-536. doi:10.1111/ppe.12408 [PubMed 28881394]Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination – updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65(49):1405-1408. [PubMed 27977643]Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702. doi: 10.15585/mmwr.mm6832a3. [PubMed 31415491]Pereira N, Kucharczyk KM, Estes JL, et al. Human papillomavirus infection, infertility, and assisted reproductive outcomes. J Pathog. 2015;2015:578423. doi:10.1155/2015/578423 [PubMed 26609434]Petrosky E, Bocchini JA Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64(11):300-304. [PubMed 25811679]Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-e100. [PubMed 24311479]Saslow D, Andrews KS, Manassaram-Baptiste D, Smith RA, Fontham ETH; American Cancer Society Guideline Development Group. Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. CA Cancer J Clin. 2020;70(4):274-280. doi:10.3322/caac.21616 [PubMed 32639044]Schmuhl NB, Mooney KE, Zhang X, Cooney LG, Conway JH, LoConte NK. No association between HPV vaccination and infertility in U.S. females 18-33 years old. Vaccine. 2020;38(24):4038-4043. doi:10.1016/j.vaccine.2020.03.035 [PubMed 32253100]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. [PubMed 7746084]World Health Organization (WHO). Guiding principles for immunization activities during the COVID-19 pandemic: interim guidance, 26 March 2020. Published March 26, 2020. Available at https://apps.who.int/iris/handle/10665/331590Topic 101845 Version 108.0

CloseSociety guideline links: Kidney transplantationSociety guideline links: Kidney transplantation Introduction — This topic includes links to society and government-sponsored guidelines from selected countries and regions around the world. We will update these links periodically; newer versions of some guidelines may be available on each society's website. Some societies may require users to log in to access their guidelines.The recommendations in the following guidelines may vary from those that appear in UpToDate topic reviews. Readers who are looking for UpToDate topic reviews should use the UpToDate search box to find the relevant content.Links to related guidelines are provided separately:●(See"Society guideline links: BK virus infection in kidney transplant recipients".)●(See"Society guideline links: Cytomegalovirus in solid organ transplant recipients".)●(See"Society guideline links: Hepatitis B infection in solid organ transplant candidates and recipients".)●(See"Society guideline links: Hepatitis C infection in solid organ transplant candidates and recipients".)●(See"Society guideline links: Immunizations in solid organ transplant recipients".)●(See"Society guideline links: Infections in solid organ transplant recipients".)●(See"Society guideline links: Solid organ transplantation in individuals with HIV".)●(See"Society guideline links: Urinary tract infections in solid organ transplant recipients".)●(See"Society guideline links: Management of potential deceased organ donors".)International●Kidney Disease: Improving Global Outcomes (KDIGO): Clinical practice guideline on the evaluation and management of candidates for kidney transplantation (2020)●The declaration of Istanbul on organ trafficking and transplant tourism, 2018 edition (published 2019)●KDIGO: Clinical practice guideline on the evaluation and care of living kidney donors (2017)●KDIGO: Clinical practice guideline for the care of kidney transplant recipients (2009)Canada●Canadian Blood Services (CBS): Organs and tissues – Leading practices and clinical guidelines•Kidney paired donation protocol for participating donors, 2014 (published 2015)•Kidney allocation in Canada – A Canadian forum (2007)●Kidney Foundation of Canada (KFOC): Position statements on organ donation●Canadian Society of Transplantation (CST) and Canadian Network for Rehabilitation and Exercise for Solid Organ Transplant Optimal Recovery (CAN-RESTORE): Joint position statement on exercise for solid organ transplant candidates and recipients (2019)●CST: Position paper on public solicitation of anonymous organ donors (2016)●CST: Generic immunosuppression in solid organ transplantation – A Canadian perspective (2012)●CST and Canadian Society of Nephrology (CSN): Policy statement on organ trafficking and transplant tourism (2011)●CST and CSN: Commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients (2010)●CST: Consensus guidelines on eligibility for kidney transplantation (2005)United States●American Institute of Ultrasound in Medicine (AIUM): Practice parameter for the performance of an ultrasound examination of solid-organ transplants (2020)●Organ Procurement and Transplantation Network (OPTN): Policies (2019)●American College of Radiology (ACR): ACR Appropriateness Criteria renal transplant dysfunction (2016)●American Society of Transplantation (AST) Living Donor Community of Practice (LDCOP): A guidance document on the independent living donor advocate (2015)●AST: Considerations for screening live kidney donors for endemic infections – A viewpoint on the UNOS policy (2014)●American Heart Association (AHA) and American College of Cardiology Foundation (ACCF): Expert consensus document on cardiac disease evaluation and management among kidney and liver transplantation candidates (2012)●National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI): Managing kidney transplant recipients – A clinical guide for nephrology and transplant professionals (2011)●NKF KDOQI: Managing your adult patients who have a kidney transplant – Implications for primary care (2011)●NKF KDOQI: US commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients (published 2010)●AST: Guidelines for post-kidney transplant management in the community setting (2009)●American Society of Transplant Surgeons (ASTS): Recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation (2009)●United Network for Organ Sharing (UNOS), ASTS, and AST: Guidelines for the psychosocial evaluation of living unrelated kidney donors in the United States (2007)Europe●Council of Europe (COE): Guide to the quality and safety of organs for transplantation, 8th edition (2022)●European Association of Urology (EAU): Renal transplantation guidelines (2019)●COE: Safety, quality and ethical matters related to the use of organs, tissues and cells of human origin, 3rd edition (2017)●Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group: Practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients – A guidance report and clinical checklist (2017)●European Renal Association (ERA)-European Dialysis Transplant Association (EDTA): ERBP guideline on the management and evaluation of the kidney donor and recipient (2013)●ERA-EDTA: Endorsem*nt of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation – A European Renal Best Practice (ERBP) position statement (2011)United Kingdom●National Health Service Blood and Transplant (NHSBT): Policy on living donor kidney transplantation (2020)●NHSBT: Policy on patient selection for deceased donor kidney only transplantation (2020)●NHSBT: Policy on kidney transplantation – Deceased donor organ allocation (2019)●National Institute for Health and Care Excellence (NICE): Guideline on renal replacement therapy and conservative management (2018)●NICE: Interventional procedures guidance on robot-assisted kidney transplant (2018)●NICE: Quality standard on renal replacement therapy services for adults (2014, updated 2018)●The Renal Association (RA) and British Transplantation Society (BTS): Guidelines for living donor kidney transplantation, 4th edition (2018)●BTS: Guidelines for kidney and pancreas transplantation in patients with HIV, 2nd edition (2015, revised 2017)●RA: Clinical practice guideline – Post-operative care in the kidney transplant recipient (2017)●NICE: Clinical guideline on organ donation for transplantation – Improving donor identification and consent rates for deceased organ donation (2011, updated 2016)●BTS: Guidelines for antibody incompatible transplantation, 3rd edition (2015)●British Society for Histocompatibility and Immunogenetics (BSHI) and BTS: Guidelines on the detection and characterisation of clinically relevant antibodies in allotransplantation (2015)●BTS: Guidelines for management of the failing kidney transplant (2014)●BTS: Guidelines for transplantation from deceased donors after circulatory death (2013)●NICE: Interventional procedures guidance on laparoscopic live donor simple nephrectomy (2004)Australia-New Zealand●Transplantation Society of Australia and New Zealand (TSANZ): Clinical guidelines for organ transplantation from deceased donors (2021)●Australian National Health and Medical Research Council (NHMRC): Ethical guidelines for organ transplantation from deceased donors (2016)●Kidney Health Australia (KHA)-Caring for Australasians with Renal Impairment (CARI): Guidelines on recipient assessment for transplantation (2013)●KHA-CARI: Adaptation of the KDIGO clinical practice guideline for the care of kidney transplant recipients (2012)Japan●[In Japanese] Japanese Society for Clinical Renal Transplantation (JSCRT): Post-renal transplant medical care guidelines for internal and pediatric complications (2011)Topic 110754 Version 21.0

The evaluation of the patient presenting with a complaint of "weakness" involves three steps:●Distinguishing true muscle weakness from lassitude or motor impairment not due to loss of muscle power●Localizing, within the neuromuscular system, the site of the lesion that is producing weakness●Determin

CloseHydroxychloroquine: Pediatric drug informationHydroxychloroquine: Pediatric drug information(For additional information see "Hydroxychloroquine: Drug information" and see "Hydroxychloroquine: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USPlaquenilBrand Names: CanadaAPO-Hydroxyquine;JAMP Hydroxychloroquine Sulf;MINT-Hydroxychloroquine;NRA-Hydroxychloroquine;Plaquenil;PRO-Hydroxychloroquine-200 [DSC]Therapeutic CategoryAntimalarial Agent;Antirheumatic, Disease ModifyingDosing: PediatricNote: All doses below expressed as hydroxychloroquine sulfate. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base. To avoid retinopathy and permanent vision loss, do not exceed recommended maximum doses. Baseline and periodic screening for retinopathy is necessary for rheumatologic uses and in long-term therapy (eg, >1 to 5 years depending on patient risk factors) (Ref).MalariaMalaria:Chemoprophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (Ref).Infants, Children, and Adolescents: Oral: 6.5 mg/kg hydroxychloroquine sulfate once weekly on the same day each week; maximum dose: 400 mg/dose hydroxychloroquine sulfate; begin 1 to 2 weeks before travel to malarious area; continue while in malarious area and for 4 weeks after leaving the area (Ref).Treatment, uncomplicated: Infants, Children, and Adolescents: Oral: Initial: 12.9 mg/kg/dose hydroxychloroquine sulfate (maximum initial dose: 800 mg/dose hydroxychloroquine sulfate); followed by 6.5 mg/kg hydroxychloroquine sulfate at 6, 24, and 48 hours after initial dose; maximum dose: 400 mg/dose hydroxychloroquine sulfate. For infection caused by Plasmodium vivax or Plasmodium ovale, use in combination with appropriate antirelapse treatment (ie, primaquine) (Ref).Juvenile dermatomyositis, skin predominantJuvenile dermatomyositis, skin predominant: Limited data available: Children and Adolescents: Oral: 5 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 400 mg/day. Dosage range reported: 2 to 6 mg/kg/day (Ref); however, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (Ref). Use in combination with nonpharmacologic measures (eg, photoprotection), topical therapies, and/or other systemic therapies (Ref).Systemic lupus erythematosusSystemic lupus erythematosus (SLE): Limited data available: Children and Adolescents: 4 to 6.5 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 400 mg/day (Ref); based upon data in adults, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricAltered kidney function: Infants, Children, and Adolescents:Note: Renal clearance accounts for 15% to 25% of total clearance (Ref).Mild to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.Hemodialysis: Not dialyzable (Ref): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.Peritoneal dialysis: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.Continuous renal replacement therapy (CRRT): Unlikely to be dialyzable based on wide volume of distribution and high lipophilicity (Ref): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; use with caution.Dosing: Adult(For additional information see "Hydroxychloroquine: Drug information")Note: Dosage forms: Variable daily dosing (eg, alternating or skipping doses on certain days each week) may be used to obtain the recommended dose for rheumatologic uses. All doses below are expressed as hydroxychloroquine sulfate salt. Hydroxychloroquine sulfate salt 200 mg is equivalent to hydroxychloroquine base 155 mg. Safety: To avoid retinopathy and permanent vision loss, do not exceed recommended maximum doses. Baseline and periodic screening for retinopathy is necessary for rheumatologic uses and in long-term therapy (eg, >1 to 5 years depending on patient risk factors) (Ref). To mitigate risk of cardiac arrhythmias, correct electrolyte imbalances prior to use. Tolerability: GI upset (nausea, vomiting, diarrhea) is a common adverse effect. Dividing doses, taking with food, and, if appropriate, gradual dose escalation (in treating rheumatologic diseases) may improve tolerability (Ref).Dermatomyositis, cutaneousDermatomyositis, cutaneous (off-label use): Note: Used in combination with antipruritic medications, topical therapy, and nonpharmacologic measures (eg, photoprotection) (Ref).Oral: 300 to 400 mg daily as a single daily dose or in 2 divided doses. Assess response after 3 months; may attempt to slowly taper after several months of satisfactory response (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).Lupus erythematosusLupus erythematosus:Systemic lupus erythematosus: Note: In general, hydroxychloroquine (or chloroquine) is indicated for all patients with systemic disease; additional therapy is individualized according to predominant disease manifestations and activity (Ref).Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).Discoid lupus erythematosus and subacute cutaneous lupus erythematosus: For use if response to local therapy is inadequate or impractical due to widespread skin lesions (Ref):Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).MalariaMalaria (alternative agent):Prophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (Ref).Oral: 400 mg once weekly on the same day each week; begin 1 to 2 weeks before travel to malarious area; continue therapy while in malarious area and for 4 weeks after leaving the area (Ref).Treatment, uncomplicated: Note: Only for treatment of nonsevere infections caused by chloroquine-sensitive malaria; for infection caused by Plasmodium vivax or Plasmodium ovale, give in combination with primaquine. Not recommended for treatment if chloroquine or hydroxychloroquine was given for chemoprophylaxis (Ref).Oral: 800 mg once, followed by 400 mg at 6, 24, and 48 hours after initial dose (total dose: 2 g) (Ref).Porphyria cutanea tardaPorphyria cutanea tarda (off-label use): Oral: 100 mg twice weekly; continue until plasma or urine porphyrin levels are normal for at least several months (Ref).Primary Sjögren syndromePrimary Sjögren syndrome (off-label use): Note: For treatment of moderate to severe extraglandular manifestations (eg, arthralgias, myalgias, fatigue) or milder symptoms unresponsive to nonpharmacologic measures and nonsteroidal anti-inflammatory drugs (NSAIDs) (Ref); some experts also use in patients with major salivary enlargement resulting in cosmetic concerns or glandular pain (Ref).Oral: Initial: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).Q feverQ fever (Coxiella burnetii) (off-label use): Note: Given higher dose recommendations for Q fever, the CDC recommends routine therapeutic drug monitoring and ophthalmic exams for retinal toxicity (Ref).Persistent localized infection (eg, endocarditis, osteomyelitis, vascular infection, prosthetic joint infection) in nonpregnant patients: Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for ≥18 months, depending on site of infection and serologic response; in prosthetic valve disease or vascular infection, extend treatment to ≥24 months (Ref).Prevention of persistent infection following acute Q fever: Note: Generally reserved for patients with valvulopathy/cardiomyopathy or antiphospholipid antibodies (Ref) or postpartum women with persistent serologic evidence of infection >12 months after delivery (Ref).Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for 12 months; patients with detectable antiphospholipid antibodies should receive treatment until levels normalize (Ref).Rheumatoid arthritisRheumatoid arthritis: Note: For use as monotherapy in disease-modifying antirheumatic drug (DMARD)–naive patients with low disease activity. May also be used as part of alternative combination therapy (with other nonbiologic DMARDs) in patients with moderate to severe disease whose treatment targets have not been met despite maximally tolerated methotrexate therapy (Ref).Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).SarcoidosisSarcoidosis (off-label use): Arthropathy: Note:As additional therapy for NSAID-resistant symptoms in patients with an inadequate response to glucocorticoids or who are unable to fully taper (Ref).Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Therapy may be continued for ~1 year and then gradually tapered in patients who have responded and are stable on therapy (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).Cutaneous disease, extensive: Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses for ≥3 months to evaluate for efficacy; if there is satisfactory improvement, may consider gradual tapering and discontinuation if response is maintained (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Mild to severe impairment: There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).Hemodialysis: Not dialyzable (Ref): There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).Peritoneal dialysis: There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).CRRT: Unlikely to be dialyzable (Ref): There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling; use with caution.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral, as sulfate: Plaquenil: 200 mg [contains corn starch]Generic: 100 mg, 200 mg, 300 mg, 400 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral, as sulfate: Plaquenil: 200 mgGeneric: 200 mgAdministration: PediatricOral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (Ref). In patients unable to swallow tablets, it has been recommended that tablets may be crushed and mixed with a small amount of applesauce, chocolate syrup, or jelly (Ref), or an extemporaneous suspension may be compounded (See Extemporaneous Preparations).Administration: AdultOral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (Ref). In patients unable to swallow tablets, it has been recommended that tablets may be crushed and mixed with a small amount of applesauce, chocolate syrup, or jelly (Ref), or an extemporaneous suspension may be compounded (See Extemporaneously Prepared).Storage/StabilityStore up to 30°C (86°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.UseProphylaxis or treatment of acute uncomplicated malaria (FDA approved in pediatric patients [age not specified] and adults); treatment of systemic lupus erythematosus (SLE) (FDA approved in adults) and acute or chronic rheumatoid arthritis (FDA approved in adults); has also been used for juvenile dermatomyositis.Medication Safety IssuesSound-alike/look-alike issues: Hydroxychloroquine may be confused with hydrocortisone, hydroxyureaPlaquenil may be confused with PlatinolAdverse Reactions (Significant): ConsiderationsCardiomyopathyA predominantly restrictive or diastolic cardiomyopathy presenting as heart failure has been reported following long-term use of antimalarials for rheumatic diseases (especially chloroquine but occasionally hydroxychloroquine); systolic impairment may also occur (Ref). Additionally, conduction abnormalities (eg, atrioventricular block, sick sinus syndrome, bundle branch block) and pulmonary hypertension have been reported (Ref). On imaging, myocardial hypertrophy is most common in patients who develop cardiomyopathy. Clinicians should note that some patients may not have any or very few clinical symptoms. Laboratory findings may include elevated creatine kinase, lactate dehydrogenase, and/or troponins (Ref). While some patients may experience improvement following discontinuation, others experience permanent damage that may result in the need for cardiac transplant or death (Ref).Mechanism: Time-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to bind to phospholipids within the myocyte, leading to accumulation in lysosomes and inhibiting lysosomal enzymes in several tissues, including peripheral nerve, cardiac, and skeletal muscle. The resulting intracellular degradation leads to accumulation of metabolic products (eg, phospholipids, glycogen) (Ref).Onset: Delayed (Ref); patients may remain clinically asymptomatic for a long period of time with symptoms only appearing at a later stage and/or with high cumulative doses (eg, several years of therapy) (Ref). Some patients may experience improvement within 1 month to 1 year following discontinuation, others experience permanent damage that may result in the need for cardiac transplant or death (Ref).Risk factors:The following confers an increased risk (Ref):• Longer duration of therapy• Higher cumulative doses• Older age• Females• Preexisting cardiac disease• Kidney impairmentG6PD deficiencyAlthough the manufacturer's labeling recommends that hydroxychloroquine be used with caution in patients with glucose-6-phospate deficiency (G6PD) due to the potential for hemolysis (hemolytic anemia), there are limited data to support this risk. Many experts consider hydroxychloroquine, when given in usual therapeutic doses to WHO Class II and III G6PD deficient patients, to probably be safe (Ref). In a retrospective chart review, no incidence of hemolytic anemia was found among the 11 patients identified with G6PD deficiency receiving hydroxychloroquine therapy, despite >700 months of exposure (all patients were African-American and located in the US) (Ref). In addition, the ACR Rheumatology guidelines do not mention the need to evaluate G6PD levels prior to initiation of therapy (Ref).Hypersensitivity reactions (delayed)Cutaneous hypersensitivity reactions ranging from maculopapular rash to severe cutaneous adverse reactions (SCARs) may occur. Various delayed, nonlife-threatening reactions have been reported, including lichenoid, urticarial, and maculopapular eruptions (Ref). Reported SCARs include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS [also known as drug hypersensitivity syndrome]), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Ref). Hydroxychloroquine is also associated with phototoxic and photoallergic dermatitis (Ref).Mechanism: Non-dose related; immunologic; delayed hypersensitivity reactions are mediated by T-cells or antibodies other than immunoglobulin E (IgE) (eg, IgG-mediated, such as some cytopenias) (Ref). SCARs are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref).Onset: Varied; most nonlife-threatening cutaneous reactions occurred 5 to 14 days after initiation of hydroxychloroquine (Ref). Onset of SCARs is generally days to weeks after administration of the causative drug (Ref) but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref). Risk factors:• Prior hypersensitivity reaction to 4-aminioquinolines. Note: There is conflicting evidence regarding cross-reactivity between the 4-aminoquinolines (eg, chloroquine, hydroxychloroquine), although most reports suggest tolerance of chloroquine in patients with nonsevere cutaneous reactions to hydroxychloroquine (Ref).• Patients with dermatomyositis, in particular those with anti-small ubiquitin-like modifier 1 activating enzyme (anti-SAE-1/2) autoantibodies (Ref).HypoglycemiaSevere hypoglycemia has rarely been reported in patients (both with and without diabetes) who were receiving hydroxychloroquine (Ref).Mechanism: Dose-related; related to the pharmacologic action. Chloroquine has been shown to reduce intracellular insulin degradation, increase intracellular insulin accumulation, slow receptor recycling, stimulate insulin-mediated glucose transport, and increase peripheral insulin sensitivity and secretion (Ref).Onset: Unknown. In one case report, a patient was initiated on hydroxychloroquine and presented to the emergency department 2 months later with symptoms secondary to severe hypoglycemia (Ref).Risk factors:• Concomitant use of other medications known to lower blood glucose concentrationsNeuromuscular effectsSkeletal muscle myopathy or neuropathy leading to asthenia and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction have been reported (Ref). Symptoms ranged from painless proximal weakness in both upper and lower extremities to severe weakness requiring hospitalization and ventilatory support (Ref). Clinicians should note that patients with rheumatic disease may experience symptoms of their underlying disease that make diagnosis of myopathy difficult (Ref).Mechanism: Time-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to bind to phospholipids within the myocyte, accumulating in lysosomes and inhibiting lysosomal enzymes in several tissues, including peripheral nerve, cardiac, and skeletal muscle. The resulting intracellular degradation leads to accumulation of metabolic products (eg, phospholipids, glycogen) (Ref). Muscle and nerve biopsies have been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes (Ref).Onset: Delayed; varies from <1 year of therapy to >10 years (Ref). In addition, the response to discontinuation of hydroxychloroquine varies with some patients experiencing resolution of symptoms within weeks to months while others experience progression of symptoms (Ref).Risk factors:Risk factors are poorly defined but may include:• White people (Ref)• Kidney failure (Ref)• Concomitant use of other myotoxic drugs, including corticosteroids (Ref)Neuropsychiatric effectsVarious neuropsychiatric effects have been described with antimalarial agents, including hydroxychloroquine. Symptoms have included hallucination, psychosis, psychom*otor agitation, suicidal ideation, and suicidal tendencies (Ref).Mechanism: Time-related; exact mechanism is not fully understood. Proposed hypotheses include a cholinergic imbalance related to the inhibition of the acetylcholinesterase, prostaglandin E antagonism, the accumulation of toxic metabolites in the lysosome, and the down-regulation of glycoprotein-P in the blood brain barrier (Ref).Onset: Varied; reported onset varies greatly from weeks to years (Ref). One case report of psychiatric symptoms following use of chloroquine demonstrated that symptoms may persist for several months (Ref).Risk factors:• Family history of neuropsychiatric symptoms (Ref)• Female patients (Ref)• Concomitant administration of drugs known to increase hydroxychloroquine concentrations (Ref)• Concomitant use of glucocorticoids (Ref)• Concomitant use of alcohol (Ref)• Low body weight (Ref)QT prolongationLong-term use or high doses of antimalarials (especially chloroquine but also hydroxychloroquine) have been associated with prolonged QT interval on ECG and subsequent ventricular arrhythmias (including torsades de pointes [TdP]), syncope, and sudden cardiac death (Ref).Mechanism: Dose-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to abnormally affect ion currents (including hyperpolarization activated ion channels, delayed rectifier potassium currents, and L-type calcium ion currents). This may cause delayed depolarization and prolonged repolarization of cardiac myocytes, which can lead to QT interval prolongation (Ref).Onset: Varied; effect is concentration-dependent; therefore, timing may be impacted by high doses or accumulation. In one study in healthy subjects administered chloroquine (100 mg base per day; n=3), QT prolongation was noted on day 3 of administration (Ref)Risk factors:In general, risk factors for drug-induced QT prolongation include:• Females (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure) (Ref)• Genetic defects of cardiac ion channels (Ref)• Congenital long QT syndrome (Ref)• Baseline QTc interval prolongation (eg, >450 msec) (Ref)• Electrolyte disturbances (eg, hypokalemia or hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Coadministration of multiple medications that prolong the QT interval or drug interactions that increase serum concentration of QT-prolonging medications (Ref)Retinal toxicityLong-term use of hydroxychloroquine may result in retinopathy characterized by parafoveal retinal damage (Ref). The clinical picture is classically characterized as a bilateral “bull's-eye” maculopathy; visual acuity generally remains intact until more severe damage has been realized. As retinopathy progresses, the area of functional deficit may expand to the foveal center with decreased visual acuity, peripheral vision, and night vision; cystoid macular edema may also occur. Clinicians should note that some patients may not experience symptoms during the early stages of retinopathy and that retinopathy is irreversible (Ref).Mechanism: Time-related; exact mechanism is not fully understood. A proposed mechanism is impaired lysosomal degradation of photoreceptor outer segments by the retinal pigment epithelium (Ref).Onset: Delayed; most commonly occurring >5 years after initiation of therapy (Ref).Risk factors:• High daily doses relative to body weight (≥5 mg/kg actual body weight) and a duration of >5 years of use in the treatment of rheumatic diseases (Ref)• Higher serum concentrations of hydroxychloroquine (Ref)• Concurrent tamoxifen use (Ref)• Kidney impairment (Ref)• Lower body weight (Ref)• Preexisting macular disease (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.1% to 10%: Ophthalmic: Retinopathy (4%; serum concentration dependent [Petri 2020b]; early changes reversible [may progress despite discontinuation if advanced])<1%: Hematologic & oncologic: Hemolysis (rare; primarily a theoretical concern in patients with glucose-6-phosphate deficiency; data do not support withholding therapy in these patients [Luzzato 2016; Mohammad 2018])Frequency not defined:Cardiovascular: Sick sinus syndromeDermatologic: Exacerbation of psoriasis, exfoliative dermatitis, hair discoloration, pruritus, urticariaEndocrine & metabolic: Weight lossGastrointestinal: Abdominal pain, anorexiaHematologic & oncologic: Anemia, aplastic anemia, bone marrow depression, leukopenia, thrombocytopeniaHepatic: Abnormal hepatic function testsHypersensitivity: AngioedemaNervous system: Ataxia, dizziness, emotional lability, fatigue, headache, irritability, nervousness, nightmares, seizure, vertigoOphthalmic: Corneal changes (corneal edema, corneal opacity), nystagmus disorder, ophthalmic signs and symptoms (decreased dark adaptation)Respiratory: BronchospasmPostmarketing:Cardiovascular: Atrioventricular block (Bae 2012), bundle branch block (Costedoat-Chalumeau 2007), cardiomyopathy (AHA [Page 2016]; Fiehn 2020; Tönnesmann 2012; Tönnesmann 2013), heart failure (Figliozzi 2021), prolonged QT interval on ECG (Chatre 2018; Chen 2006; O’Laughlin 2016; Stas 2008), torsades de pointes (Chatre 2018; O’Laughlin 2016), ventricular arrhythmia (Chatre 2018; O’Laughlin 2016), ventricular tachycardia (Abdelmaseih 2020)Dermatologic: Acute generalized exanthematous pustulosis (Charfi 2015; Soria 2015), alopecia (Sharma 2020), erythema multiforme (Abou Assalie 2017), erythroderma (Pai 2017), hyperpigmentation (Bahloul 2017; Sharma 2020), skin photosensitivity (Sharma 2020), skin rash (Borik 2019), Stevens-Johnson syndrome (Leckie 2002), toxic epidermal necrolysis (Lateef 2009; Soria 2015)Endocrine & metabolic: Hypoglycemia (including severe hypoglycemia; Cansu 2008; FDA Safety Alert, April 1, 2020; Shojania 1999; Unübol 2011)Gastrointestinal: Abdominal cramps (Abdelmaseih 2020), diarrhea (can be severe) (Abdelmaseih 2020), nausea (Abdelmaseih 2020), vomiting (Abdelmaseih 2020)Genitourinary: ProteinuriaHematologic & oncologic: Agranulocytosis (Andrès 2017), neutropenia (FDA Safety Alert, April 1, 2020), pancytopenia (FDA Safety Alert, April 1, 2020), thrombotic thrombocytopenia purpura (Arikan 2020)Hepatic: Acute hepatic failure (Makin 1994)Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (Soria 2015; Volpe 2008)Nervous system: Confusion (FDA Safety Alert, April 1, 2020), delirium (FDA Safety Alert, April 1, 2020), extrapyramidal reaction (FDA Safety Alert, April 1, 2020), hallucination (Das 2014; FDA Safety Alert, April 1, 2020), psychom*otor agitation (FDA Safety Alert, April 1, 2020; Manzo 2017), psychosis (Das 2014), suicidal ideation (Mascolo 2018; Pinho de Oliveira Ribeiro 2013), suicidal tendencies (Mascolo 2018; Pinho de Oliveira Ribeiro 2013)Neuromuscular & skeletal: Myopathy (including paralysis or neuromyopathy, leading to progressive weakness and atrophy of proximal muscle groups; may be associated with mild sensory changes, loss of deep tendon reflexes, and abnormal nerve conduction; Casado 2006)Ophthalmic: Blurred vision (Wang 2021), corneal deposits (Grierson 1997), decreased visual acuity (Eldeeb 2018), epithelial keratopathy (Dosso 2007), macular degeneration (Wang 2021), maculopathy (Warner 2001), photophobia (Grierson 1997), retinal pigment changes (Stelton 2013), scotoma (Eldeeb 2018, Stelton 2013), vision color changes (Stelton 2013), visual disturbance (Grierson 1997), visual field defect (Warner 2001)Otic: Sensorineural hearing loss (Fernandes 2018), tinnitus (Fernandes 2018)Renal: Renal insufficiency (FDA Safety Alert, April 1, 2020)Respiratory: Pulmonary hypertension (Bae 2012)ContraindicationsKnown hypersensitivity to hydroxychloroquine, 4-aminoquinoline derivatives, or any component of the formulation.Canadian labeling: Additional contraindications (not in the US labeling): Preexisting retinopathy; use in children <6 years or weighing <35 kgWarnings/PrecautionsDisease-related concerns:• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction may be needed.• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Jallouli 2012; MGFA 2020).• Porphyria: Avoid use in patients with porphyria unless benefits outweigh risks; may exacerbate or precipitate disease.• Psoriasis: Avoid use in patients with psoriasis unless benefits outweigh risks; may exacerbate or precipitate disease.• Renal impairment: Use with caution in patients with renal impairment; dosage reduction may be needed.Special populations:• Glucose-6-phosphate dehydrogenase deficiency: Although the manufacturer's labeling recommends hydroxychloroquine be used with caution in patients with G6PD deficiency due to a potential for hemolytic anemia, there are limited data to support this risk. Many experts consider hydroxychloroquine, when given in usual therapeutic doses to the World Health Organization Class II and III G6PD deficient patients, to probably be safe (Cappellini 2008; Luzzatto 2016; Youngster 2010). In a retrospective chart review, no incidence of hemolytic anemia was found among the 11 patients identified with G6PD deficiency receiving hydroxychloroquine therapy, despite >700 months of exposure (all patients were African American and located in the United States) (Mohammad 2018). In addition, the American College of Rheumatology guidelines for the treatment of rheumatoid arthritis do not mention the need to evaluate G6PD levels prior to initiation of therapy (ACR [Fraenkel 2021]).• Pediatric: Pediatric patients have an increased sensitivity to aminoquinolines.Metabolism/Transport EffectsSubstrate of CYP2D6 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAgalsidase Alfa: Hydroxychloroquine may diminish the therapeutic effect of Agalsidase Alfa.Risk C: Monitor therapyAgalsidase Beta: Hydroxychloroquine may diminish the therapeutic effect of Agalsidase Beta.Risk C: Monitor therapyAndrogens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyAntidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapyArtemether and Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Artemether and Lumefantrine.Management: Artemether/lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. If combined, monitor patients for increased toxicities of both agents, including QTc interval prolongation. Risk D: Consider therapy modificationCardiac Glycosides: Aminoquinolines (Antimalarial) may increase the serum concentration of Cardiac Glycosides.Risk C: Monitor therapyChlorproMAZINE: Antimalarial Agents may increase the serum concentration of ChlorproMAZINE.Risk C: Monitor therapyCimetidine: May increase the serum concentration of Hydroxychloroquine. Risk X: Avoid combinationCiprofloxacin (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Ciprofloxacin (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Ciprofloxacin (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Ciprofloxacin (Systemic).Risk C: Monitor therapyCitalopram: May enhance the hypoglycemic effect of Hydroxychloroquine. Hydroxychloroquine may enhance the QTc-prolonging effect of Citalopram. Risk C: Monitor therapyCycloSPORINE (Systemic): Hydroxychloroquine may increase the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyDapsone (Systemic): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Dapsone (Systemic) may enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions.Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Risk D: Consider therapy modificationDapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased.Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Risk D: Consider therapy modificationEscitalopram: May enhance the hypoglycemic effect of Hydroxychloroquine. Hydroxychloroquine may enhance the QTc-prolonging effect of Escitalopram. Risk C: Monitor therapyGemifloxacin: Hydroxychloroquine may enhance the hyperglycemic effect of Gemifloxacin. Hydroxychloroquine may enhance the hypoglycemic effect of Gemifloxacin. Hydroxychloroquine may enhance the QTc-prolonging effect of Gemifloxacin.Risk C: Monitor therapyHaloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol.Risk C: Monitor therapyHerbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapyHypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapyLevofloxacin-Containing Products (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic).Risk C: Monitor therapyLevoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Levoketoconazole.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyMaitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyMefloquine: Aminoquinolines (Antimalarial) may enhance the adverse/toxic effect of Mefloquine. Specifically, the risk for QTc-prolongation and the risk for convulsions may be increased.Management: Avoid concurrent use, and delay administration of mefloquine until at least 12 hours after the last dose of an aminoquinoline antimalarial. Risk X: Avoid combinationMetoprolol: Hydroxychloroquine may increase the serum concentration of Metoprolol.Risk C: Monitor therapyMonoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyMoxifloxacin (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Moxifloxacin (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Moxifloxacin (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Moxifloxacin (Systemic).Risk C: Monitor therapyPegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyProthionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyQT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQuinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapyRabies Vaccine: Aminoquinolines (Antimalarial) may diminish the therapeutic effect of Rabies Vaccine.Management: If coadministration is unavoidable during rabies post-exposure vaccination, give a 5th dose of the rabies vaccine. If coadministration is unavoidable during rabies pre-exposure vaccination, ensure antibody titers are greater than or equal to 0.5 IU/mL. Risk D: Consider therapy modificationRemdesivir: Hydroxychloroquine may diminish the therapeutic effect of Remdesivir.Risk X: Avoid combinationSalicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySelective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySparfloxacin: Hydroxychloroquine may enhance the hyperglycemic effect of Sparfloxacin. Hydroxychloroquine may enhance the hypoglycemic effect of Sparfloxacin. Hydroxychloroquine may enhance the QTc-prolonging effect of Sparfloxacin.Risk C: Monitor therapyTamoxifen: May enhance the adverse/toxic effect of Hydroxychloroquine. Specifically, concomitant use of tamoxifen and hydroxychloroquine may increase the risk of retinal toxicity. Risk C: Monitor therapyReproductive ConsiderationsHydroxychloroquine is recommended for use in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).Information related to paternal use of hydroxychloroquine is limited; however, available data have not shown hydroxychloroquine adversely impacts male fertility or increases the risk of adverse pregnancy outcomes when used prior to conception (Bermas 2019; Mouyis 2019). Hydroxychloroquine is recommended for use in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).Pregnancy ConsiderationsHydroxychloroquine can be detected in the cord blood at delivery in concentrations similar to those in the maternal serum (Costedoat-Chalumeau 2002).Adverse perinatal outcomes have not been associated with daily maternal doses of hydroxychloroquine ≤400 mg (Bérard 2021; Birru Talabi 2020; Costedoat-Chalumeau 2003; Diav-Citrin 2013; Huybrechts 2020). Retinal toxicity is a known risk following long-term use or high doses of hydroxychloroquine. Although animal reproduction studies have shown accumulation of chloroquine in fetal ocular tissues, an association between hydroxychloroquine and fetal ocular toxicity has not been confirmed in available human studies (Gaffar 2019; Levy 2001; Motta 2005; Osadchy 2011).Maternal lupus is associated with adverse maternal and fetal events. If pregnancy is detected during therapy, hydroxychloroquine should not be stopped; cessation of hydroxychloroquine could precipitate a flare in maternal disease. Continued treatment is needed to control maternal disease and decrease the risk of maternal thrombosis and congenital heart block (Baer 2011; Izmirly 2012; Levy 2001; Petri 2020a; Tunks 2013).Available guidelines recommend treatment with hydroxychloroquine for systemic lupus erythematosus (SLE) during pregnancy. Hydroxychloroquine may be beneficial for some pregnant patients with antiphospholipid syndrome (ACR [Sammaritano 2020]; EULAR [Andreoli 2017]).Malaria infection in pregnant patients may be more severe than in nonpregnant patients and has a high risk of maternal and perinatal morbidity and mortality. Therefore, pregnant patients and patients who are likely to become pregnant are advised to avoid travel to malaria-risk areas. When travel is unavoidable, pregnant patients should take precautions to avoid mosquito bites and use effective prophylactic medications. Hydroxychloroquine is recommended for the treatment of uncomplicated malaria during pregnancy in chloroquine-sensitive regions (refer to current guidelines) (CDC 2020).Due to pregnancy-induced physiologic changes, some pharmaco*kinetic properties of hydroxychloroquine may be altered during pregnancy; however, dosage adjustments are not needed (Balevic 2019b). In one study, hydroxychloroquine concentrations ≤100 ng/mL correlated with increased disease activity and adverse maternal/fetal outcomes in patients with SLE, but there was no association between disease activity, pregnancy outcomes, and hydroxychloroquine blood levels in pregnant patients under treatment for LN (Balevic 2019a). Due to tissue binding, if hydroxychloroquine is discontinued, it would take 6 to 8 weeks to be completely eliminated.Data collection to monitor pregnancy and infant outcomes following exposure to hydroxychloroquine is ongoing. Patients exposed to hydroxychloroquine while pregnant are encouraged to enroll in the pregnancy registry (1-877-311-8972).Monitoring ParametersNote: Determinants for laboratory testing (ie, specific tests to monitor and how frequently) should take into consideration patient's clinical status and duration of therapy. Laboratory monitoring may be unnecessary in patients receiving short-term therapy.CBC and platelet count with differential, liver function, and renal function at baseline and periodically during therapy; blood glucose (if symptoms of hypoglycemia occur); muscle strength (especially proximal) and deep tendon reflexes during prolonged therapy; monitor ECG at baseline and as clinically indicated in patients at elevated risk of QTc prolongation.Ophthalmologic exam within the first year of prolonged or high-dose treatment (fundus examination plus visual fields and spectral-domain optical coherence tomography if maculopathy is present) to screen for retinal toxicity, followed by annual screening beginning after 3 to 5 years of use (or sooner if major risk factors are present) (AAO [Marmor 2016]; WHO 2012).Mechanism of ActionAntimalarial: Interferes with digestive vacuole function within sensitive malarial parasites by increasing the pH and interfering with lysosomal degradation of hemoglobin; inhibits locomotion of neutrophils and chemotaxis of eosinophils; impairs complement-dependent antigen-antibody reactions.Pharmaco*kinetics (Adult data unless noted)Onset of action: Rheumatic disease: May require several weeks to respond Absorption: Incomplete and variable (~70% [range: 25 to 100%]) (Tett 1993) Protein binding: ~40%, primarily albumin (Tett 1993)Metabolism: Hepatic; metabolites include bidesethylchloroquine, desethylhydroxychloroquine, and desethylchloroquine (McChesney 1966)Half-life elimination: ~40 days (Tett 1993)Excretion: Urine (15% to 25% [Tett 1993]; as metabolites and unchanged drug [up to 60%, McChesney 1966]); may be enhanced by urinary acidificationExtemporaneous Preparations25 mg/mL Oral SuspensionA 25 mg/mL hydroxychloroquine sulfate oral suspension may be made with tablets. Crush fifteen 200 mg hydroxychloroquine sulfate tablets in a mortar and reduce to a fine powder. Add small portions of Oral Mix (or Oral Mix SF) and mix to a uniform paste; mix while adding the vehicle in incremental portions to almost 120 mL; transfer to a graduated cylinder. Rinse mortar and pestle with vehicle and to graduated cylinder; add sufficient quantity of vehicle to make 120 mL. Transfer into an amber bottle. Label "shake well". Stable for 112 days at room temperature or refrigerated.McHenry AR, Wempe MF, Rice PJ. Stability of extemporaneously prepared hydroxychloroquine sulfate 25-mg/mL suspensions in plastic bottles and syringes. Int J Pharm Compd. 2017;21(3):251-254.28557788A 25 mg/mL hydroxychloroquine sulfate oral suspension may be made with tablets. With a towel moistened with alcohol, remove the coating from fifteen 200 mg hydroxychloroquine sulfate tablets. Crush tablets in a mortar and reduce to a fine powder. Add 15 mL of Ora-Plus and mix to a uniform paste; add an additional 45 mL of vehicle and mix until uniform. Mix while adding sterile water for irrigation in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with sterile water, and add sufficient quantity of sterile water to make 120 mL. Label "shake well". A 30-day expiration date is recommended, although stability testing has not been performed.Pesko LJ. Compounding: Hydroxychloroquine. Am Druggist. 1993;207(4):57.Pricing: USTablets (Hydroxychloroquine Sulfate Oral)100 mg (per each): $2.24200 mg (per each): $0.40 - $4.36300 mg (per each): $6.72400 mg (per each): $8.96Tablets (Plaquenil Oral)200 mg (per each): $0.18Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAdvaquenil (JO);Axokine (AR);Chloguin (TW);Dimard (CO, EC);Dolquine (ES, LB);Duloc (KR);Duroc (KR);Ercoquin (DK);Evoquin (AR, UY);Fen Le (CN);Futarhomal (EG);Geniquin (TW);Haloxin (SG);HCQS (IN, PE, TH, ZW);Hequinel (AU);Hydroquin (TH);Hydroquine (TW);Hyquin (BD, LK);Ilinol (CL);Immard (UA);Maquil (TW);Metirel (UY);Oxcq (LK);Oxiklorin (FI, KR);Planil (BD);Plaquenil (CR, CY, DO, EG, GB, GT, HU, IS, JP, KW, LT, LU, LV, MX, NI, PA, QA, RO, SA, SG, SV, UA, VN);Plaquenil Sulfate (AR, AU, BB, BE, BF, BG, BJ, BM, BS, BZ, CH, CI, CZ, DK, EE, ET, FR, GH, GM, GN, GR, GY, HK, HN, IE, IL, IT, JM, KE, LR, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, NZ, PH, RU, SC, SD, SE, SK, SL, SN, SR, TH, TN, TR, TT, TW, TZ, UG, ZA, ZM);Plaquinol (BR, CL, CO, EC, PE, PT, PY, VE);Quinoric (MT);Reconil (BD);Reuquinol (BR);Roquin (BD);Supretic (PY);Winflam (LK);Yuma (KR);Zyq (LK)For country code abbreviations (show table)Abdel-Hamid H, Oddis CV, Lacomis D. Severe hydroxychloroquine myopathy. Muscle Nerve. 2008;38(3):1206‐1210. doi:10.1002/mus.21091 [PubMed 18720511]Abdelmaseih R, Abdelmasih R, Hasan M, Tadepalli S, Patel J. Serious adverse events associated with hydroxychloroquine amidst COVID-19 pandemic: case series and literature review. Cureus. 2020;12(6):e8415. doi:10.7759/cureus.8415 [PubMed 32626630]Abou Assalie N, Durcan R, Durcan L, Petri MA. Hydroxychloroquine-induced erythema multiforme. J Clin Rheumatol. 2017;23(2):127-128. doi:10.1097/RHU.0000000000000417 [PubMed 28099213]Agarwal V, Agrawal V, Aggarwal A, et al; Arthritis in Sarcoidosis Group (ASG). Arthritis in sarcoidosis: a multicentric study from India. Int J Rheum Dis. 2018;21(9):1728-1733. doi:10.1111/1756-185X.13349 [PubMed 30187668]Aggarwal R. Sarcoid arthropathy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 25, 2021.Anderson A, Bijlmer H, Fournier PE, et al. Diagnosis and management of Q fever--United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62(RR-03):1-30. [PubMed 23535757]Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis. 2017;76(3):476-485. doi:10.1136/annrheumdis-2016-209770 [PubMed 27457513]Ang GC, Werth VP. Combination antimalarials in the treatment of cutaneous dermatomyositis: a retrospective study. Arch Dermatol. 2005;141(7):855-859. doi: 10.1001/archderm.141.7.855 [PubMed 16027300]Arıkan F, Yıldız Y, Ercan T, et al. Hydroxychloroquine-associated thrombotic thrombocytopenic purpura. Turk J Haematol. 2020;37(4):302-304. doi:10.4274/tjh.galenos.2020.2020.0322 [PubMed 32702948]Avina-Zubieta JA, Johnson ES, Suarez-Almazor ME, Russell AS. Incidence of myopathy in patients treated with antimalarials. A report of three cases and a review of the literature. Br J Rheumatol. 1995;34(2):166‐170. doi:10.1093/rheumatology/34.2.166 [PubMed 7704464]Bae SM, Jung HO, Ihm SM, et al. Hydroxychloroquine-induced cardiomyopathy that presented as pulmonary hypertension: a newly noted complication. Cardiology. 2012;123(3):197-200. doi:10.1159/000343142 [PubMed 23154245]Baer AN, Vivino FB. Treatment of Sjögren's syndrome: Constitutional and non-sicca organ-based manifestations. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 15, 2019.Baer AN, Witter FR, Petri M. Lupus and Pregnancy. Obstet Gynecol Surv. 2011;66(10):639-653. [PubMed 22112525]Bahloul E, Jallouli M, Garbaa S, et al. Hydroxychloroquine-induced hyperpigmentation in systemic diseases: prevalence, clinical features and risk factors: a cross-sectional study of 41 cases. Lupus. 2017;26(12):1304‐1308. doi:10.1177/0961203317700486 [PubMed 28355984]Bailey K, McKee D, Wismer J, Shear N. Acute generalized exanthematous pustulosis induced by hydroxychloroquine: first case report in Canada and review of the literature. J Cutan Med Surg. 2013;17(6):414‐418. doi:10.2310/7750.2013.12105 [PubMed 24138979]Balevic SJ, Cohen-Wolkowiez M, Eudy AM, Green TP, Schanberg LE, Clowse MEB. Hydroxychloroquine levels throughout pregnancies complicated by rheumatic disease: implications for maternal and neonatal outcomes. J Rheumatol. 2019a;46(1):57-63. doi:10.3899/jrheum.180158 [PubMed 30275257]Balevic SJ, Green TP, Clowse MEB, Eudy AM, Schanberg LE, Cohen-Wolkowiez M. Pharmaco*kinetics of hydroxychloroquine in pregnancies with rheumatic diseases. Clin Pharmaco*kinet. 2019b;58(4):525-533. doi:10.1007/s40262-018-0712-z [PubMed 30255310]Barlow A, Landolf KM, Barlow B, et al. Review of emerging pharmacotherapy for the treatment of coronavirus disease 2019 [published online April 7, 2020]. Pharmacotherapy. doi:10.1002/phar.2398 [PubMed 32259313]Barnabas RV, Brown ER, Bershteyn A, et al. Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection: a randomized trial. Ann Intern Med. 2020:M20-6519. doi:10.7326/M20-6519 [PubMed 33284679]Based on expert opinion.Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021;58(6):2004079. doi:10.1183/13993003.04079-2020 [PubMed 34140301]Bellón T. Mechanisms of severe cutaneous adverse reactions: recent advances. Drug Saf. 2019;42(8):973‐992. doi:10.1007/s40264-019-00825-2. [PubMed 31020549]Bérard A, Sheehy O, Zhao JP, Vinet E, Quach C, Bernatsky S. Chloroquine and hydroxychloroquine use during pregnancy and the risk of adverse pregnancy outcomes using real-world evidence. Front Pharmacol. 2021;12:722511. doi:10.3389/fphar.2021.722511 [PubMed 34408654]Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) Recommendations For the Management of Adult and Paediatric Lupus Nephritis. Ann Rheum Dis. 2012;71(11):1771-1782. [PubMed 22851469]Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 infection. http://www.idsociety.org/COVID19guidelines. Published April 11, 2020. Accessed September 25, 2020.Birru Talabi M, Clowse MEB. Antirheumatic medications in pregnancy and breastfeeding. Curr Opin Rheumatol. 2020;32(3):238-246. doi:10.1097/BOR.0000000000000710 [PubMed 32205567]Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183‐198. doi:10.1016/S0140-6736(18)32218-9 [PubMed 30558872]Borik L, Petzelbauer P, Quint T, Wöhrl S, Kinaciyan T, Heil PM. Type IV allergy to antimalarials can mimic cutaneous manifestations of lupus erythematosus. J Eur Acad Dermatol Venereol. 2019;33(3):e94‐e96. doi:10.1111/jdv.15249 [PubMed 30223310]Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19. N Engl J Med. 2020;383(6):517-525. doi:10.1056/NEJMoa2016638 [PubMed 32492293]Brockow K, Przybilla B, Aberer W, et al. Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (ÖGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM). Allergo J Int. 2015;24(3):94‐105. doi:10.1007/s40629-015-0052-6 [PubMed 26120552]Bustos MD, Gay F, Diquet B, Thomare P, Warot D. The pharmaco*kinetics and electrocardiographic effects of chloroquine in healthy subjects. Trop Med Parasitol. 1994;45(2):83‐86. [PubMed 7939166]Cansu DU, Korkmaz C. Hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient treated for RA. Rheumatology (Oxford). 2008;47(3):378-379. [PubMed 18222983]Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64-74. doi:10.1016/S0140-6736(08)60073-2 [PubMed 18177777]Caramaschi P, Barbazza R, Tinazzi I, Biasi D. Desensitization to hydroxychloroquine: 4 cases. J Rheumatol. 2011;38(10):2267. doi:10.3899/jrheum.110345 [PubMed 21965696]Carsons SE, Vivino FB, Parke A, et al. Treatment guidelines for rheumatologic manifestations of Sjögren's syndrome: use of biologic agents, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken). 2017;69(4):517-527. doi: 10.1002/acr.22968 [PubMed 27390247]Casado E, Gratacós J, Tolosa C, et al. Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann Rheum Dis. 2006;65(3):385‐390. doi:10.1136/ard.2004.023200 [PubMed 16096334]Centers for Disease Control and Prevention (CDC). CDC Yellow Book 2020: Health Information for International Travel. Oxford University Press; 2019.Centers for Disease Control and Prevention (CDC). Treatment of malaria: guidelines for clinicians (United States). https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html. Updated May 29, 2020. Accessed June 8, 2020.Charfi O, Kastalli S, Sahnoun R, Lakhoua G. Hydroxychloroquine-induced acute generalized exanthematous pustulosis with positive patch-testing. Indian J Pharmacol. 2015;47(6):693‐694. doi:10.4103/0253-7613.169589 [PubMed 26729969]Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41(10):919‐931. doi:10.1007/s40264-018-0689-4 [PubMed 29858838]Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila). 2006;44(2):173‐175. doi:10.1080/15563650500514558 [PubMed 16615675]Chong WS, Tan HH, Tan SH. Cutaneous sarcoidosis in Asians: a report of 25 patients from Singapore. Clin Exp Dermatol. 2005;30(2):120-124. doi:10.1111/j.1365-2230.2005.01729.x [PubMed 15725234]Cimaz R, Brucato A, Meregalli E, Muscará M, Sergi P. Electroretinograms of children born to mothers treated with hydroxychloroquine during pregnancy and breast-feeding: comment on the article by Costedoat-Chalumeau et al. Arthritis Rheum. 2004;50(9):3056-3057; author reply 3057-3058. [PubMed 15457485]Cissoko HRJ, Zahr N, Darrouzain F, Jonville-Bera AP, Autret-Leca E. Breast milk concentrations of hydroxychloroquine. Fundam Clin Pharmacol. 2010;24(suppl 1):420. Abstract 420-106. doi.org/10.1111/j.1472-8206.2010.00819.xClarke J. Initial management of discoid lupus and subacute cutaneous lupus. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 5, 2020.Cosnes A, Amaudric F, Gherardi R, et al. Dermatomyositis without muscle weakness. Long-term follow-up of 12 patients without systemic corticosteroids. Arch Dermatol. 1995;131(12):1381-1385. doi: 10.1001/archderm.131.12.1381 [PubMed 7492125]Costedoat-Chalumeau N, Amoura Z, Aymard G, et al. Evidence of Transplacental Passage of Hydroxychloroquine in Humans. Arthritis Rheum. 2002;46(4):1123-1124. [PubMed 11953993]Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. 2003;48(11):3207-3211. doi:10.1002/art.11304 [PubMed 14613284]Costedoat-Chalumeau N, Hulot JS, Amoura Z, et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford). 2007;46(5):808-810. doi:10.1093/rheumatology/kel402 [PubMed 17202178]Costedoat-Chalumeau N, Isenberg D, Petri M. Letter in response to the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis et al. Ann Rheum Dis. 2019;0:1.Das P, Rai A, Chopra A, Philbrick K. Psychosis likely induced by hydroxychloroquine in a patient with chronic Q fever: a case report and clinically relevant review of pharmacology. Psychosomatics. 2014;55(4):409‐413. doi:10.1016/j.psym.2013.06.017 [PubMed 24268495]Demarchi J, Papasidero S, Medina MA, et al. Primary Sjögren's syndrome: extraglandular manifestations and hydroxychloroquine therapy. Clin Rheumatol. 2017;36(11):2455-2460. doi:10.1007/s10067-017-3822-3 [PubMed 28913747]Diav-Citrin O, Blyakhman S, Shechtman S, Ornoy A. Pregnancy outcome following in utero exposure to hydroxychloroquine: a prospective comparative observational study. Reprod Toxicol. 2013;39:58-62. doi:10.1016/j.reprotox.2013.04.005 [PubMed 23602891]Dosso A, Rungger-Brändle E. In vivo confocal microscopy in hydroxychloroquine-induced keratopathy. Graefes Arch Clin Exp Ophthalmol. 2007; 245(2):318-320. [PubMed 16738856]Drugs for Parasitic Infections. Med Lett Drugs Ther. 1993;35(911):111-122. [PubMed 8246830]Duman H, Topal IO, Kocaturk E, Cure K, Mansuroglu I. Acute generalized exanthematous pustulosis induced by hydroxychloroquine: a case with atypical clinical presentation. An Bras Dermatol. 2017;92(3):404‐406. doi:10.1590/abd1806-4841.20175561 [PubMed 29186260]Eldeeb M, Chan EW, Omar A. Case report: hydroxychloroquine retinopathy. Optom Vis Sci. 2018;95(6):545-549. doi:10.1097/OPX.0000000000001226 [PubMed 29787487]Emery H. Clinical Aspects of Systemic Lupus Erythematosus in Childhood. Pediatr Clin North Am. 1986;33(5):1177-1190. [PubMed 3763254]Estes ML, Ewing-Wilson D, Chou SM, et al. Chloroquine neuromyotoxicity. Clinical and pathologic perspective. Am J Med. 1987;82(3):447‐455. doi:10.1016/0002-9343(87)90444-x [PubMed 3826099]Fanouriakis A, Bertsias G, Boumpas DT. Hydroxychloroquine dosing in systemic lupus erythematosus: response to 'Comment on the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis et al' by Costedoat-Chalumeau et al. Ann Rheum Dis. 2020;79(8):e91. [PubMed 31201171]Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736-745. [PubMed 30926722]FDA Safety Alert. MedWatch. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Food and Drug Administration website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or. Accessed April 27, 2020.Fernandes MRN, Soares DBR, Thien CI, Carneiro S. Hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus. An Bras Dermatol. 2018;93(3):469-470. doi:10.1590/abd1806-4841.20187615 [PubMed 29924251]Fiehn C, Ness T, Weseloh C, et al. Safety management in treatment with antimalarials in rheumatology. Interdisciplinary recommendations on the basis of a systematic literature review. Z Rheumatol. Published online March 31, 2020. doi:10.1007/s00393-020-00785-4 [PubMed 32236844]Figliozzi S, Rizzo S, De Gaspari M, Tarantini G. End-stage heart failure secondary to low-dose hydroxychloroquine treatment. Eur Heart J. 2021;42(2):207. doi:10.1093/eurheartj/ehaa595 [PubMed 32725108]Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum. 1993;23(2)(suppl 1):S82-S91. [PubMed 8278823]Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjögren's syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus. 1996;5(suppl 1):S31-S36. [PubMed 8803908]Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-939. doi:10.1002/acr.24596 [PubMed 34101387]Gaffar R, Pineau CA, Bernatsky S, Scott S, Vinet É. Risk of ocular anomalies in children exposed In utero to antimalarials: a systematic literature review. Arthritis Care Res (Hoboken). 2019;71(12):1606-1610. doi:10.1002/acr.23808 [PubMed 30418703]Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. Int J Antimicrob Agents. Published online March 20, 2020. doi:10.1016/j.ijantimicag.2020.105949Giannini EH, ca*wkwell GD. Drug Treatment in Children With Juvenile Rheumatoid Arthritis. Past, Present, and Future. Pediatr Clin North Am. 1995;42(5):1099-1125. [PubMed 7567188]Gonzalez CD, Hansen C, Clarke JT. Adverse cutaneous drug reactions with antimalarials in cutaneous lupus and dermatomyositis: A retrospective cohort study. J Am Acad Dermatol. 2019;81(3):859‐860. doi:10.1016/j.jaad.2019.04.068 [PubMed 31085265]Gottenberg JE, Ravaud P, Puéchal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA. 2014;312(3):249-258. doi:10.1001/jama.2014.7682 [PubMed 25027140]Gould FK, Denning DW, Elliott TS, et al. Guidelines for the Diagnosis and Antibiotic Treatment of Endocarditis in Adults: A Report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2012;67(2):269-289. [PubMed 22086858]Grierson DJ. Hydroxychloroquine and visual screening in a rheumatology outpatient clinic. Ann Rheum Dis. 1997;56(3):188-190. doi:10.1136/ard.56.3.188 [PubMed 9135223]Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology Guidelines For Screening, Treatment, and Management of Lupus Nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797-808. [PubMed 22556106]Huybrechts KF, Bateman BT, Zhu Y, et al. Hydroxychloroquine early in pregnancy and risk of birth defects. Am J Obstet Gynecol. Published online September 19, 2020. doi:10.1016/j.ajog.2020.09.007 [PubMed 32961123]Hydroxychloroquine tablet [prescribing information]. Durham, NC: Accord Healthcare Inc; September 2019.Hydroxychloroquine tablet [prescribing information]. Princeton, NJ: Dr. Reddy's Laboratories Inc; May 2018.Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. [PubMed 10891521]Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal Use of Hydroxychloroquine Is Associated With a Reduced Risk of Recurrent Anti-SSA/Ro-Antibody-Associated Cardiac Manifestations of Neonatal Lupus. Circulation. 2012;126(1):76-82. [PubMed 22626746]Jallouli M, Galicier L, Zahr N, et al; Plaquenil Lupus Systemic Study Group. Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus. Arthritis Rheumatol. 2015;67(8):2176-2184. doi:10.1002/art.39194 [PubMed 25989906]Jallouli M, Saadoun D, Eymard B, et al. The association of systemic lupus erythematosus and myasthenia gravis: a series of 17 cases, with a special focus on hydroxychloroquine use and a review of the literature. J Neurol. 2012;259(7):1290‐1297. doi:10.1007/s00415-011-6335-z [PubMed 22160434]James WD, Dawson N, Rodman OG. The treatment of dermatomyositis with hydroxychloroquine. J Rheumatol. 1985;12(6):1214-1216. [PubMed 4093940]Jones E, Callen JP. Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas. J Am Acad Dermatol. 1990;23(3, pt 1):487-489. doi: 10.1016/0190-9622(90)70246-e [PubMed 2212149]Jones SK. Ocular Toxicity and Hydroxychloroquine: Guidelines for Screening. Br J Derm. 1999;140(1):3-7. [PubMed 10215761]Jorge A, Ung C, Young LH, Melles RB, Choi HK. Hydroxychloroquine retinopathy - implications of research advances for rheumatology care. Nat Rev Rheumatol. 2018;14(12):693‐703. doi:10.1038/s41584-018-0111-8 [PubMed 30401979]Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care. 2013;2(1):77‐83. doi:10.1177/2048872612471215 [PubMed 24062937]Kim S, Kahn P, Robinson AB, et al. Childhood Arthritis and Rheumatology Research Alliance consensus clinical treatment plans for juvenile dermatomyositis with skin predominant disease. Pediatr Rheumatol Online J. 2017;15(1):1. [PubMed 28077146]Kliegman RM and St. Geme J, eds. Nelson Textbook of Pediatrics. 21st ed. Saunders Elsevier; 2020.Kruize AA, Hené RJ, Kallenberg CG, et al. Hydroxychloroquine treatment for primary Sjögren's syndrome: a two year double blind crossover trial. Ann Rheum Dis. 1993;52(5):360-364. doi:10.1136/ard.52.5.360 [PubMed 8323383]Kuhn A, Aberer E, Bata-Csörgő Z, et al. S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2017;31(3):389-404. doi:10.1111/jdv.14053 [PubMed 27859683]Kumar P, Banik S. Pharmacotherapy options in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:35-43. doi:10.4137/CMAMD.S5558 [PubMed 23997576]Lam NC, Ghetu MV, Bieniek ML. Systemic lupus erythematosus: primary care approach to diagnosis and management. Am Fam Physician. 2016;94(4):284-294. [PubMed 27548593]Lateef A, Tan KB, Lau TC. Acute generalized exanthematous pustulosis and toxic epidermal necrolysis induced by hydroxychloroquine. Clin Rheumatol. 2009;28(12):1449‐1452. doi:10.1007/s10067-009-1262-4 [PubMed 19727917]Leckie MJ, Rees RG. Stevens-Johnson syndrome in association with hydroxychloroquine treatment for rheumatoid arthritis. Rheumatology (Oxford). 2002;41(4):473‐474. doi:10.1093/rheumatology/41.4.473 [PubMed 11961185]Levy RA, Vilela VS, Cataldo MJ, et al. Hydroxychloroquine (HCQ) in Lupus Pregnancy: Double-Blind and Placebo-Controlled Study. Lupus. 2001;10(6):401-404. [PubMed 11434574]Luzzatto L, Nannelli C, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Hematol Oncol Clin North Am. 2016;30(2):373-393. doi:10.1016/j.hoc.2015.11.006 [PubMed 27040960]Makin AJ, Wendon J, Fitt S, Portmann BC, Williams R. Fulminant hepatic failure secondary to hydroxychloroquine. Gut. 1994;35(4):569-570. doi:10.1136/gut.35.4.569 [PubMed 8175002]Manzo C, Gareri P, Castagna A. Psychom*otor agitation following treatment with hydroxychloroquine. Drug Saf Case Rep. 2017;4(1):6. doi:10.1007/s40800-017-0048-x [PubMed 28258476]Marks SD, Tullus K. Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paediatr. 2010;99(7):967-974. [PubMed 20222881]Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology (AAO). Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386-1394. doi: 10.1016/j.ophtha.2016.01.058 [PubMed 26992838]Mascolo A, Berrino PM, Gareri P, et al. Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article. Inflammopharmacology. 2018;26(5):1141‐1149. doi:10.1007/s10787-018-0498-5 [PubMed 29948492]Mates M, Zevin S, Breuer GS, Navon P, Nesher G. Desensitization to hydroxychloroquine--experience of 4 patients. J Rheumatol. 2006;33(4):814‐816. [PubMed 16463436]Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The management of Sjögren's syndrome. Nat Clin Pract Rheumatol. 2006;2(5):252-261. doi:10.1038/ncprheum0165 [PubMed 16932698]McChesney EW, Conway WD, Banks WF, et al. Studies of the metabolism of some compounds of the 4-amino-7-chloroquinolone series. J Pharmacol Exp Ther. 1966;151(3):482-493. [PubMed 4957157]McLaughlin GE. Coated plaquenil tablets: potential risk for children? JAMA. 1991;266(20):2832. [PubMed 1942444]Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy [published correction appears in JAMA Ophthalmol. 2014;132(12):1493]. JAMA Ophthalmol. 2014;132(12):1453-1460. [PubMed 25275721]Million M, Walter G, Thuny F, Habib G, Raoult D. Evolution from acute Q fever to endocarditis is associated with underlying valvulopathy and age and can be prevented by prolonged antibiotic treatment. Clin Infect Dis. 2013;57(6):836-844. doi:10.1093/cid/cit419 [PubMed 23794723]Mitjà O, Corbacho-Monné M, Ubals M, et al; BCN-PEP-CoV2 Research Group. A cluster-randomized trial of hydroxychloroquine for prevention of covid-19. N Engl J Med. 2021;384(5):417-427. doi:10.1056/NEJMoa2021801 [PubMed 33289973]Modi S, Rosen T. Micropapular cutaneous sarcoidosis: case series successfully managed with hydroxychloroquine sulfate. Cutis. 2008;81(4):351-354. [PubMed 18491485]Mohammad S, Clowse MEB, Eudy AM, Criscione-Schreiber LG. Examination of hydroxychloroquine use and hemolytic anemia in G6PDH-deficient patients. Arthritis Care Res (Hoboken). 2018;70(3):481‐485. doi:10.1002/acr.23296 [PubMed 28556555]Motta M, Tincani A, Faden D, Zinzini E, Chirico G. Antimalarial agents in pregnancy. Lancet. 2002;359(9305):524-525. [PubMed 11853823]Motta M, Tincani A, Faden D, et al. Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. J Perinatol. 2005;25(2):86-89. [PubMed 15496869]Muthukrishnan P, Roukoz H, Grafton G, Jessurun J, Colvin-Adams M. Hydroxychloroquine-induced cardiomyopathy: a case report. Circ Heart Fail. 2011;4(2):e7‐e8. doi:10.1161/CIRCHEARTFAILURE.110.959916 [PubMed 21406675]Myasthenia Gravis Foundation of America (MGFA). Drugs and MG: Cautionary Drugs. https://myasthenia.org/Portals/0/Cautionary_Drugs_2020_1.pdf. Accessed June 17, 2020Nation RL, Hackett LP, Dusci LJ, Ilett KF. Excretion of hydroxychloroquine in human milk. Br J Clin Pharmacol. 1984;17(3):368-369.National Institute for Health and Care Excellence (NICE). Drug allergy: diagnosis and management. Clinical guideline [CG183]. September 3, 2014. https://www.nice.org.uk/guidance/cg183. Accessed May 26, 2020.National Institutes of Health (NIH). Coronavirus disease (COVID-19) treatment guidelines. https://www.covid19treatmentguidelines.nih.gov/about-the-guidelines/whats-new. Updated October 27, 2021. Accessed October 29, 2021.O'Dell JR, Mikuls TR, Taylor TH, et al; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013;369(4):307-318. doi:10.1056/NEJMoa1303006 [PubMed 23755969]O'Laughlin JP, Mehta PH, Wong BC. Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine. Case Rep Cardiol. 2016;2016:4626279. doi:10.1155/2016/4626279 [PubMed 27478650]Olson NY, Lindsley CB. Adjunctive use of hydroxychloroquine in childhood dermatomyositis. J Rheumatol. 1989;16(12):1545-1547. [PubMed 2483176]Osadchy A, Ratnapalan T, Koren G. Ocular Toxicity in Children Exposed in utero to Antimalarial Drugs: Review of the Literature. J Rheumatol. 2011;38(12):2504-2508. [PubMed 22002012]Østensen M, Brown ND, Chiang PK, et al. Hydroxychloroquine in Human Breast Milk. Eur J Clin Pharmacol. 1985;28(3):357. [PubMed 4007043]Page RL 2nd, O'Bryant CL, Cheng D, et al; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016;134(6):e32-e69. [PubMed 27400984]Pai SB, Sudershan B, Kuruvilla M, Kamath A, Suresh PK. Hydroxychloroquine-induced erythroderma. Indian J Pharmacol. 2017;49(1):132-134. doi:10.4103/0253-7613.201027 [PubMed 28458440]Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch Dermatol. 2002;138(9):1231‐1233. doi:10.1001/archderm.138.9.1231 [PubMed 12224986]Peng W, Liu R, Zhang L, Fu Q, Mei D, Du X. Breast milk concentration of hydroxychloroquine in Chinese lactating women with connective tissue diseases. Eur J Clin Pharmacol. 2019;75(11):1547-1553. doi:10.1007/s00228-019-02723-z [PubMed 31375884]Pereira A, Cruz-Melguizo S, Adrien M, Fuentes L, Marin E, Perez-Medina T. Clinical course of coronavirus disease-2019 in pregnancy. Acta Obstet Gynecol Scand. Published online May 22, 2020. doi:10.1111/aogs.13921 [PubMed 32441332]Petri M, Elkhalifa M, Li J, Magder LS, Goldman DW. Hydroxychloroquine blood levels predict hydroxychloroquine retinopathy. Arthritis Rheumatol. 2020b;72(3):448-453. doi:10.1002/art.41121 [PubMed 31532077]Petri M. Pregnancy and systemic lupus erythematosus. Best Pract Res Clin Obstet Gynaecol. 2020a;64:24-30. doi:10.1016/j.bpobgyn.2019.09.002 [PubMed 31677989]Pierce-Williams RAM, Burd J, Felder L, et al. Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study. Am J Obstet Gynecol MFM. Published online May 8, 2020. doi:10.1016/j.ajogmf.2020.100134 [PubMed 32391519]Pinho de Oliveira Ribeiro N, Rafael de Mello Schier A, Ornelas AC, Pinho de Oliveira CM, Nardi AE, Silva AC. Anxiety, depression and suicidal ideation in patients with rheumatoid arthritis in use of methotrexate, hydroxychloroquine, leflunomide and biological drugs. Compr Psychiatry. 2013;54(8):1185‐1189. doi:10.1016/j.comppsych.2013.05.010 [PubMed 23829886]Plaquenil (hydroxychloroquine) [prescribing information]. Dublin, Ireland: Concordia Pharmaceuticals Inc; May 2022.Plaquenil (hydroxychloroquine) [product monograph]. Laval, Quebec, Canada: Sanofi-aventis Canada Inc; June 2022.Prystowsky S, Sanchez M. Cutaneous sarcoidosis: Management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 12, 2021.Raoult D. Treatment and prevention of Q fever. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 13, 2021.Rath T, Rubbert A. Drug combinations with methotrexate to treat rheumatoid arthritis. Clin Exp Rheumatol. 2010;28(5)(suppl 61):S52-S57. [PubMed 21044434]Refer to manufacturer's labeling.Riley K, Schwager Z, Stern M, Vleugels RA, Femia A. Assessment of antimalarial therapy in patients who are hypersensitive to hydroxychloroquine. JAMA Dermatol. 2019;155(4):491‐493. doi:10.1001/jamadermatol.2018.5212 [PubMed 30758479]Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013‐1022. doi:10.1056/NEJMra032426 [PubMed 14999113]Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529-556. doi:10.1002/art.41191 [PubMed 32090480]Sharma AN, Mesinkovska NA, Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review. J Am Acad Dermatol. 2020;83(2):563-578. doi:10.1016/j.jaad.2020.04.024 [PubMed 32289395]Shojania K, Koehler BE, Elliott T. Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis. J Rheumatol. 1999;26(1):195‐196. [PubMed 9918262]Singal AK, Kormos-Hallberg C, Lee C, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012;10(12):1402-1409. doi:10.1016/j.cgh.2012.08.038 [PubMed 22985607]Singal AK, Anderson KE. Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 6, 2021.Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. doi:10.1002/art.39480 [PubMed 26545940]Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis [published correction appears in Lancet. 2016;388(10055):1984]. Lancet. 2016;388(10055):2023-2038. doi:10.1016/S0140-6736(16)30173-8 [PubMed 27156434]Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-699. doi: 10.1136/annrheumdis-2019-216655 [PubMed 31969328]Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509. doi:10.1136/annrheumdis-2013-204573 [PubMed 24161836]Society for Maternal-Fetal Medicine (SMFM). Coronavirus (COVID-19). https://www.smfm.org/covid19. Updated May 26, 2020. Accessed June 16, 2020.Soria A, Barbaud A, Assier H, et al. Cutaneous adverse drug reactions with antimalarials and allergological skin tests. Dermatology. 2015;231(4):353‐359. doi:10.1159/000438787 [PubMed 26457932]Stas P, Faes D, Noyens P. Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine. Int J Cardiol. 2008;127(2):e80‐e82. doi:10.1016/j.ijcard.2007.04.055 [PubMed 17590456]Stelton CR, Connors DB, Walia SS, Walia HS. Hydrochloroquine retinopathy: characteristic presentation with review of screening. Clin Rheumatol. 2013;32(6):895-898. doi:10.1007/s10067-013-2226-2 [PubMed 23515601]Takamasu E, Yokogawa N, Shimada K, Sugii S. Simple dose-escalation regimen for hydroxychloroquine-induced hypersensitivity reaction in patients with systemic lupus erythematosus enabled treatment resumption. Lupus. 2019;28(12):1473‐1476. doi:10.1177/0961203319879987 [PubMed 31575325]Tal Y, Maoz Segal R, Langevitz P, Kivity S, Darnizki Z, Agmon-Levin N. Hydroxychloroquine desensitization, an effective method to overcome hypersensitivity-a multicenter experience. Lupus. 2018;27(5):703‐707. doi:10.1177/0961203317735185 [PubMed 28992797]Targoff IN. Initial treatment of dermatomyositis and polymyositis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 24, 2022.Telgt DS, van der Ven AJ, Schimmer B, Droogleever-Fortuyn HA, Sauerwein RW. Serious psychiatric symptoms after chloroquine treatment following experimental malaria infection. Ann Pharmacother. 2005;39(3):551‐554. doi:10.1345/aph.1E409 [PubMed 15728331]Tett SE. Clinical pharmaco*kinetics of slow-acting antirheumatic drugs. Clin Pharmaco*kinet. 1993;25(5):392-407. doi:10.2165/00003088-199325050-00005 [PubMed 7904547]Thorbinson C, Oni L, Smith E, Midgley A, Beresford MW. Pharmacological management of childhood-onset systemic lupus erythematosus. Paediatr Drugs. 2016;18(3):181-195. [PubMed 26971103]Tincani A, Faden D, Lojacono A, et al. Hydroxychloroquine in pregnant patients with rheumatic disease. Arthritis Rheum. 2001;44 (Suppl 9):S397.Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479‐487. doi:10.1161/CIRCOUTCOMES.113.000152 [PubMed 23716032]Tisdale JE, Jaynes HA, Kingery JR, et al. Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2014;7(3):381‐390. doi:10.1161/CIRCOUTCOMES.113.000651 [PubMed 24803473]Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol. 2013;35(3):434‐442. doi:10.3109/08923973.2013.780078 [PubMed 23635029]Tönnesmann E, Stroehmann I, Kandolf R, et al. Cardiomyopathy caused by longterm treatment with chloroquine: a rare disease, or a rare diagnosis? J Rheumatol. 2012;39(5):1099‐1103. doi:10.3899/jrheum.110959 [PubMed 22550010]Travassos M, Laufer MK. Antimalarial drugs: An overview. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 15, 2019.Tsang-A-Sjoe MW, Bultink IE. Systemic lupus erythematosus: review of synthetic drugs. Expert Opin Pharmacother. 2015;16(18):2793-2806. doi:10.1517/14656566.2015.1101448 [PubMed 26479437]Tunks RD, Clowse ME, Miller SG, Brancazio LR, Barker PC. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208(1):64.e1-64.e647. doi:10.1016/j.ajog.2012.09.020 [PubMed 23063019]Unübol M, Ayhan M, Guney E. Hypoglycemia induced by hydroxychloroquine in a patient treated for rheumatoid arthritis. J Clin Rheumatol. 2011; 17(1):46-47. [PubMed 21169846 ]Vleugels RA. Cutaneous dermatomyositis in adults: Overview and initial management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 21, 2020.Volpe A, Marchetta A, Caramaschi P, Biasi D, Bambara LM, Arcaro G. Hydroxychloroquine-induced DRESS syndrome. Clin Rheumatol. 2008;27(4):537‐539. doi:10.1007/s10067-007-0772-1 [PubMed 17952481]Wallace DJ. Antimalarial drugs in the treatment of rheumatic disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 25, 2022.Wang C, Fortin PR, Li Y, Panaritis T, Gans M, Esdaile JM. Discontinuation of antimalarial drugs in systemic lupus erythematosus. J Rheumatol. 1999;26(4):808‐815. [PubMed 10229401]Wang G, Zhuo N, Liao Z, et al. Retinal toxicity caused by hydroxychloroquine in patients with systemic lupus erythematosus: a case report. Medicine (Baltimore). 2021;100(22):e25688. doi:10.1097/MD.0000000000025688 [PubMed 34087822]Warner AE. Early hydroxychloroquine macular toxicity. Arthritis Rheum. 2001;44(8):1959-1961. doi:10.1002/1529-0131(200108)44:8<1959::AID-ART334>3.0.CO;2-A [PubMed 11508449]Wolstencroft PW, Casciola-Rosen L, Fiorentino DF. Association between autoantibody phenotype and cutaneous adverse reactions to hydroxychloroquine in dermatomyositis. JAMA Dermatol. 2018;154(10):1199‐1203. doi:10.1001/jamadermatol.2018.2549 [PubMed 30140893]World Health Organization (WHO). Guidelines for the Treatment of Malaria. 3rd ed. Geneva, Switzerland: World Health Organization; April 2015. https://apps.who.int/iris/bitstream/handle/10665/162441/9789241549127_eng.pdf;jsessionid=5E6B69DD1F9A124C2DFEA30D5F8D6E8E?sequence=1. Accessed August 15, 2019.World Health Organization (WHO). International travel and health. World Health Organization; 2012. Available at https://www.who.int/publications/i/item/9789241580472World Health Organization (WHO). The cardiotoxicity of antimalarials. Geneva, Switzerland: World Health Organization; March 2017. https://www.who.int/malaria/mpac/mpac-mar2017-erg-cardiotoxicity-report-session2.pdf. Accessed May 26, 2020.Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno R, Hawkins C. Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol. 1984;10(4):592-600. doi: 10.1016/s0190-9622(84)80263-7 [PubMed 6715608]Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010;33(9):713-726. doi:10.2165/11536520-000000000-00000 [PubMed 20701405]Topic 13366 Version 460.0

CloseAdalimumab (including biosimilars): Drug informationAdalimumab (including biosimilars): Drug information(For additional information see "Adalimumab (including biosimilars): Patient drug information" and see "Adalimumab (including biosimilars): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningSerious infections:Patients treated with adalimumab are at increased risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.Discontinue adalimumab if a patient develops a serious infection or sepsis. Reported infections include the following:Active tuberculosis (TB), including reactivation of latent TB. Patients with TB frequently have presented with disseminated or extrapulmonary disease. Test patients for latent TB before adalimumab use and during therapy. Initiate treatment for latent infection prior to adalimumab use.Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk of invasive fungal infections who develop severe systemic illness.Bacterial, viral, and other infections caused by opportunistic pathogens, including Legionella and Listeria.Carefully consider the risks and benefits of treatment with adalimumab prior to initiating therapy in patients with chronic or recurrent infection.Monitor patients closely for the development of signs and symptoms of infection during and after treatment with adalimumab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.Malignancy:Lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with tumor necrosis factor (TNF)–blockers, including adalimumab. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF-blockers, including adalimumab. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF-blocker cases have occurred in patients with Crohn disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF-blocker or a TNF-blocker in combination with these other immunosuppressants.Brand Names: USHumira;Humira Pediatric Crohns Start;Humira Pen;Humira Pen-CD/UC/HS Starter;Humira Pen-Pediatric UC Start;Humira Pen-Ps/UV/Adol HS Start;Humira Pen-Psor/Uveit StarterBrand Names: CanadaAbrilada;Amgevita;Amgevita SureClick;Hadlima;Hadlima PushTouch;Hulio;Humira;Hyrimoz;Idacio;Simlandi;YuflymaPharmacologic CategoryAntirheumatic, Disease Modifying;Gastrointestinal Agent, Miscellaneous;Monoclonal Antibody;Tumor Necrosis Factor (TNF) Blocking AgentDosing: AdultNote: Patient should be under the care of a clinician experienced with use of adalimumab for the specific indication. Pretreatment screening: Screen for latent tuberculosis (TB) and hepatitis B virus before starting therapy; additional pretreatment screening (eg, hepatitis C, varicella zoster virus) may be warranted. For patients with significant active or latent infection, consultation with infectious diseases or other appropriate specialists (eg, pulmonary or hepatology) is generally warranted before initiating therapy. Treatment of latent TB is required before starting adalimumab (Ref). Avoid use in patients with severe active infections (Ref). Pretreatment immunizations: Patients should receive appropriate immunizations prior to starting therapy when feasible. Biosimilar agents: In Canada, Abrilada, Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Simlandi, and Yuflyma are also approved as biosimilars to Humira; refer to Canadian product monograph(s) for biosimilar-specific indication details.Axial spondyloarthritis, including ankylosing spondylitisAxial spondyloarthritis, including ankylosing spondylitis:Note: Reserve for patients who do not have an adequate response to nonsteroidal anti-inflammatory drugs (NSAIDs); may continue NSAIDs and/or analgesics (Ref).SUBQ: 40 mg every other week.Crohn disease, moderate to severe, induction and maintenance of remissionCrohn disease, moderate to severe, induction and maintenance of remission:Note: Combination therapy with an immunomodulator is generally preferred (Ref).Initial: SUBQ: 160 mg (given over 1 or 2 days), then 80 mg 2 weeks later (day 15). Note: If switching from another anti-tumor necrosis factor agent, may use this induction regimen.Maintenance: SUBQ: 40 mg every other week beginning day 29.Hidradenitis suppurativa, moderate to severe, refractoryHidradenitis suppurativa, moderate to severe, refractory:Initial: SUBQ: 160 mg (given over 1 or 2 days), then 80 mg 2 weeks later (day 15).Maintenance: SUBQ: 40 mg every week beginning day 29 or 80 mg every other week beginning day 29 (Ref). Note: 40 mg every week regimen has been more extensively studied and is therefore preferred by some experts (Ref).Nonradiographic axial spondyloarthritisNonradiographic axial spondyloarthritis (off-label use):Note: Reserve for patients who do not have an adequate response to NSAIDs; may continue NSAIDs and/or analgesics (Ref).SUBQ: 40 mg every other week.Peripheral spondyloarthritis, nonpsoriaticPeripheral spondyloarthritis, nonpsoriatic (off-label use):Note: May continue methotrexate, other nonbiologic DMARDs, corticosteroids, NSAIDs, and/or analgesics (Ref).SUBQ: 40 mg every other week (Ref).Plaque psoriasis, moderate to severePlaque psoriasis, moderate to severe:Note: Generally used as systemic monotherapy; may continue adjuvant topical therapies (eg, emollients, corticosteroids) as needed. A clinician experienced with use of adalimumab for plaque psoriasis should be involved in treatment.Initial: SUBQ: 80 mg as a single dose.Maintenance: SUBQ: 40 mg every other week beginning 1 week after initial dose. Note: Some patients may require 40 mg every week (Ref).Psoriatic arthritisPsoriatic arthritis:Note: May continue methotrexate, other nonbiologic DMARDs, corticosteroids, NSAIDs, and/or analgesics.SUBQ: 40 mg every other week.Rheumatoid arthritisRheumatoid arthritis:Note: For use as an alternative to methotrexate in disease-modifying antirheumatic drug (DMARD)–naive patients with moderate to high disease activity, or as adjunctive therapy in patients who have not met treatment goals despite maximally tolerated methotrexate therapy (Ref). May use in combination with other nonbiologic DMARDs, glucocorticoids, NSAIDs, and/or analgesics. A clinician experienced, NSAIDs, and/or analgesics. A clinician experienced with use of adalimumab for rheumatoid arthritis should be involved in treatment.SUBQ: Initial: 40 mg every other week; for select patients with an inadequate response, may increase dose to 40 mg every week or 80 mg every other week.Sarcoidosis, refractorySarcoidosis, refractory (adjunctive agent) (off-label use):Note: For use as an adjunctive agent in patients in whom treatment goals have not been met despite glucocorticoids and other immunosuppressants (eg, methotrexate) (Ref). A clinician experienced with use of adalimumab should be involved in treatment.Initial: SUBQ: The optimal dosing strategy is not known; one example of an initial regimen is 40 to 120 mg on week 0, 40 to 80 mg on week 1, and 40 mg on week 2 (Ref).Maintenance: SUBQ: 40 mg every 1 to 2 weeks (Ref). The optimal frequency and duration of therapy are not known and must be individualized based on response; after a stable response is achieved (eg, after 6 months), one option is to gradually prolong the dosing interval (eg, to every 2 weeks) and discontinue after 3 months if response remains adequate (Ref).Ulcerative colitis, moderate to severe, induction and maintenance of remissionUlcerative colitis, moderate to severe, induction and maintenance of remission:Initial: SUBQ: 160 mg (given over 1 or 2 days), then 80 mg 2 weeks later (day 15).Maintenance: SUBQ: 40 mg every other week beginning day 29. If a disease flare occurs, some experts increase to 40 mg every week (Ref). Note: Only continue maintenance treatment in patients demonstrating clinical remission by 8 weeks (day 57) of therapy.Uveitis, noninfectiousUveitis, noninfectious:Note: Generally reserved for patients with an incomplete response to first-line agents and ≥1 other systemic therapies (Ref).Initial: SUBQ: 80 mg as a single dose.Maintenance: SUBQ: 40 mg every other week beginning 1 week after initial dose.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Pediatric(For additional information see "Adalimumab (including biosimilars): Pediatric drug information")Note: Amjevita (adalimumab-atto), Cyltezo (adalimumab-adbm), Hadlima (adalimumab-bwwd), Hulio (adalimumab-fkjp), and Hyrimoz (adalimumab-adaz) are approved as biosimilar agents to Humira. Approved ages and uses may vary (Ref).Crohn disease; moderate to severeCrohn disease; moderate to severe:Children ≥6 years and Adolescents:17 kg to <40 kg: SUBQ:Initial: 80 mg on day 1, then 40 mg administered 2 weeks later (day 15).Maintenance (beginning day 29): 20 mg every other week (Ref). Patients who continue to experience flares after 12 weeks of therapy may benefit from weekly dosing (Ref).≥40 kg: SUBQ:Initial: 160 mg (administered on day 1 or split and administered over 2 consecutive days), then 80 mg administered 2 weeks later (day 15).Maintenance (beginning day 29): 40 mg every other week (Ref). Weekly dosing should be considered for patients with loss of response or low trough concentrations (<7.5 mcg/mL) (Ref).Hidradenitis suppurativaHidradenitis suppurativa:Children ≥12 years and Adolescents:30 to <60 kg: SUBQ:Initial: 80 mg on day 1.Maintenance (beginning day 8): 40 mg every other week.≥60 kg: SUBQ:Initial: 160 mg (administered as full dose on day 1 or dose split and administered over 2 consecutive days), then 80 mg 2 weeks later (day 15).Maintenance (beginning day 29): 40 mg weekly or 80 mg every other week.Juvenile idiopathic arthritisJuvenile idiopathic arthritis (JIA):Fixed dosing:Children ≥2 years and Adolescents:10 kg to <15 kg: SUBQ: 10 mg every other week.15 to <30 kg: SUBQ: 20 mg every other week.≥30 kg: SUBQ: 40 mg every other week.BSA-directed dosing: Note: Dosing based on trials performed with Humira product.Children 2 to <4 years: SUBQ: 24 mg/m2/dose every other week; maximum dose: 20 mg/dose (Ref).Children and Adolescents 4 to 17 years: SUBQ: 24 mg/m2/dose every other week; maximum dose: 40 mg/dose (Ref).Ulcerative colitis; moderate to severeUlcerative colitis; moderate to severe:Fixed dosing: Children ≥5 years and Adolescents:20 to <40 kg: SUBQ:Initial: 80 mg on day 1, then 40 mg administered weekly for 2 weeks (a dose on day 8 and day 15).Maintenance (beginning day 29): 40 mg every other week or 20 mg every week.≥40 kg: SUBQ:Initial: 160 mg on day 1 (administered as full dose on day 1 or dose split and administered over 2 consecutive days), then 80 mg administered weekly for 2 weeks (a dose on day 8 and day 15).Maintenance (beginning day 29): 80 mg every other week or 40 mg every week.BSA-directed dosing: Children and Adolescents: SUBQ: Initial: 92 mg/m2 (maximum dose: 160 mg/dose), then 46 mg/m2 (maximum dose: 80 mg/dose) 2 weeks later, then on day 29, begin maintenance therapy: 23 mg/m2 every other week (maximum dose: 40 mg/dose) (Ref). Note: Trials performed with Humira product.UveitisUveitis (noninfectious intermediate, posterior, and panuveitis):Fixed dosing: Children ≥2 years and Adolescents:10 kg to <15 kg: SUBQ: 10 mg every other week.15 to <30 kg: SUBQ: 20 mg every other week.≥30 kg: SUBQ: 40 mg every other week.BSA-directed dosing: Children ≥4 years and Adolescents: SUBQ: 24 or 40 mg/m2/dose every 2 weeks; maximum dose 40 mg/dose (Ref). Dosing based on one prospective trial comparing 24 mg/m2/dose every 2 weeks of adalimumab (n=16, ages 6 to 12 years) to infliximab (n=17, ages 5 to 13 years) and on a retrospective trial of biologic response modifiers, including 5 patients who received adalimumab at 40 mg/m2/dose every 2 weeks. Note: Trials performed with Humira product.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productPen-injector Kit, Subcutaneous [preservative free]: Humira Pen: 40 mg/0.8 mL (1 ea); 40 mg/0.4 mL (1 ea); 80 mg/0.8 mL (1 ea) [contains polysorbate 80]Humira Pen-CD/UC/HS Starter: 40 mg/0.8 mL (1 ea); 80 mg/0.8 mL (1 ea) [contains polysorbate 80]Humira Pen-Pediatric UC Start: 80 mg/0.8 mL (1 ea) [latex free; contains polysorbate 80]Humira Pen-Ps/UV/Adol HS Start: 40 mg/0.8 mL (1 ea) [contains polysorbate 80]Humira Pen-Psor/Uveit Starter: 80 MG/0.8ML & 40MG/0.4ML (1 ea) [contains polysorbate 80]Prefilled Syringe Kit, Subcutaneous [preservative free]: Humira: 10 mg/0.2 mL (1 ea [DSC]); 20 mg/0.4 mL (1 ea [DSC]); 40 mg/0.8 mL (1 ea); 10 mg/0.1 mL (1 ea); 20 mg/0.2 mL (1 ea); 40 mg/0.4 mL (1 ea) [contains polysorbate 80]Humira Pediatric Crohns Start: 40 mg/0.8 mL (1 ea [DSC]); 80 mg/0.8 mL (1 ea); 80 MG/0.8ML & 40MG/0.4ML (1 ea) [contains polysorbate 80]Generic Equivalent Available: USNoDosage Forms ConsiderationsThe 10 mg/0.1 mL, 20 mg/0.2 mL, 40 mg/0.4 mL, and 80 mg/0.8 mL formulations are citrate free.Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productAuto-injector Kit, Subcutaneous: Simlandi: 40 mg/0.4 mL (1 ea, 2 ea) [contains polysorbate 80]Pen-injector Kit, Subcutaneous: Hulio: 40 mg/0.8 mL (2 ea) [contains polysorbate 80]Yuflyma: 40 mg/0.4 mL (1 ea, 2 ea, 4 ea, 6 ea) [contains polysorbate 80]Prefilled Syringe Kit, Subcutaneous: Hulio: 20 mg/0.4 mL (2 ea); 40 mg/0.8 mL (2 ea) [contains polysorbate 80]Simlandi: 40 mg/0.4 mL (1 ea, 2 ea); 80 mg/0.8 mL (1 ea, 2 ea) [contains polysorbate 80]Solution, Subcutaneous: Humira: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Solution Auto-injector, Subcutaneous: Abrilada: 40 mg/0.8 mL (0.8 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]Amgevita SureClick: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Hadlima PushTouch: 40 mg/0.8 mL (0.8 mL)Hyrimoz: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Idacio: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Solution Pen-injector, Subcutaneous: Humira: 40 mg/0.4 mL ([DSC]) [contains polysorbate 80]Solution Prefilled Syringe, Subcutaneous: Abrilada: 40 mg/0.8 mL (0.8 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]Amgevita: 20 mg/0.4 mL (0.4 mL); 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Hadlima: 40 mg/0.8 mL (0.8 mL)Humira: 20 mg/0.2 mL (0.2 mL); 40 mg/0.4 mL ([DSC]) [contains polysorbate 80]Hyrimoz: 20 mg/0.4 mL (0.4 mL); 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Idacio: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Product AvailabilityAbrilada (adalimumab-afzb): FDA approved November 2019; availability anticipated in 2023. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Amjevita (adalimumab-atto): FDA approved September 2016; anticipated availability is currently unknown. Amjevita is approved as biosimilar to Humira. Consult the prescribing information for additional information.Cyltezo (adalimumab-adbm): FDA approved August 2017; anticipated availability is currently unknown. Cyltezo is approved as biosimilar to Humira. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Hadlima (adalimumab-bwwd): FDA approved July 2019; anticipated availability is currently unknown. Hadlima is approved as biosimilar to Humira. Consult the prescribing information for additional information.Hulio (adalimumab-fkjp): FDA approved July 2020; availability anticipated July 2023. Hulio is approved as a biosimilar to Humira.Hyrimoz (adalimumab-adaz): FDA approved October 2018; availability anticipated in 2023. Hyrimoz is approved as biosimilar to Humira. Consult the prescribing information for additional information.Idacio (adalimumab-aacf): FDA approved December 2022; availability anticipated in July 2023. Idacio is approved as biosimilar to Humira. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Yusimry (adalimumab-aqvh): FDA approved December 2021; availability anticipated July 2023. Yusimry is approved as a biosimilar to Humira.Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Abrilada (adalimumab-afzb): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761118s006lbl.pdf#page=44Amjevita (adalimumab-atto): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761024s010lbl.pdf#page=46Cyltezo (adalimumab-adbm): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761058s008lbl.pdf#page=33Hadlima (adalimumab-bwwd): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761059s004lbl.pdf#page=40Hulio (adalimumab-fkjp): https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761154s000lbl.pdf#page=41Humira: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125057s417lbl.pdf#page=60Hyrimoz (adalimumab-adaz): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761071s010s012lbl.pdf#page=41Yusimry (adalimumab-aqvh): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761216s000lbl.pdf#page=38Administration: AdultSUBQ: For SUBQ injection at separate sites in the thigh or lower abdomen (avoiding areas within 2 inches of navel); rotate injection sites. May leave at room temperature for ~15 to 30 minutes prior to use; do not remove cap or cover while allowing product to reach room temperature. Do not use if solution is discolored or contains particulate matter. Do not administer to skin which is red, tender, bruised, hard, or that has scars, stretch marks, or psoriasis plaques. Needle cap of the prefilled syringe or needle cover for the adalimumab pen may contain latex. Prefilled pens and syringes are available for use by patients and the full amount of the syringe should be injected (self-administration); the vial is intended for institutional use only. Vials do not contain a preservative; discard unused portion. Citrate-free formulations may be associated with less pain on injection.Administration: PediatricSubQ: Administer subcutaneously into thigh or lower abdomen (avoid areas within 2 inches of navel); rotate injection sites. If single dose requires multiple injections, administer each injection at a separate site at least 1 inch apart. Do not administer into skin that is red, tender, bruised, or hard. May leave at room temperature for ~15 to 30 minutes prior to use; do not remove cap or cover while allowing product to reach room temperature. Do not use if solution is discolored or contains particulate matter.Single-use vial: Intended for institutional use only; does not contain a preservative; discard unused portion.Prefilled pens/syringe: Citrate-free formulations are available and may be associated with less pain on injection. Needle cap of the prefilled syringe or needle cover may contain latex. Pinch area of skin prepped for injection and continue to hold until injection complete. Hold pen firmly against pinched skin and press button. A loud click is heard when injection has begun. Continue to hold pen against skin until injection complete (may take 10 seconds). When injection is complete, the yellow indicator will fully appear in the window view and stop moving. See product labeling for administration details.Use: Labeled IndicationsCrohn disease, moderate to severe, induction and maintenance of remission: Treatment of moderately to severely active Crohn disease in adults and pediatric patients ≥6 years of age.Guideline recommendations: Adalimumab is recommended with or without an immunomodulator for treatment-naive patients with moderate to severe Crohn disease, and may also be effective in patients with fistulizing disease (AGA [Feuerstein 2021]). In addition, adalimumab is effective for prophylactic therapy in patients following surgical resection who are at higher risk for clinical recurrence (ACG [Lichtenstein 2018]; AGA [Nguyen 2017]).Hidradenitis suppurativa, moderate to severe, refractory (Humira only): Treatment of moderate to severe hidradenitis suppurativa in adults and children ≥12 years of age.Juvenile idiopathic arthritis: Treatment (to reduce signs/symptoms) of active polyarticular juvenile idiopathic arthritis (moderate to severe) in pediatric patients ≥2 years of age; may be used alone or in combination with methotrexate.Plaque psoriasis, moderate to severe: Treatment of chronic plaque psoriasis (moderate to severe) in adults who are candidates for systemic therapy or phototherapy, and when other systemic therapies are less appropriate (with close monitoring and regular follow-up).Rheumatoid arthritis: Treatment (to reduce signs/symptoms, induce major clinical response, inhibit progression of structural damage, and improve physical function) of active rheumatoid arthritis (moderate to severe) in adults; may be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).Spondyloarthritis: Axial spondyloarthritis (eg, ankylosing spondylitis): Treatment (to reduce signs/symptoms) of active ankylosing spondylitis in adults. May also be used off label for nonradiographic axial spondyloarthritis (ACR [Ward 2019]).Psoriatic arthritis: Treatment (to reduce signs/symptoms, inhibit progression of structural damage, and improve physical function) of psoriatic arthritis (a form of peripheral spondyloarthritis) in adults; may be used alone or in combination with nonbiologic DMARDs. May also be used off label for nonpsoriatic peripheral spondyloarthritis (eg, reactive arthritis, arthritis associated with inflammatory bowel disease) (Mease 2015; Paramarta 2013).Ulcerative colitis, moderate to severe, induction and maintenance of remission: Treatment of moderately to severely active ulcerative colitis in adults and pediatric patients ≥5 years of age. Note: Efficacy in patients intolerant of or no longer responsive to other tumor necrosis factor blockers has not been established.Uveitis, noninfectious: Treatment of noninfectious intermediate, posterior, and panuveitis in adults and children ≥2 years of age.Note: In Canada, Abrilada, Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Simlandi, and Yuflyma are also approved as biosimilars to Humira; refer to Canadian product monograph(s) for biosimilar-specific indication details.Use: Off-Label: AdultSarcoidosis, refractoryMedication Safety IssuesSound-alike/look-alike issues:Adalimumab may be confused with sarilumab.Humira may be confused with Humulin, HumalogHumira Pen may be confused with HumaPen Memoir (used with HumaLOG)High alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.Adverse Reactions (Significant): ConsiderationsAutoimmune disorderAntibody development may occur with the use of tumor necrosis factor alpha inhibitors (TNFai), including adalimumab. Most frequently, autoantibodies include anti-nuclear antibody (ANA) and anti-double stranded DNA (dsDNA); less frequently, anti-ENA, anti-histone Ab, and anti-cardiolipin Ab (Ref). Frequency of autoantibody development varies depending on underlying disease, specific TNFai medication, and the duration of use; the clinical significance of asymptomatic antibody positivity is unclear (Ref). Antibody positivity may rarely result in the development of an autoimmune disorder, such as lupus-like syndrome (Ref). Symptoms may include arthralgia, myalgia, mucocutaneous symptoms (eg, skin rash), cytopenia, fatigue, fever, serositis and kidney injury (Ref). Development of an autoimmune disorder is associated with a poor treatment response of the original disease to TNFai therapy (Ref). It is unclear if the development of an autoimmune disorder is a TNFai class effect; several reports of rechallenge with the same TNFai or a different TNFai after treatment of the initial autoimmune disorder did not result in a recurrence (Ref).Mechanism: Unknown; Postulated mechanisms include bystander activation of autoreactive lymphocytes due to drug-specific immunity, nonspecific activation of lymphocytes, direct cytotoxicity with release of autoantigens, and disruption of central T-cell tolerance (Ref).Onset: Varied; ranged from 5 weeks to 2 years (Ref).Risk factors: • Longer disease duration (Ref)• Females (Ref)• Ulcerative colitis (Ref)Demyelinating diseaseNew-onset or exacerbation of central and peripheral nervous system demyelinating disease, such as multiple sclerosis, optic neuritis, acute transverse myelitis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy may occur with tumor necrosis factor alpha inhibitors (TNFai), although causality has not been proven (Ref). Symptomatic CNS demyelination associated with TNFai may be monophasic and/or clinically isolated (Ref). Partial or complete resolution may occur after discontinuation of TNFai (Ref); however, approximately one-third of TNFai associated demyelinating episodes evolve into clinically definite multiple sclerosis (Ref).Mechanism: Unknown; several mechanisms have been postulated, including the following: May trigger CNS demyelination directly by immune activation in genetically and/or immunologically predisposed individuals (Ref); may inhibit remyelination via TNF type-2 receptor (TNRF2) (Ref); may increase ingress of auto-reactive T cells in the CNS; may alter downstream cytokine responses; may neutralize TNF systemically but not within the CNS, creating an artificially high local concentration of brain TNF (known as sponge effect); may permit latent CNS viral infection; or may promote anti-drug antibodies and immune complexes that are contributory to demyelination events (Ref).Onset: Varied; mean time of exposure to TNFai before onset of symptoms: 18 months (Ref).Risk factors:• Preexisting or recent onset central or peripheral nervous system demyelinating diseaseDermatologic reactionsVarious cutaneous eruptions have been reported, including psoriasiform eruption (either new-onset or exacerbation), hidradenitis suppurativa, lupus-like syndrome, eczematous rash, pustular rash, lichenoid eruption, and hypersensitivity angiitis (Ref).Mechanism: Psoriasiform eruptions, lichenoid drug eruptions: Non–dose-related; possibly related to cytokine imbalance or imbalance between tumor necrosis factor (TNF)-alpha and interferon-alpha (Ref).Onset: Psoriasiform eruptions: Delayed: Mean 15.6 ± 10.7 months (Ref). Hidradenitis suppurativa: Delayed; median 12 months (range: 1 to 72) (Ref).Risk factors:• Adult females (psoriatic lesions) (Ref)• Smoking (psoriatic lesions) (Ref)• Males (palmoplantar pustulosis) (Ref)• Younger patients (<40 years of age) (palmoplantar pustulosis) (Ref)• Patients with inflammatory bowel disease compared to other inflammatory diseases (psoriasiform reactions more frequent and severe) (Ref).• Females (hidradenitis suppurativa) (Ref)• Cross-reactivity data among TNFai in patients who develop psoriatic lesions are conflicting (Ref)Heart failureNew-onset heart failure (HF) and worsening of heart failure have been reported with tumor necrosis factor-alpha inhibitors (TNFai), including adalimumab; however, data are conflicting, and risk is unclear (Ref). Rheumatoid arthritis (RA) may be a risk factor for HF development (Ref). Some data suggest that TNFai may reduce the risk of HF in the RA population by improving inflammation, lowering disease activity, and improving surrogate markers of cardiovascular disease (Ref).Mechanism: Not clearly established; postulated mechanisms include pro-inflammatory cytokine activation, accelerated atherosclerosis, and reduced physical activity related to the underlying rheumatologic disease (Ref). "Reverse-signaling" may occur, leading to cardiotoxic effects; TNF on cardiomyocytes of the failing heart may act as receptors, activating intracellular signaling pathways, potentiating the toxic effect of the cytokine (Ref).Onset: Varied; median 8.5 months (range: 5 to 17 months (data with infliximab) (Ref).Risk factors:• Preexisting heart failure• Higher disease activity (inflammation) (eg, disease activity score (DAS28), C-reactive protein, erythrocyte sedimentation rate) (Ref)Hepatitis B virus reactivationReactivation of hepatitis B virus (HBV) may occur with immunosuppressive or biologic therapy, including tumor necrosis factor-alpha inhibitors (TNFai) (Ref). Reactivation of HBV may occur in both patients who are HBsAg-positive and in patients who are HBsAg-negative/HBcAb-positive with detectable HBV DNA (Ref). Criteria for HBV reactivation includes (1) a rise in HBV DNA compared to baseline (or an absolute level of HBV DNA when a baseline is unavailable) and (2) reverse seroconversion (seroreversion) from HBsAg negative to HBsAg positive for patients who are HBsAg-negative and anti-HBc–positive (Ref).Mechanism: Inhibit stimulation of HBV specific T-lymphocytes, promoting reactivation (Ref).Onset: Varied; 2 weeks after initiation, up to a year after discontinuation (Ref).Risk factors:• Males (Ref)• Older age (Ref)• Presence of cirrhosis (Ref)• High baseline HBV-DNA level (Ref)• HBeAg or HBsAg seropositivity (Ref)• Absence of anti-HBs among patients with resolved HBV infection (Ref)• Chronic HBV (Ref)• Non-A HBV genotype (Ref)• Hepatitis C, hepatitis D, or HIV co-infection (Ref)HepatoxicityAdalimumab has been associated with increased serum transaminases and hepatotoxicity (Ref). Cholestatic hepatitis, reactivation of hepatitis B virus, and autoimmune hepatitis have been reported (Ref). Elevated aminotransferases between 2 to 3 times the upper limit of normal may occur that are usually transient and asymptomatic (Ref). Resolution of symptoms in patients who develop an autoimmune hepatitis may require initiation of corticosteroid therapy (Ref). Immunomodulatory use, in particular methotrexate, may decrease the risk of hepatotoxicity associated with tumor necrosis factor-alpha inhibitors (TNFai) (Ref). Patients often tolerate a different TNFai (Ref); although, hepatotoxicity may recur with an alternative agent in some cases (Ref). Hepatotoxicity is more commonly associated with infliximab, as compared to adalimumab and other TNFai (Ref).Mechanism: Unknown; idiosyncratic drug reaction (Ref), or autoimmunity due to development of autoantibodies (Ref).Onset: Varied; ranges from 4 weeks to 52 weeks (Ref). Autoimmune hepatitis has a longer latency period than non-immune cases (16 weeks vs 10 weeks, respectively) (Ref).InfectionTumor necrosis factor-alpha inhibitors (TNFai) may be associated with infection (including serious infection). In clinical trials, serious infections were numerically higher among patients treated with TNFai than among patients who received placebo. Meta-analyses and observational studies have reported inconsistency in risk. One study reported an increase in serious infection in patients treated with TNFai (Ref). Another study found no increase in risk (Ref). An observational study did not demonstrate an increased infection risk among patients receiving TNFai versus comparators (Ref). Infections may present as disseminated (rather than local) disease. Active tuberculosis (including reactivation of latent tuberculosis), invasive fungal infection (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial infection, viral infection, or other opportunistic infections (including legionellosis and listeriosis) have been reported.Mechanism: Dose-related; TNFa is important in the immune response against infections, suggesting that medications that inhibit TNFa may increase the risk of infections (Ref).Risk factors:• Higher doses (Ref)• Older age (Ref)• Chronic lung or kidney disease (Ref)• Concurrent immunosuppressants (eg, corticosteroids, methotrexate) (Ref)• History of an opportunistic infection• Chronic or recurrent infection• Conditions that predispose to infections (eg, advanced or poorly controlled diabetes)• Residence/travel in areas of endemic tuberculosis or mycoses (blastomycosis, coccidioidomycosis, histoplasmosis)Injection-site reactionsAdalimumab is associated with injection-site reactions and delayed reactions (Ref). Concurrent immunomodulators (eg, methotrexate, cyclosporine) reduce the development of anti-adalimumab antibodies and may reduce risk (Ref). Most reactions do not require discontinuation and do not recur (Ref). Cross-reactivity between tumor necrosis factor-alpha inhibitors is not well-described (Ref). Anti-infliximab antibodies do not crossreact with adalimumab; although, patients who develop anti-infliximab antibodies are more prone to develop anti-adalimumab antibodies (Ref). Adalimumab has been tolerated in patients with previous infusion reactions with infliximab (Ref). In contrast, there are reports of immediate hypersensitivity reactions with adalimumab in patients who had previous infliximab-related reactions (Ref).Mechanism: Unknown; T-cell mediated (Ref) or IgE-mediated (Ref).Onset: Varied; 12 to 24 hours following injection (but may occur immediately following injection). Injection-site reactions often occur within the first month of treatment and last up to 4 days (Ref).Risk factors:• Younger age (Ref)MalignancyLymphoma and other malignancies (some fatal) have been reported in children and adolescents receiving tumor necrosis factor-alpha inhibitors (TNFai), including adalimumab. Half of the malignancies reported in children and adolescents were lymphomas (Hodgkin lymphoma and non-Hodgkin lymphoma), while other cases varied and included rare malignancies usually associated with immunosuppression and malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants. Hepatosplenic T-cell lymphoma, a rare T-cell lymphoma, has been reported (some fatal), primarily in patients with Crohn disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males.Long-term observational studies and meta-analyses indicate no association between TNFai therapy and an overall increased risk of cancer (Ref). One study reported a significant increase in lymphomas in patients with rheumatoid arthritis (RA) receiving TNFai compared to the general population. However, there was no significant increased risk of lymphomas in patients receiving TNFai compared to those receiving csDMARD or with dose, increasing time since initiation, or cumulative duration (Ref). Another study reported no difference in the risk of solid tumors in patients with RA receiving TNFai compared to those receiving csDMARDs (Ref). Other studies reported no increased risk of malignancy recurrence in patients receiving TNFai (Ref).Mechanism: May contribute to protumor activity and suppress the anti-tumor response (Ref).Onset: Delayed; median 30 months (range: 1 to 84 months).TuberculosisPatients treated with tumor necrosis factor-alpha inhibitors (TNFai) are at risk for developing active tuberculosis (TB) (including reactivated tuberculosis) (Ref). A meta-analysis of randomized controlled trials (RTC) of TNFai versus control and registry/longitudinal cohort studies of TNFai versus other DMARDs found a significant increase in TB risk in patients with rheumatoid arthritis (RA) treated with TNFai. In the non-RTC studies, incidence rates with adalimumab were higher than etanercept. Preventive treatment for latent TB infection reduced TB risk (Ref). In the RCT studies, no difference in TB rates were found; however, this failure to detect a difference in TB rates between the two groups may be due to a short observational period (Ref).Mechanism: TNFai interfere with TNFa induction of the granuloma, which is a crucial defense mechanism in controlling TB (Ref). TNFai modulates T-cell number, function, and cytokine signaling, important for the control of TB infection (Ref).Onset: Varied; median 3 to ~73 months (Ref).Risk factors:• Residence in an area with high TB prevalence (Ref)• Known TB exposure or ongoing risk factors for TB exposure (eg, travel to areas with high TB prevalence, residence in correctional facilities, long-term care facilities, or homeless shelters, certain healthcare workers (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Dermatologic: Skin rash (12%) (table 1)Skin RashAdalimumab: Adverse Reaction: Skin RashDrug (Adalimumab)Placebo PopulationDoseIndicationNumber of Patients (Adalimumab)Number of Patients (Placebo)12%6%Adults40 mg every other weekRheumatoid Arthritis705690Hematologic & oncologic: Positive ANA titer (12%)Immunologic: Antibody development (3% to 26%)Infection: InfectionLocal: Injection-site reaction (5% to 20%; including bleeding at injection site, erythema at injection site, injection-site pruritus, pain at injection site, swelling at injection site) (table 2)Injection-Site ReactionAdalimumab: Adverse Reaction: Injection-Site ReactionDrug (Adalimumab)Placebo PopulationDoseIndicationNumber of Patients (Adalimumab)Number of Patients (Placebo)16%N/AChildren and adolescentsEither 24 mg/m2 up to maximum 40 mg every other week or 20 mg every other week (<30 kg), 40 mg every other week (≥30 kg) dependent on phase of studyJuvenile idiopathic arthritis171N/A5%N/AChildren and adolescentsHigh dose: 40 mg every other week (≥40 kg) or 20 mg every other week (<40 kg); low dose: 20 mg every other week (≥40 kg) or 10 mg every other week (<40 kg)Crohn disease192N/A8%1%Adults40 mg every other weekRheumatoid Arthritis70569020%14%N/AN/APooled placebo-controlled clinical trialsN/AN/ANervous system: Headache (12%)Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (children and adolescents: 15%)Respiratory: Sinusitis (11%), upper respiratory tract infection (17%)1% to 10%:Cardiovascular: Acute myocardial infarction (<5%), atrial fibrillation (<5%), cardiac arrhythmia (<5%), chest pain (<5%), coronary artery disease (<5%), deep vein thrombosis (<5%), hypertension (5%), hypertensive encephalopathy (<5%), palpitations (<5%), pericardial effusion (<5%), pericarditis (<5%), peripheral edema (<5%), syncope (<5%), tachycardia (<5%)Endocrine & metabolic: Dehydration (<5%), hypercholesterolemia (6%), hyperlipidemia (7%), ketosis (<5%), menstrual disease (<5%), parathyroid disease (<5%)Gastrointestinal: Abdominal pain (7%), cholecystitis (<5%), cholelithiasis (<5%), esophagitis (<5%), gastroenteritis (<5%), gastrointestinal hemorrhage (<5%), nausea (9%), vomiting (<5%)Genitourinary: Cystitis (<5%), hematuria (5%), pelvic pain (<5%), urinary tract infection (8%)Hematologic & oncologic: Adenoma (<5%), agranulocytosis (<5%), paraproteinemia (<5%), polycythemia (<5%)Hepatic: Hepatic necrosis (<5%), increased serum alkaline phosphatase (5%)Hypersensitivity: Hypersensitivity reaction (children and adolescents: 5% to 6%)Infection: Herpes simplex infection (≤4%), herpes zoster infection (≤4%), serious infection (4% to 5%)Nervous system: Confusion (<5%), myasthenia (<5%), paresthesia (<5%), subdural hematoma (<5%), torso pain (<5%), tremor (<5%)Neuromuscular & skeletal: Arthralgia (3%), arthritis (<5%, including pyogenic arthritis), arthropathy (<5%), back pain (6%), bone disease (<5%), bone fracture (<5%), limb pain (<5%), muscle cramps (<5%), osteonecrosis (<5%), synovitis (<5%), tendinopathy (<5%)Ophthalmic: Cataract (<5%)Renal: Nephrolithiasis (<5%)Respiratory: Asthma (<5%), bronchospasm (<5%), dyspnea (<5%), flu-like symptoms (7%), pharyngitis (≤4%), pleural effusion (<5%), pneumonia (≤4%), respiratory depression (<5%)Miscellaneous: Abnormal healing (<5%), accidental injury (10%)<1%: Neuromuscular & skeletal: Lupus-like syndrome (Schiff 2006)Frequency not defined:Dermatologic: Basal cell carcinoma of skin, cellulitis, erysipelas, malignant melanoma, skin granuloma (annulare; children and adolescents)Gastrointestinal: AppendicitisGenitourinary: Uterine hemorrhageHematologic & oncologic: Carcinoma (including breast, gastrointestinal, lung, skin, urogenital), malignant lymphoma, neutropenia (children and adolescents)Hepatic: Increased serum transaminasesInfection: Atypical mycobacterial infection, bacterial infection, fungal infection (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and infection due to an organism in genus Pneumocystis), influenza (H1N1), opportunistic infection (including Legionella and listeriosis), parasitic infection, postoperative infection, sepsis (including catheter related sepsis), viral infectionNeuromuscular & skeletal: Myositis (children and adolescents), septic arthritisRenal: PyelonephritisRespiratory: Bronchitis, nasopharyngitis, streptococcal pharyngitis (children and adolescents), tuberculosis (including reactivated tuberculosis; disseminated, miliary, lymphatic, peritoneal, and pulmonary)Postmarketing:Cardiovascular: Heart failure (Mansitó López 2021), pulmonary embolism, vasculitis (systemic), worsening of heart failureDermatologic: Alopecia, cutaneous lupus erythematosus (Gonzalez-Cuevas 2020), eczematous rash (Moustou 2009), erythema multiforme, fixed drug eruption, lichenoid eruption (Moustou 2009), Merkel cell carcinoma, psoriasiform eruption (Bae 2018a), psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pustular rash (Moustou 2009), Stevens-Johnson syndrome (Mounach 2013), urticaria (Grace 2020)Gastrointestinal: Diverticulitis of the gastrointestinal tract, gastrointestinal perforation (appendiceal perforations), intestinal perforation, pancreatitisHematologic & oncologic: Aplastic anemia, hepatosplenic T-cell lymphomas (children, adolescents, and young adults), leukopenia, pancytopenia, thrombocytopeniaHepatic: Autoimmune hepatitis (Adar 2010), cholestatic hepatitis (Latus 2013), hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2021)Hypersensitivity: Anaphylaxis (Steenholdt 2012), angioedema (Hansel 2019), hypersensitivity angiitis (Amarantee 2015), nonimmune anaphylaxisImmunologic: SarcoidosisInfection: Reactivation of HBV (Loomba 2017)Nervous system: Cerebrovascular accident, demyelinating disease (peripheral; including Guillain-Barré syndrome) (Kemanetzoglou 2017), demyelinating disease of the central nervous system (including multiple sclerosis) (Kemanetzoglou 2017)Ophthalmic: Optic neuritisRespiratory: Interstitial lung disease (including pulmonary fibrosis)Miscellaneous: Fever (Choi 2021)ContraindicationsThere are no contraindications listed in the manufacturer's US labeling.Canadian labeling: Known hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection); moderate-to-severe heart failure (NYHA class III/IV)Warnings/PrecautionsConcerns related to adverse effects:• Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioneurotic edema; medications for the treatment of hypersensitivity reactions should be available for immediate use.• Antibody formation: Formation of neutralizing anti-drug antibodies may occur with biologic tumor necrosis factor (TNF) inhibitors and may be associated with loss of efficacy (AAD-NPF [Menter 2019]).• Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop.• Demyelinating disease: Rare cases of new-onset or exacerbation of demyelinating disorders (eg, multiple sclerosis, optic neuritis, peripheral demyelinating disease, including Guillain-Barré syndrome) have been reported; there is a known association between intermediate uveitis and central demyelinating disorders. Consider discontinuing use in patients who develop peripheral or central nervous system demyelinating disorders during treatment. Use with caution in patients with preexisting or recent onset central or peripheral nervous system demyelinating disorders.• Heart failure: Worsening and new-onset heart failure (HF) has been reported with adalimumab and other TNF blockers. Use with caution in patients with HF or decreased left ventricular function. In a scientific statement from the American Heart Association, TNF blockers have been determined to be agents that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).• Hematologic disorders: Rare cases of pancytopenia and aplastic anemia have been reported with TNF-blockers. Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias; discontinue if significant hematologic abnormalities are confirmed. Use with caution in patients with a history of significant hematologic abnormalities.• Hepatitis B: Rare reactivation of hepatitis B (HBV) has occurred in chronic carriers of the virus, usually in patients receiving concomitant immunosuppressants (some have been fatal); evaluate for HBV prior to initiation in all patients. Monitor during and for several months following discontinuation of treatment in HBV carriers; interrupt therapy if reactivation occurs and treat appropriately with antiviral therapy; if resumption of therapy is deemed necessary, exercise caution and monitor patient closely.• Infections: [US Boxed Warning]: Patients receiving adalimumab are at increased risk for serious infections which may result in hospitalization and/or fatality; infections usually developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate, corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis (including reactivation of latent tuberculosis), invasive fungal (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial, viral or other opportunistic infections (including legionellosis and listeriosis) have been reported. Monitor closely for signs/symptoms of infection during and after treatment. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to initiating therapy in patients with chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infections who develop severe systemic illness. Caution should be exercised when considering use in the elderly, patients with a history of an opportunistic infection, patients taking concomitant immunosuppressants (eg, corticosteroids, methotrexate), or in patients with conditions that predispose them to infections (eg, advanced or poorly controlled diabetes) or residence/travel in areas of endemic tuberculosis or mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent infections. Do not initiate adalimumab in patients with an active infection, including clinically important localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely.• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies (some fatal) have been reported in children and adolescents receiving TNF-blocking agents, including adalimumab. Half of the malignancies reported in children and adolescents were lymphomas (Hodgkin and non-Hodgkin) while other cases varied and included rare malignancies usually associated with immunosuppression and malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants. [US Boxed Warning]: Hepatosplenic T-cell lymphoma (HSTCL), a rare T-cell lymphoma, has been reported (some fatal) primarily in patients with Crohn disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males. The impact of adalimumab on the development and course of malignancy is not fully defined. Compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis alone has been previously associated with an increased rate of lymphoma and leukemia. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.7/100 patient years), when compared to the control group (0.2/100 patient years).• Tuberculosis: [US Boxed Warnings]: Active tuberculosis (disseminated or extrapulmonary), including reactivation of latent tuberculosis, has been reported in patients receiving adalimumab. Evaluate patients for tuberculosis risk factors and latent tuberculosis infection (with a skin test) prior to and during therapy. Treatment for latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis during and after treatment. Consider antituberculosis treatment if an adequate course of treatment cannot be confirmed in patients with a history of latent or active tuberculosis or with risk factors despite negative skin test. Some patients who tested negative prior to therapy have developed active infection; tests for latent tuberculosis infection may be falsely negative while on adalimumab therapy. Use with caution in patients who have traveled to or resided in regions where tuberculosis is endemic. Monitor for signs and symptoms of tuberculosis in all patients.Disease-related concerns:• HIV: Use with caution in HIV-positive patients; TNF-α inhibitors may be appropriate in patients receiving highly active antiretroviral therapy, provided they have normal CD4 counts, no viral load, and no recent opportunistic infections (AAD-NPF [Menter 2019]).Special populations:• Older adult: Infection and malignancy has been reported at a higher incidence; use caution in elderly patients.• Pediatric: Malignancies have been reported among children and adolescents.• Surgery patients: Limited experience with patients undergoing surgical procedures while on therapy; consider long half-life with planned procedures. Monitor closely for infection.Dosage form specific issues:• Latex: The packaging (needle cover of prefilled syringe and autoinjector) may contain latex.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy; live vaccines should not be given concurrently. There are no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.Warnings: Additional Pediatric ConsiderationsPostmarketing reports of lymphomas and other malignancies were primarily in pediatric patients with Crohn disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. In an analysis of children and adolescents who had received TNF-blockers (etanercept and infliximab), the FDA identified 48 cases of malignancy. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin and non-Hodgkin lymphoma). Other malignancies, such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate). The role of TNF-blockers in the development of malignancies in children cannot be excluded. The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients (children and adults) using TNF-blockers. Average onset time to development of leukemia was within the first 1 to 2 years of TNF-blocker initiation.Reactivation of TB has been reported in pediatric patients receiving biologic response modifiers (infliximab and etanercept); prior to therapy, patients with no TB risk factors should be screened for latent TB infection (LTBI) with an age appropriate test (ie, <5 years of age: tuberculin skin test, and ≥5 years of age: IGRA [interferon gamma release assay]); if any TB risk factors are present or symptoms, both LTBI screening tests should be performed (AAP [Davies 2016])Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abatacept: Anti-TNF Agents may enhance the immunosuppressive effect of Abatacept.Risk X: Avoid combinationAbrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationAnakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported.Risk X: Avoid combinationAnifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab.Risk X: Avoid combinationBaricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib.Risk X: Avoid combinationBCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBelimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combinationBiologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combinationBrincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCanakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased.Risk X: Avoid combinationCertolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol.Risk X: Avoid combinationCladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationCoccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modificationCOVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCycloSPORINE (Systemic): Adalimumab may decrease the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyDengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab.Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modificationDeucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationEfgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapyFilgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationInebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modificationLeflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modificationNatalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationOcrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyPidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus.Risk X: Avoid combinationPneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationRabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept.Risk X: Avoid combinationRubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modificationSphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapyTacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationTheophylline Derivatives: Adalimumab may decrease the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyThiopurine Analogs: Anti-TNF Agents may enhance the adverse/toxic effect of Thiopurine Analogs. Specifically, the risk for T-cell non-Hodgkin's lymphoma (including hepatosplenic T-cell lymphoma) may be increased.Risk C: Monitor therapyTocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Risk X: Avoid combinationTofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib.Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combinationTyphoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib.Risk X: Avoid combinationVaccines (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modificationVaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationVedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab.Risk X: Avoid combinationWarfarin: Adalimumab may decrease the serum concentration of Warfarin.Risk C: Monitor therapyYellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationReproductive ConsiderationsThe American Academy of Dermatology considers tumor necrosis factor (TNF) blocking agents for the treatment of psoriasis to be compatible for use in patients planning to father a child (AAD-NPF [Menter 2019]). Patients with psoriasis planning to become pregnant may continue treatment with adalimumab. Patients with well-controlled psoriasis who wish to avoid fetal exposure can consider discontinuing adalimumab 10 weeks prior to attempting to become pregnant (Rademaker 2018).Biologics, such as adalimumab, may be continued in patients with inflammatory bowel disease (eg, Crohn disease, ulcerative colitis) planning to become pregnant (Mahadevan 2019). Treatment algorithms are available for use of biologics in patients with Crohn disease who are planning to become pregnant (Weizman 2019).Pregnancy ConsiderationsAdalimumab crosses the placenta.Adalimumab is a humanized monoclonal antibody (IgG1). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).Following administration to pregnant patients with inflammatory bowel disease (eg, Crohn disease, ulcerative colitis), cord blood and newborn serum concentrations of adalimumab are greater than maternal serum at delivery (Julsgaard 2016; Mahadevan 2013). The mean time to adalimumab clearance was 4 months (range: 2.9 to 5 months) in a study in 36 infants exposed in utero. The estimated mean half-life of adalimumab in these infants was 26 days (Julsgaard 2016). One case report notes adalimumab was detectable in the infant serum for 19 months following in utero exposure (Labetoulle 2018).Based on available data, an increased risk of adverse maternal or fetal effects has not been observed following adalimumab exposure during pregnancy (Nielsen 2020). Adalimumab information from a pregnancy registry collected between 2004 and 2016 is available. Included were pregnant women with rheumatoid arthritis (RA) or Crohn disease (CD) treated with adalimumab at least during the first trimester (n=257), pregnant women with RA or CD not treated with adalimumab (disease untreated control, n=120), and pregnant women without RA or CD (healthy unexposed control, n=225); 42 cases lost to follow-up. The incidence of major birth defects was not significantly different between the study groups and no pattern of specific defects was observed. An increased risk of growth restriction or serious opportunistic infections was not associated with maternal adalimumab therapy when compared to the disease untreated controls. An increased risk of preterm delivery was observed in pregnant patients with RA or CD, regardless of adalimumab exposure (Chambers 2019). Information related to this class of medications is emerging, but based on available data, tumor necrosis factor alpha (TNFα) blocking agents are considered to have low to moderate risk when used in pregnancy (ACOG 776 2019).The risk of immunosuppression may be increased following third trimester maternal use of TNFα blocking agents; the fetus, neonate/infant should be considered immunosuppressed for 1 to 3 months following in utero exposure (AAD-NPF [Menter 2019]). Vaccination with live vaccines (eg, rotavirus vaccine) should be avoided for the first 6 months of life if exposure to a biologic agent occurs during the third trimester of pregnancy (eg, >27 weeks' gestation) (Mahadevan 2019).Maternal adalimumab serum concentrations remain stable as pregnancy progresses (Flanagan 2020; Seow 2017).Inflammatory bowel disease is associated with adverse pregnancy outcomes including an increased risk of miscarriage, premature delivery, delivery of a low birth weight infant, and poor maternal weight gain. Management of maternal disease should be optimized prior to pregnancy. Treatment decreases disease flares, disease activity, and the incidence of adverse pregnancy outcomes (Mahadevan 2019).Use of immune modulating therapies in pregnancy should be individualized to optimize maternal disease and pregnancy outcomes (ACOG 776 2019). The American Academy of Dermatology considers TNFα blocking agents for the treatment of psoriasis to be compatible with pregnancy (AAD-NPF [Menter 2019]). When treatment for inflammatory bowel disease is needed in pregnant women, appropriate biologic therapy can be continued without interruption. Serum levels should be evaluated prior to conception and optimized to avoid subtherapeutic concentrations or high levels which may increase placental transfer. Dosing can be adjusted so delivery occurs at the lowest serum concentration. For adalimumab, the final injection can be given 2 to 3 weeks prior to the estimated date of delivery (1 to 2 weeks if weekly dosing), then continued 48 hours postpartum (Mahadevan 2019).Data collection to monitor pregnancy and infant outcomes following exposure to adalimumab is ongoing. Women exposed to adalimumab during pregnancy for the treatment of an autoimmune disease (eg, inflammatory bowel disease) may contact the OTIS Autoimmune Diseases Study at 877-311-8972.Breastfeeding ConsiderationsAdalimumab is present in breast milkBased on information from three cases, adalimumab concentrations in breast milk are 0.1% to 1% of the maternal serum concentrations (Ben-Horin 2010; Fritzsche 2012). In one case, the highest milk concentration was observed 6 days following a maternal dose of adalimumab 40 mg SubQ when maternal treatment for Crohn disease was restarted 4 weeks' postpartum (Ben-Horin 2010). The same maternal dose was used in cases two and three. Adalimumab was not measurable (<40 ng/mL) in the serum of one breastfeeding infant (9 days after the last maternal dose, 8 weeks' postpartum); serum concentrations were not evaluated in the other infant (Fritzsche 2012). In a study of 21 women, only two had detectable adalimumab in their breast milk, with maximum concentrations occurring between 12 and 24 hours after the infusion (dose not stated) (Matro 2018). An increased risk of infection has not been observed in breastfeeding infants whose mothers were using adalimumab monotherapy (Mahadevan 2012).According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. However, tumor necrosis factor alpha blocking agents are considered compatible with breastfeeding (AAD-NPF [Menter 2019]; ACOG 776 2019; Mahadevan 2019).Monitoring ParametersCBC with differential (baseline); complete metabolic panel (baseline); tuberculosis (TB) screening prior to initiating and during therapy (chest X-ray if TB positive); Hepatitis C virus/hepatitis B virus (HBV) screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); HIV screening in high risk patients (baseline) (AAD-NPF [Menter 2019]); signs/symptoms of infection, hypersensitivity reaction, lupus-like syndrome, or malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss). Monitor improvement of symptoms and physical function assessments.The American Gastroenterological Association suggests reactive therapeutic drug monitoring to guide treatment changes in adult patients treated with adalimumab for active inflammatory bowel disease (eg, Crohn disease, ulcerative colitis) (Feuerstein 2017).Reference RangeInflammatory bowel disease (IBD) (eg, Crohn disease, ulcerative colitis):Reactive therapeutic drug monitoring has been suggested to guide treatment changes in adults with active IBD.Timing of serum sample: Draw trough <24 hours prior to next scheduled doseTherapeutic reference range: ≥7.5 mcg/mL (Feuerstein 2017)Mechanism of ActionAdalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFα receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn disease and ulcerative colitis; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.Pharmaco*kineticsOnset of action: Response best determined after 3 to 4 months (AAD-NPF [Menter 2019]).Distribution: Vd: 4.7 to 6 L; Synovial fluid concentrations: 31% to 96% of serumBioavailability: Absolute: 64%Half-life elimination: Terminal: ~2 weeks (range: 10 to 20 days)Time to peak, serum: SubQ: 131 ± 56 hoursPharmaco*kinetics: Additional ConsiderationsOlder adult: In patients with rheumatoid arthritis (RA), there was a trend toward lower clearance with increasing age in patients 40 to >75 years of age.Pricing: USPen-injector Kit (Humira Pen Subcutaneous)40 mg/0.4 mL (per each): $3,845.9040 mg/0.8 mL (per each): $3,845.9080 mg/0.8 mL (per each): $7,691.82Pen-injector Kit (Humira Pen-CD/UC/HS Starter Subcutaneous)40 mg/0.8 mL (per each): $3,845.9180 mg/0.8 mL (per each): $7,691.83Pen-injector Kit (Humira Pen-Pediatric UC Start Subcutaneous)80 mg/0.8 mL (per each): $7,691.82Pen-injector Kit (Humira Pen-Ps/UV/Adol HS Start Subcutaneous)40 mg/0.8 mL (per each): $3,845.91Pen-injector Kit (Humira Pen-Psor/Uveit Starter Subcutaneous)80 MG/0.8ML &40MG/0.4ML (per each): $5,127.88Prefilled Syringe Kit (Humira Pediatric Crohns Start Subcutaneous)80 mg/0.8 mL (per each): $7,691.8380 MG/0.8ML &40MG/0.4ML (per each): $5,768.87Prefilled Syringe Kit (Humira Subcutaneous)10MG/0.1ML (per each): $3,845.9020 mg/0.2 mL (per each): $3,845.9040 mg/0.4 mL (per each): $3,845.9040 mg/0.8 mL (per each): $3,845.90Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAmgevita (AT, BE, FI, HR, NL, RO, TW);Amsparity (AT);Cyltezo (AT, BE, HU, LV, NL, PT);Exemptia (IN);Hadlima (AU);Halimatoz (NL);Hulio (HR, RO);Humira (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IQ, IR, IS, IT, JO, JP, KR, KW, LB, LT, LU, LV, LY, MT, MX, MY, NI, NL, NO, NZ, OM, PA, PE, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, SV, SY, TR, TW, UA, UY, VE, VN, YE, ZA);Hyrimoz (AT, AU, CZ, DE, EE, ES, HR, HU, LT, LV, NL, PL, PT, RO, SK);Idacid (TW);Idacio (HR, RO);Imraldi (BE, HR, NL, RO);Solymbic (AT);Trudexa (BE, BG, CH, CZ, DE, DK, EE, FI, FR, GB, GR, IT, PT, RU, SE, SK, TR)For country code abbreviations (show table)A-Rahim YI, Farrell RJ. Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 4, 2021.Abrilada (adalimumab) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; April 2021.Adalimumab. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; February 10, 2017. [PubMed 31643860]Adalimumab injection [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; January 2021.Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol. 2010;44(1):e20-e22. doi:10.1097/MCG.0b013e3181a745e7 [PubMed 19593165]Ai JW, Zhang S, Ruan QL, et al. The risk of tuberculosis in patients with rheumatoid arthritis treated with tumor necrosis factor-α antagonist: a metaanalysis of both randomized controlled trials and registry/cohort studies. J Rheumatol. 2015;42(12):2229-2237. doi:10.3899/jrheum.150057 [PubMed 26472414]Al Hashash J, Regueiro M. Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed November 2, 2021.Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Amarante CF, Acedo LM, Rabay FM, Campos Bdo E, Lira ML, Mandelbaum SH. Drug-induced lupus with leukocytoclastic vasculitis: a rare expression associated with adalimumab. An Bras Dermatol. 2015;90(3 suppl 1):121-124. doi:10.1590/abd1806-4841.20153834 [PubMed 26312693]American College of Obstetricians and Gynecologists (ACOG). Committee opinion no. 776: immune modulating therapies in pregnancy and lactation. Obstet Gynecol. 2019;133(4):e287-e295. [PubMed 30913201]Amgevita (adalimumab) [product monograph]. Mississauga, Ontario, Canada: Amgen Canada Inc; July 2021.Angel K, Provan SA, Gulseth HL, Mowinckel P, Kvien TK, Atar D. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension. 2010;55(2):333-338. doi:10.1161/HYPERTENSIONAHA.109.143982 [PubMed 20038753]Arts EE, Fransen J, den Broeder AA, Popa CD, van Riel PL. The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients. Ann Rheum Dis. 2015;74(6):998-1003. doi:10.1136/annrheumdis-2013-204531 [PubMed 24458537]Askling J, Baecklund E, Granath F, et al. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis. 2009;68(5):648-653. doi:10.1136/ard.2007.085852 [PubMed 18467516]Askling J, Fored CM, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64(10):1421-1426. doi:10.1136/ard.2004.033993 [PubMed 15829572]Averbukh LD, Wu GY. Role of biologics in the development of autoimmune hepatitis: a review. J Clin Transl Hepatol. 2018;6(4):402-409. doi:10.14218/JCTH.2018.00039 [PubMed 30637218]Bae JM, Kwon HS, Kim GM, Park KS, Kim KJ. Paradoxical psoriasis following anti-TNF therapy in ankylosing spondylitis: a population-based cohort study. J Allergy Clin Immunol. 2018;142(3):1001-1003.e2. doi:10.1016/j.jaci.2018.05.015 [PubMed 29859201]Bae JM, Lee HH, Lee BI, et al. Incidence of psoriasiform diseases secondary to tumour necrosis factor antagonists in patients with inflammatory bowel disease: a nationwide population-based cohort study. Aliment Pharmacol Ther. 2018;48(2):196-205. doi:10.1111/apt.14822 [PubMed 29869804]Barešić M, Reihl Crnogaj M, Zadro I, Anić B. Demyelinating disease (multiple sclerosis) in a patient with psoriatic arthritis treated with adalimumab: a case-based review. Rheumatol Int. 2021;41(12):2233-2239. doi:10.1007/s00296-021-04995-0 [PubMed 34557936]Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021;58(6):2004079. doi:10.1183/13993003.04079-2020 [PubMed 34140301]Baumgart DC, Grittner U, Steingräber A, Azzaro M, Philipp S. Frequency, phenotype, outcome, and therapeutic impact of skin reactions following initiation of adalimumab therapy: experience from a consecutive cohort of inflammatory bowel disease patients. Inflamm Bowel Dis. 2011;17(12):2512-2520. doi:10.1002/ibd.21643 [PubMed 21351201]Bavbek S, Ataman Ş, Akıncı A, Castells M. Rapid subcutaneous desensitization for the management of local and systemic hypersensitivity reactions to etanercept and adalimumab in 12 patients. J Allergy Clin Immunol Pract. 2015;3(4):629-632. doi:10.1016/j.jaip.2015.01.009 [PubMed 25725941]Bavbek S, Ataman Ş, Bankova L, Castells M. Injection site reaction to adalimumab: positive skin test and successful rapid desensitisation. Allergol Immunopathol (Madr). 2013;41(3):204-206. doi:10.1016/j.aller.2012.04.006 [PubMed 23063342]Ben-Horin S, Yavzori M, Katz L, et al. Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol. 2010;8(5):475-476. [PubMed 20005982]Benucci M, Manfredi M, Demoly P, Campi P. Injection site reactions to TNF-alpha blocking agents with positive skin tests. Allergy. 2008;63(1):138-139. doi:10.1111/j.1398-9995.2007.01536.x [PubMed 18053024]Björnsson ES, Gunnarsson BI, Gröndal G, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2015;13(3):602-608. doi:10.1016/j.cgh.2014.07.062 [PubMed 25131534]Björnsson HK, Gudbjornsson B, Björnsson ES. Infliximab-induced liver injury: clinical phenotypes, autoimmunity and the role of corticosteroid treatment. J Hepatol. 2022;76(1):86-92. doi:10.1016/j.jhep.2021.08.024 [PubMed 34487751]Boggs JME, Ramsay B, Lynch M. Paradoxical psoriasis caused by tumour necrosis factor inhibitor therapy. Clin Exp Dermatol. 2021;46(3):580-582. doi:10.1111/ced.14500 [PubMed 33151572]Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-2285. doi:10.1001/jama.295.19.2275 [PubMed 16705109]Burgos-Vargas R, Tse SM, Horneff G, et al. A randomized, double-blind, placebo-controlled multicenter study of adalimumab in pediatric patients with enthesitis-related arthritis. Arthritis Care Res (Hoboken). 2015;67(11):1503-1512. [PubMed 26223543]Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis. 2013;72(4):517-524. doi:10.1136/annrheumdis-2011-201244 [PubMed 22562972]Canu D, Seneschal J, Milpied B, Taieb A, Darrigade AS. TNFα inhibitor-induced urticaria: a class effect. Eur J Dermatol. 2019;29(5):543-544. doi:10.1684/ejd.2019.3625 [PubMed 31789277]Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep. 2000;49(RR-6):1-51. [PubMed 10881762]Centers for Disease Control and Prevention (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm [PubMed 6423951]Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966. [PubMed 24935270]Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR; Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2021;116(5):878-898. doi:10.14309/ajg.0000000000001259 [PubMed 33929376]Chambers CD, Johnson DL, Xu R, et al; OTIS Collaborative Research Group. Birth outcomes in women who have taken adalimumab in pregnancy: a prospective cohort study. PLoS One. 2019;14(10):e0223603. doi:10.1371/journal.pone.0223603 [PubMed 31626646]Chen HK, Shao SC, Weng MY, et al. Risk of heart failure in rheumatoid arthritis patients treated with tumor necrosis factor-α inhibitors. Clin Pharmacol Ther. 2021;110(6):1595-1603. doi:10.1002/cpt.2415 [PubMed 34496051]Choi SJ, Ahn SM, Oh JS, et al. Anti-tumor necrosis factor-induced lupus in patients with inflammatory bowel disease: a hospital-based cohort study from Korea. Therap Adv Gastroenterol. 2021;14:1756284821997794. doi:10.1177/1756284821997794 [PubMed 33747126]Choi SJ, Oh JS, Hong S, Lee CK, Yoo B, Kim YG. Liver enzyme elevation in patients with ankylosing spondylitis treated with tumor necrosis factor inhibitors: a single-center historical cohort study. Korean J Intern Med. 2020;35(3):723-731. doi:10.3904/kjim.2018.407 [PubMed 31870134]Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut. 2009;58(7):940-948. doi: 10.1136/gut.2008.159251. [PubMed 19201775]Conti F, Atzeni F, Massaro L, et al. The influence of comorbidities on the efficacy of tumour necrosis factor inhibitors, and the effect of tumour necrosis factor inhibitors on comorbidities in rheumatoid arthritis: report from a National Consensus Conference. Rheumatology (Oxford). 2018;57(57 suppl 7):vii11-vii22. doi:10.1093/rheumatology/key209 [PubMed 30289537]Cossio ML, Genois A, Jantchou P, Hatami A, Deslandres C, McCuaig C. Skin manifestations in pediatric patients treated with a TNF-alpha inhibitor for inflammatory bowel disease: a retrospective study. J Cutan Med Surg. 2020;24(4):333-339. doi:10.1177/1203475420917387 [PubMed 32527153]Crommelin HA, van der Burg LM, Vorselaars AD, et al. Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab. Respir Med. 2016;115:72-77. doi:10.1016/j.rmed.2016.04.011 [PubMed 27215507]Crowson CS, Liao KP, Davis JM 3rd, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166(4):622-628.e1. doi:10.1016/j.ahj.2013.07.010 [PubMed 24093840]Cyrenne BM, Parpia AS, Sibbald C. Paradoxical psoriasis in pediatric patients: a systematic review. Pediatr Dermatol. 2021;38(5):1086-1093. doi:10.1111/pde.14712 [PubMed 34402108]Darrigade AS, Milpied B, Truchetet ME, et al. Pattern and severity of psoriasiform eruptions in patients with inflammatory bowel diseases, arthritis or skin inflammatory disorders treated with TNF-alpha inhibitors. Acta Derm Venereol. 2017;97(6):731-734. doi:10.2340/00015555-2636 [PubMed 28218339]Davies HD, Committee on Infectious Disease. Infectious complications with the use of biologic response modifiers in infants and children. Pediatrics. 2016;138(2):e20161209. [PubMed 27432853]Drent M, Cremers JP, Jansen TL, Baughman RP. Practical eminence and experience-based recommendations for use of TNF-α inhibitors in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(2):91-107. [PubMed 25078637]Dubinsky MC, Rosh J, Faubion WA Jr, et al. Efficacy and safety of escalation of adalimumab therapy to weekly dosing in pediatric patients with Crohn's disease. Inflamm Bowel Dis. 2016;22(4):886-893. [PubMed 26950307]Eickstaedt JB, Killpack L, Tung J, Davis D, Hand JL, Tollefson MM. Psoriasis and psoriasiform eruptions in pediatric patients with inflammatory bowel disease treated with anti-tumor necrosis factor alpha agents. Pediatr Dermatol. 2017;34(3):253-260. doi:10.1111/pde.13081 [PubMed 28211161]Eissner G, Kirchner S, Lindner H, et al. Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages. J Immunol. 2000;164(12):6193-6198. doi:10.4049/jimmunol.164.12.6193 [PubMed 10843670]Engel S, Luessi F, Mueller A, Schopf RE, Zipp F, Bittner S. PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders. Ther Adv Neurol Disord. 2020;13:1756286419895155. doi:10.1177/1756286419895155 [PubMed 31921355]Faivre C, Villani AP, Aubin F, et al. Hidradenitis suppurativa (HS): an unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases. J Am Acad Dermatol. 2016;74(6):1153-1159. doi:10.1016/j.jaad.2016.01.018 [PubMed 26965410]Fernández-Crehuet P, Ruiz-Villaverde R. Acneiform eruption as a probable paradoxical reaction to adalimumab. Int J Dermatol. 2015;54(8):e306-e308. doi:10.1111/ijd.12416 [PubMed 24697221]Feuerstein JD, Cheifetz AS. Miscellaneous adverse events with biologic agents (excludes infection and malignancy). Gastroenterol Clin North Am. 2014;43(3):543-563. doi:10.1016/j.gtc.2014.05.002 [PubMed 25110258]Feuerstein JD, Ho EY, Shmidt E, et al; American Gastroenterological Association Institute Clinical Guidelines Committee. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn's disease. Gastroenterology. 2021;160(7):2496-2508. doi:10.1053/j.gastro.2021.04.022 [PubMed 34051983]Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827-834. doi: 10.1053/j.gastro.2017.07.032. [PubMed 28780013]Flanagan E, Gibson PR, Wright EK, et al; PICCOLO Study Group. Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure. Aliment Pharmacol Ther. 2020;52(10):1551-1562. doi:10.1111/apt.16102 [PubMed 32981127]Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-939. doi:10.1002/acr.24596 [PubMed 34101387]French JB, Bonacini M, Ghabril M, Foureau D, Bonkovsky HL. Hepatotoxicity associated with the use of anti-TNF-α agents. Drug Saf. 2016;39(3):199-208. doi:10.1007/s40264-015-0366-9 [PubMed 26692395]Frider B, Bruno A, Ponte M, Amante M. Drug-induced liver injury caused by adalimumab: a case report and review of the bibliography. Case Reports Hepatol. 2013;2013:406901. doi:10.1155/2013/406901 [PubMed 25431703]Fritzsche J, Pilch A, Mury D, Schaefer C, Weber-Schoendorfer C. Infliximab and adalimumab use during breastfeeding. J Clin Gastroenterol. 2012;46(8):718-719. [PubMed 22858514]Furst DE, Keystone EC, Braun J, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis. 2011;70(suppl 1):s2-s36. doi:10.1136/ard.2010.146852 [PubMed 21339216]Gallagher M, Quinones K, Cervantes-Castañeda RA, Yilmaz T, Foster CS. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol. 2007;91(10):1341-1344. [PubMed 17556427]Ghabril M, Bonkovsky HL, Kum C, et al. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013;11(5):558-564.e3. doi:10.1016/j.cgh.2012.12.025 [PubMed 23333219]Gilotra NA, Wand AL, Pillarisetty A, et al. Clinical and imaging response to tumor necrosis factor alpha inhibitors in treatment of cardiac sarcoidosis: a multicenter experience. J Card Fail. 2021;27(1):83-91. doi:10.1016/j.cardfail.2020.08.013 [PubMed 32889044]Godfrey MS, Friedman LN. Tuberculosis and biologic therapies: anti-tumor necrosis factor-α and beyond. Clin Chest Med. 2019;40(4):721-739. doi:10.1016/j.ccm.2019.07.003 [PubMed 31731980]González-Cuevas R, Peruilh-Bagolini L, Valenzuela F, Vargas-Mora P. Cutaneous lupus erythematosus induced by adalimumab: a case report. Dermatol Ther. 2020;33(6):e14339. doi:10.1111/dth.14339 [PubMed 32975341]Grace E, Goldblum O, Renda L, et al. Injection site reactions in the Federal Adverse Event Reporting System (FAERS) post-marketing database vary among biologics approved to treat moderate-to-severe psoriasis. Dermatol Ther (Heidelb). 2020;10(1):99-106. doi:10.1007/s13555-019-00341-2 [PubMed 31734937]Grasland A, Sterpu R, Boussoukaya S, Mahe I. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. Eur J Clin Pharmacol. 2012;68(5):895-898. doi:10.1007/s00228-011-1191-4 [PubMed 22205272]Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011;306(21):2331-2339. doi:10.1001/jama.2011.1692 [PubMed 22056398]Gulsen A, Wedi B, Jappe U. Hypersensitivity reactions to biologics (part II): classifications and current diagnostic and treatment approaches. Allergo J Int. 2020;29:139-154. doi:10.1007/s40629-020-00127-5Hammam N, Evans M, Morgan E, et al. Treatment of sarcoidosis in US rheumatology practices: data from the American College of Rheumatology's Rheumatology Informatics System for Effectiveness (RISE) Registry. Arthritis Care Res (Hoboken). 2022;74(3):371-376. doi:10.1002/acr.24496 [PubMed 33105057]Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33(11):2167-2172. [PubMed 16981296]Hansel K, Bianchi L, Tramontana M, et al. Immediate local and systemic hypersensitivity due to etanercept and adalimumab. J Allergy Clin Immunol Pract. 2019;7(2):726-727. doi:10.1016/j.jaip.2018.06.020 [PubMed 30006049]Hawryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. J Cutan Pathol. 2012;39(5):481-492. doi:10.1111/j.1600-0560.2012.01894.x [PubMed 22515220]Her M, Kavanaugh A. Alterations in immune function with biologic therapies for autoimmune disease. J Allergy Clin Immunol. 2016;137(1):19-27. doi:10.1016/j.jaci.2015.10.023 [PubMed 26768759]Hohlfeld R. Inhibitors of tumor necrosis factor-alpha: promising agents for the treatment of multiple sclerosis? Mult Scler. 1996;1(6):376-378. doi:10.1177/135245859600100619 [PubMed 9345421]Hulio (adalimumab) [product monograph]. Etobico*ke, Ontario, Canada: BGP Pharma ULC; August 2022.Hutto SK, Rice DR, Mateen FJ. CNS demyelination with TNFα inhibitor exposure: a retrospective cohort study. J Neuroimmunol. 2021;356:577587. doi:10.1016/j.jneuroim.2021.577587 [PubMed 33945946]Humira (adalimumab) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2021.Humira (adalimumab) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; March 2018.Humira (adalimumab) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; April 2021.Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology. 2012;143(2):365-374. [PubMed 22562021]Hyrimoz (adalimumab) [product monograph]. Boucherville, Québec, Canada: Sandoz Canada Inc; September 2021.Idacio (adalimumab) [product monograph]. Toronto, Ontario, Canada: Fresenius Kabi Canada Ltd; October 2020.Ingram JR. Hidradenitis suppurativa: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 14, 2021.Inoue A, Sawada Y, Yamaguchi T, et al. Lichenoid drug eruption caused by adalimumab: a case report and literature review. Eur J Dermatol. 2017;27(1):69-70. doi:10.1684/ejd.2016.2898 [PubMed 27777187]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-313. [PubMed 12534540]Juhász K, Buzás K, Duda E. Importance of reverse signaling of the TNF superfamily in immune regulation. Expert Rev Clin Immunol. 2013;9(4):335-348. doi:10.1586/eci.13.14 [PubMed 23557269]Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology. 2016;151(1):110-119. [PubMed 27063728]Kalinowska-Lyszczarz A, Fereidan-Esfahani M, Guo Y, Lucchinetti CF, Tobin WO. Pathological findings in central nervous system demyelination associated with infliximab. Mult Scler. 2020;26(9):1124-1129. doi:10.1177/1352458519894710 [PubMed 31845616]Kelly D, O'Connell O, Henry M. Adalimumab-induced lupus serositis. BMJ Case Rep. 2015;2015:bcr2014207323. Published 2015 Mar 4. doi:10.1136/bcr-2014-207323 [PubMed 25739794]Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers. Curr Neurol Neurosci Rep. 2017;17(4):36. doi:10.1007/s11910-017-0742-1 [PubMed 28337644]Kim E, Bressler B, Schaeffer DF, Yoshida EM. Severe cholestasis due to adalimumab in a Crohn's disease patient. World J Hepatol. 2013;5(10):592-595. doi:10.4254/wjh.v5.i10.592 [PubMed 24179620]Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016;375(5):422-434. doi:10.1056/NEJMoa1504370 [PubMed 27518661]Kingsbury DJ, Bader-Meunier B, Patel G, et al. Safety, effectiveness, and pharmaco*kinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years. Clin Rheumatol. 2014;33(10):1433–1441. [PubMed 24487484]Klarenbeek NB, van der Kooij SM, Huizinga TJ, et al. Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial. Ann Rheum Dis. 2010;69(7):1342-1345. doi:10.1136/ard.2009.124180 [PubMed 20472597]Kok B, Lester ELW, Lee WM, et al. Acute liver failure from tumor necrosis factor-α antagonists: report of four cases and literature review. Dig Dis Sci. 2018;63(6):1654-1666. doi:10.1007/s10620-018-5023-6 [PubMed 29564668]Koller T, Galambosova M, Filakovska S, et al. Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study. World J Gastroenterol. 2017;23(22):4102-4111. doi:10.3748/wjg.v23.i22.4102 [PubMed 28652663]Kotyla PJ. Bimodal function of anti-TNF treatment: shall we be concerned about anti-TNF treatment in patients with rheumatoid arthritis and heart failure? Int J Mol Sci. 2018;19(6):1739. doi:10.3390/ijms19061739 [PubMed 29895751]Kumar N, Abboud H. Iatrogenic CNS demyelination in the era of modern biologics. Mult Scler. 2019;25(8):1079-1085. doi:10.1177/1352458519828601 [PubMed 30767720]Kunchok A, Aksamit AJ Jr, Davis JM 3rd, et al. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77(8):937-946. doi:10.1001/jamaneurol.2020.1162 [PubMed 32421186]Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138(10):807-811. doi:10.7326/0003-4819-138-10-200305200-00008 [PubMed 12755552]Labetoulle R, Roblin X, Paul S. Prolonged persistence of adalimumab transferred from mother to infant during pregnancy. Ann Intern Med. 2018;169(1):60-61. [PubMed 29507939]Lan JL, Chen YM, Hsieh TY, et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2011;70(10):1719-1725. doi:10.1136/ard.2010.148783 [PubMed 21719446]Latus J, Klein R, Koetter I, et al. Cholestatic liver disease after rituximab and adalimumab and the possible role of cross-reacting antibodies to Fab 2 fragments. PLoS One. 2013;8(11):e78856. doi:10.1371/journal.pone.0078856 [PubMed 24244376]Lau G, Yu ML, Wong G, et al. APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021;15(5):1031-1048. doi:10.1007/s12072-021-10239-x [PubMed 34427860]Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis. 2009;68(7):1136-1145. doi:10.1136/ard.2008.091025 [PubMed 18753157]Li PH, Watts TJ, Lui MS, Lau CS, Chung HY. Recall urticaria in adalimumab hypersensitivity. J Allergy Clin Immunol Pract. 2018;6(3):1032-1033. doi:10.1016/j.jaip.2017.10.031 [PubMed 29175008]Li SJ, Perez-Chada LM, Merola JF. TNF Inhibitor-induced psoriasis: proposed algorithm for treatment and management. J Psoriasis Psoriatic Arthritis. 2019;4(2):70-80. doi:10.1177/2475530318810851 [PubMed 31093599]Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG clinical guideline: management of Crohn's disease in adults. Am J Gastroenterol. 2018;113(4):481-517. doi: 10.1038/ajg.2018.27. [PubMed 29610508]Lieberman MR, Liebman TN, Alapati U, Khachemoune A. TNF-inhibitor induced lupus in a patient treated with adalimumab for rheumatoid arthritis. Dermatol Online J. 2014;21(2):13030/qt18r2916d. [PubMed 25756476]Lok ASF, Bonis PAL. Hepatitis B virus reactivation associated with immunosuppressive therapy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed September 31, 2021.Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017;152(6):1297-1309. doi:10.1053/j.gastro.2017.02.009 [PubMed 28219691]Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810-820. [PubMed 18716298]Lower EE, Sturdivant M, Grate L, Baughman RP. Use of third-line therapies in advanced sarcoidosis. Clin Exp Rheumatol. 2020;38(5):834-840. [PubMed 31820728]Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Mahadevan U, Martin CF, Sandler RS et al. PIANO: A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142 (Suppl 1):S149.Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group. Am J Obstet Gynecol. 2019;220(4):308-323. doi:10.1016/j.ajog.2019.02.027 [PubMed 30948039]Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-92; quiz e24. doi:10.1016/j.cgh.2012.11.011 [PubMed 23200982]Mansitó López C, Torres Laboy P, Ortiz Bou M, Quintero Noriega A, Cintron Rivera V. Fatal new-onset congestive heart failure related to adalimumab use in a patient with relapsing hidradenitis suppurativa: a case report. Am J Case Rep. 2021;22:e929148. doi:10.12659/AJCR.929148 [PubMed 33563886]Marzano AV, Tavecchio S, Berti E, Gelmetti C, Cugno M. Pustular skin reaction to tumor necrosis factor alpha antagonists in patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2015;21(11):E26-E27. doi:10.1097/MIB.0000000000000600 [PubMed 26422518]Massarotti M, Marasini B. Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity. Int J Immunopathol Pharmacol. 2009;22(2):547-549. doi:10.1177/039463200902200234 [PubMed 19505409]Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure concentrations of infants breastfed by women receiving biologic therapies for inflammatory bowel diseases and effects of breastfeeding on infections and development. Gastroenterology. 2018;155(3):696-704. [PubMed 29857090]Matsui T, Umetsu R, Kato Y, et al. Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015. Int J Med Sci. 2017;14(2):102-109. doi:10.7150/ijms.17025 [PubMed 28260984]Mease P, Sieper J, Van den Bosch F, Rahman P, Karunaratne PM, Pangan AL. Randomized controlled trial of adalimumab in patients with nonpsoriatic peripheral spondyloarthritis. Arthritis Rheumatol. 2015;67(4):914-923. doi:10.1002/art.39008 [PubMed 25545240]Melani AS, Bigliazzi C, Cimmino FA, Bergantini L, Bargagli E. A comprehensive review of sarcoidosis treatment for pulmonologists. Pulm Ther. 2021;7(2):325-344. doi:10.1007/s41030-021-00160-x [PubMed 34143362]Melo FJ, Magina S. Clinical management of Anti-TNF-alpha-induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review. Int J Dermatol. 2018;57(12):1521-1532. doi:10.1111/ijd.14072 [PubMed 30028008]Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029-1072. doi:10.1016/j.jaad.2018.11.057 [PubMed 30772098]Mercer LK, Lunt M, Low AL, et al. Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2015;74(6):1087-1093. doi:10.1136/annrheumdis-2013-204851 [PubMed 24685910]Mocci G, Marzo M, Papa A, Armuzzi A, Guidi L. Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease. J Crohns Colitis. 2013;7(10):769-779. doi:10.1016/j.crohns.2013.01.009 [PubMed 23453887]Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862-2869. doi:10.1002/1529-0131(200112)44:12<2862::aid-art474>3.0.co;2-w [PubMed 11762947]Montolio Chiva L, Martínez Ferrer À, Mateu Puchades A, Campos Fernández C, Narváez Garcia J, Alegre Sancho JJ. Psoriasis induced by biological therapy. Reumatol Clin (Engl Ed). 2021;17(8):437-439. doi:10.1016/j.reumae.2020.06.003 [PubMed 34625145]Mounach A, Rezqi A, Nouijai A, et al. Stevens-Johnson syndrome complicating adalimumab therapy in rheumatoid arthritis disease. Rheumatol Int. 2013;33(5):1351-1353. doi:10.1007/s00296-011-2212-4 [PubMed 22187054]Moustou AE, Matekovits A, Dessinioti C, Antoniou C, Sfikakis PP, Stratigos AJ. Cutaneous side effects of anti-tumor necrosis factor biologic therapy: a clinical review. J Am Acad Dermatol. 2009;61(3):486-504. doi:10.1016/j.jaad.2008.10.060 [PubMed 19628303]Murdaca G, Spanò F, Contatore M, et al. Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety? Expert Opin Drug Saf. 2016;15(1):43-52. doi:10.1517/14740338.2016.1112375 [PubMed 26559805]Murdaca G, Spanò F, Puppo F. Selective TNF-α inhibitor-induced injection site reactions. Expert Opin Drug Saf. 2013;12(2):187-193. doi:10.1517/14740338.2013.755957 [PubMed 23330811]Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011;70(3):482-487. doi:10.1136/ard.2010.135871 [PubMed 21216812]Nakamizo S, Miyachi Y, Kabashima K. Addition of cyclosporine to adalimumab improved psoriasis and adalimumab-induced injection site reaction. Indian J Dermatol. 2014;59(5):522-523. doi:10.4103/0019-5154.139924 [PubMed 25284873]Navarro-Millán I, Yang S, DuVall SL, et al. Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration. Ann Rheum Dis. 2016;75(2):341-347. doi:10.1136/annrheumdis-2013-204987 [PubMed 25609412]Neves JM, Cunha N, Lencastre A, Cabete J. Paradoxical hidradenitis suppurativa to biologic agents: a case series and literature review. Int J Dermatol. 2019;58(11):e226-e228. doi:10.1111/ijd.14585 [PubMed 31290151]Nguyen GC, Loftus EV Jr, Hirano I, Falck-Ytter Y, Singh S, Sultan S; AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on the management of Crohn's disease after surgical resection. Gastroenterology. 2017;152(1):271-275. doi:10.1053/j.gastro.2016.10.038 [PubMed 27840074]Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52(2):412-420. doi:10.1002/art.20855 [PubMed 15692992]Nielsen OH, Gubatan JM, Juhl CB, Streett SE, Maxwell C. Biologics for inflammatory bowel disease and their safety in pregnancy: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2020:S1542-3565(20)31281-31287. doi:10.1016/j.cgh.2020.09.021 [PubMed 32931960]Page RL 2nd, O'Bryant CL, Cheng D, et al; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association [published correction appears in Circulation. 2016;134(12):e261]. Circulation. 2016;134(6):e32-e69. [PubMed 27400984]Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646. [PubMed 22235228]Paltiel M, Gober LM, Deng A, et al. Immediate type I hypersensitivity response implicated in worsening injection site reactions to adalimumab. Arch Dermatol. 2008;144(9):1190-1194. doi:10.1001/archderm.144.9.1190 [PubMed 18794465]Paramarta JE, De Rycke L, Heijda TF, et al. Efficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritis. Ann Rheum Dis. 2013;72(11):1793-1799. doi:10.1136/annrheumdis-2012-202245 [PubMed 23139265]Parekh R, Kaur N. Liver injury secondary to anti-TNF-alpha therapy in inflammatory bowel disease: a case series and review of the literature. Case Rep Gastrointest Med. 2014;2014:956463. doi:10.1155/2014/956463 [PubMed 24707412]Pariser RJ, Paul J, Hirano S, Torosky C, Smith M. A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis. J Am Acad Dermatol. 2013;68(5):765-773. doi:10.1016/j.jaad.2012.10.056 [PubMed 23276549]Pasadyn SR, Knabel D, Fernandez AP, Warren CB. Cutaneous adverse effects of biologic medications. Cleve Clin J Med. 2020;87(5):288-299. doi:10.3949/ccjm.87a.19119 [PubMed 32357984]Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res B Dev Reprod Toxicol. 2009;86(4):328-344. [PubMed 19626656]Picard M, Galvão VR. Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract. 2017;5(3):600-609. doi:10.1016/j.jaip.2016.12.001 [PubMed 28110056]Pugliese D, Guidi L, Ferraro PM, et al. Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study. Aliment Pharmacol Ther. 2015;42(7):880-888. doi:10.1111/apt.13352 [PubMed 26235565]Puxeddu I, Giori L, Rocchi V, et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol. 2012;108(2):123-124. doi:10.1016/j.anai.2011.11.004 [PubMed 22289732]Raaschou P, Frisell T, Askling J; ARTIS Study Group. TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis. 2015;74(12):2137-2143. doi:10.1136/annrheumdis-2014-205745 [PubMed 25107559]Rademaker M, Agnew K, Andrews M, et al. Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration. Australas J Dermatol. 2018;59(2):86-100. [PubMed 28543445]Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore). 2007;86(4):242-251. doi:10.1097/MD.0b013e3181441a68 [PubMed 17632266]Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, Cuadrado MJ, Khamashta MA; BIOGEAS Study Group. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010;9(3):188-193. doi:10.1016/j.autrev.2009.10.003 [PubMed 19854301]Refer to manufacturer's labeling.Rodrigues S, Lopes S, Magro F, et al. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol. 2015;21(24):7584-7588. doi:10.3748/wjg.v21.i24.7584 [PubMed 26140007]Rubin RL. Drug-induced lupus. Toxicology. 2005;209(2):135-147. doi:10.1016/j.tox.2004.12.025 [PubMed 15767026]Salomon BL, Leclerc M, Tosello J, Ronin E, Piaggio E, Cohen JL. Tumor necrosis factor α and regulatory T cells in oncoimmunology. Front Immunol. 2018;9:444. doi:10.3389/fimmu.2018.00444 [PubMed 29593717]Salvador-Rodriguez L, Montero-Vílchez T, Arias-Santiago S, Molina-Leyva A. Paradoxical hidradenitis suppurativa in patients receiving TNF-α inhibitors: case series, systematic review, and case meta-analysis. Dermatology. 2020;236(4):307-313. doi:10.1159/000506074 [PubMed 32135533]Schiff MH, Burmester GR, Kent JD, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(7):889-894. doi:10.1136/ard.2005.043166 [PubMed 16439435]Sedger LM, McDermott MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453-472. doi:10.1016/j.cytogfr.2014.07.016 [PubMed 25169849]Seow CH, Leung Y, Vande Casteele N, et al. The effects of pregnancy on the pharmaco*kinetics of infliximab and adalimumab in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45(10):1329-1338. [PubMed 28318043]Seror R, Richez C, Sordet C, et al. Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatology (Oxford). 2013;52(5):868-874. doi:10.1093/rheumatology/kes375 [PubMed 23287362]Shah P, Sundaram V, Björnsson E. Biologic and checkpoint inhibitor-induced liver injury: a systematic literature review. Hepatol Commun. 2020;4(2):172-184. doi:10.1002/hep4.1465 [PubMed 32025603]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. [PubMed 7746084]Shelton E, Chaudrey K, Sauk J, et al. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2015;41(10):972-979. doi:10.1111/apt.13159 [PubMed 25756190]Sieper J, van der Heijde D, Dougados M, et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis. 2013;72(6):815-822. doi:10.1136/annrheumdis-2012-201766 [PubMed 22772328]Simlandi (adalimumab) [product monograph]. Boucherville, Quebec, Canada: Pfizer Canada ULC; January 2022.Simonini G, Taddio A, Cattalini M, et al. Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab. Arthritis Care Res (Hoboken). 2011;63(4):612-618. doi:10.1002/acr.20404 [PubMed 21452272]Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625-639. doi:10.1002/acr.21641 [PubMed 22473917]Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2011(2):CD008794. doi:10.1002/14651858.CD008794.pub2 [PubMed 21328309]Singh S, Facciorusso A, Dulai PS, Jairath V, Sandborn WJ. Comparative risk of serious infections with biologic and/or immunosuppressive therapy in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2020;18(1):69-81.e3. doi:10.1016/j.cgh.2019.02.044 [PubMed 30876964]Solomon DH, Reed GW, Kremer JM, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol. 2015;67(6):1449-1455. doi:10.1002/art.39098 [PubMed 25776112]Sridhar S, Maltz RM, Boyle B, Kim SC. Dermatological manifestations in pediatric patients with inflammatory bowel diseases on anti-TNF therapy. Inflamm Bowel Dis. 2018;24(9):2086-2092. doi:10.1093/ibd/izy112 [PubMed 29718343]Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Acute and delayed hypersensitivity reactions to infliximab and adalimumab in a patient with Crohn's disease. J Crohns Colitis. 2012;6(1):108-111. doi:10.1016/j.crohns.2011.08.001 [PubMed 22261535]Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34(1):51-58. doi:10.1111/j.1365-2036.2011.04682.x [PubMed 21535447]Strangfeld A, Eveslage M, Schneider M, et al. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis. 2011;70(11):1914-1920. doi:10.1136/ard.2011.151043 [PubMed 21791449]Strangfeld A, Hierse F, Rau R, et al. Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res Ther. 2010;12(1):R5. doi:10.1186/ar2904 [PubMed 20064207]Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(1):46-54. [PubMed 24751453]Taylor TRP, Galloway J, Davies R, Hyrich K, Dobson R. Demyelinating events following initiation of anti-TNFα therapy in the British Society for Rheumatology Biologics Registry in Rheumatoid Arthritis. Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e992. doi:10.1212/NXI.0000000000000992 [PubMed 33863839]Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599. doi:10.1002/hep.29800 [PubMed 29405329]Thorne JE. Uveitis: treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 24, 2021.Titos Arcos JC, Hallal H, Robles M, Andrade RJ. Recurrent hepatotoxicity associated with etanercept and adalimumab but not with infliximab in a patient with rheumatoid arthritis. Rev Esp Enferm Dig. 2012;104(5):282-284. doi:10.4321/s1130-01082012000500014 [PubMed 22662786]Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;67(2):257-291. [PubMed 30044357]van Rheenen PF, Aloi M, Assa A, et al. The medical management of paediatric Crohn's disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis. Published online October 7, 2020. [PubMed 33026087]Vermeire S, Noman M, Van Assche G, et al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study. Gastroenterology. 2003;125(1):32-39. doi:10.1016/s0016-5085(03)00701-7 [PubMed 12851868]Wagner UG, Koetz K, Weyand CM, Goronzy JJ. Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1998;95(24):14447-14452. doi:10.1073/pnas.95.24.14447 [PubMed 9826720]Ward MM, Deodhar A, Gensler LS, et al. 2019 update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Care Res (Hoboken). 2019;71(10):1285-1299. doi:10.1002/acr.24025 [PubMed 31436026]Weizman AV, Nguyen GC, Seow CH, et al. Appropriateness of biologics in the management of Crohn's disease using RAND/UCLA appropriateness methodology. Inflamm Bowel Dis. 2019;25(2):328-335. doi: 10.1093/ibd/izy333. [PubMed 30346529]Williams EL, Gadola S, Edwards CJ. Anti-TNF-induced lupus. Rheumatology (Oxford). 2009;48(7):716-720. doi:10.1093/rheumatology/kep080 [PubMed 19416947]Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum. 2006;54(2):628-634. doi:10.1002/art.21568 [PubMed 16447241]Yanai H, Shuster D, Calabrese E, Mlynarsky L, Tumuluri S, Cohen RD. The incidence and predictors of lupus-like reaction in patients with IBD treated with anti-TNF therapies. Inflamm Bowel Dis. 2013;19(13):2778-2786. doi:10.1097/01.MIB.0000435435.91988.b6 [PubMed 24185311]Yuflyma (adalimumab) [product monograph]. Toronto, Ontario, Canada: Celltrion Healthcare Canada Limited; December 2021.Topic 8583 Version 388.0

CloseBaclofen: Pediatric drug informationBaclofen: Pediatric drug information(For additional information see "Baclofen: Drug information" and see "Baclofen: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningAbrupt withdrawal (injection): Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, which in rare cases has advanced to rhabdomyolysis, multiple organ-system failure, and death.Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Advise patients and caregivers of the importance of keeping scheduled refill visits and educate them on the early symptoms of baclofen withdrawal. Give special attention to patients at apparent risk (eg, spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information.Brand Names: USFleqsuvy;Gablofen;Lioresal;Lyvispah;OzobaxBrand Names: CanadaAPO-Baclofen;Baclofen-10;Baclofen-20;Lioresal DS [DSC];Lioresal Intrathecal;Lioresal [DSC];MYLAN-Baclofen;PMS-Baclofen;RATIO-Baclofen [DSC];RIVA-BaclofenTherapeutic CategorySkeletal Muscle Relaxant, NonparalyticDosing: PediatricNote: Gradual dose reduction is advised unless discontinuation is due to significant adverse effects or overdose-related emergencies; chronic oral baclofen therapy should be discontinued slowly (eg, over at least 1 to 2 weeks or longer if withdrawal symptoms occur) (Ref). Abrupt discontinuation of oral or intrathecal baclofen may result in severe adverse effects, including multiple organ system failure and death (Ref). Baclofen is available as both an oral solution and oral suspension; concentration varies by product; use extra caution during product selection and preparation and verify correct product/concentration is chosen.SpasticitySpasticity: Oral: Note: Dose-related side effects (eg, sedation) may be minimized by slow titration; lower initial doses than described below (2.5 to 10 mg administered daily) may be used with subsequent titration to 8 hourly doses (Ref).Infants ≥4 months and Children <2 years: Very limited data available: Oral: Usual dose: 10 to 20 mg/day in divided doses every 8 hours; begin at low end of range and titrate dose to patient response (Ref); titration intervals of every 7 days have been used in pediatric patients ≥2 years (Ref). Maximum daily dose: 40 mg/day (Ref). Dosing based on a retrospective study of 87 patients (age 9 ± 6 years; range: 0.4 to 23.5 years) with spasticity due to cerebral palsy or traumatic brain injury (Ref). Note: To minimize dose-related side effects (eg, sedation), lower initial doses (ie, 2.5 mg once to 3 times daily) may be considered and have been reported in pediatric patients >2 years (Ref).Children 2 to 7 years: Limited data available: Oral: Initial: 2.5 mg 3 times daily; titrate dose by 5 mg increments at weekly intervals to patient response; usual dose: 20 to 40 mg/day. Maximum daily dose: 60 mg/day (Ref). Note: Initial doses of 5 to 10 mg/day divided every 8 hours and more frequent titration intervals (ie, every 3 days) have also been described (Ref).Children ≥8 years and Adolescents: Limited data available in children <12 years: Oral: Initial: 5 mg 3 times daily; titrate dose to patient response every 3 to 7 days to usual dose of 30 to 40 mg/day; some patients ≥12 years may require every-6-hour dosing; maximum daily dose: 80 mg/day (Ref). Note: Lower initial doses (5 to 10 mg/day) have also been described (Ref). Higher maximum daily doses (up to 200 mg/day) have been described in some patients in a retrospective review; usually the higher doses were needed over time (Ref).Intrathecal: Note: Dosage adjustments may be required often during the first few months of therapy to adjust for lifestyle changes due to alleviation of spasticity. Maintain lowest dose that produces adequate response. Most patients require gradual increases over time to maintain optimal response. Sudden large requirements for a dose increase may indicate a catheter complication (eg, kink, dislodgement). Titrate dose to allow sufficient muscle tone and occasional spasms to optimize activities of daily living, support circulation, and possibly prevent deep vein thrombosis (DVT) formation. Use extreme caution when filling the pump; follow manufacturer instructions carefully. With chronic therapy, 5% to 10% of patients will become refractory to dose adjustments; may consider a drug holiday (hospitalized patients only) with a gradual withdrawal over 2 to 4 weeks and use of alternative spasticity management methods. Following the drug holiday, intrathecal baclofen may be resumed at the initial continuous infusion dose. Limited data available in children <4 years; dosing for this age group based on expert consensus recommendations (Ref).Screening dose: Children <4 years: Limited data available: Intrathecal: Initial: 25 mcg; if response is inadequate, double the initial dose and administer 24 hours after the first dose (Ref).Children ≥4 years and Adolescents: Intrathecal: Initial: 50 mcg (1 mL) for 1 dose; for patients considered very small for age, a 25 mcg initial screening dose may be considered; following administration of screening dose, observe patient for 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. If response is inadequate, may increase screening dose in 25 mcg increments every 24 hours until a 4- to 8-hour positive clinical response is demonstrated or 100 mcg/dose is given. Patients not responding to screening dose of 100 mcg should not be considered for chronic infusion/implanted pump (Ref).Initial dose titration following pump implant: Children and Adolescents: After positive response to screening dose, a maintenance intrathecal infusion can be administered via an implanted intrathecal pump.Initial total daily dose via pump: Children and Adolescents: Intrathecal: Double the screening dose that gave a positive response and administer over 24 hours, unless efficacy of the bolus dose was maintained for >8 hours or if negative reactions to the screening test dose (change in mental status, loss of function, or change in vital signs) occurred, then infuse a dose equivalent to the screening dose over 24 hours (Ref).Do not increase dose in first 24 hours (to allow steady state to be achieved); thereafter, increase daily dose slowly by 5% to 15% once every 24 hours until satisfactory response is achieved; usual range: 50 to 100 mcg daily (Ref).Maintenance dose titration (Ref):Children and Adolescents: Intrathecal:Inpatient titration: Daily dose may be increased periodically (eg, during pump refills) by 10% to 20% of dose; usual dose change is 50 mcg; maximum increment change: 100 mcg. Note: At lower doses, a 20% increase may be reasonable, but at higher doses a 20% increase may be excessive. Daily dose may be decreased by 10% to 20% for adverse effects.Outpatient titration: Daily dose may be increased periodically (eg, during pump refills) by 5% to 10% of daily dose (usual dose change is 25 mcg). Daily dose may be decreased by 10% to 20% for adverse effects.Usual maintenance dose: Children and Adolescents: Intrathecal: 100 to 2,000 mcg daily (Ref); the manufacturer provides the following:Children 4 to 12 years: Intrathecal: 24 to 1,199 mcg daily (average: 274 mcg/day).Children ≥12 years and Adolescents: Intrathecal: 90 to 703 mcg daily; daily doses have ranged from 22 to 1,400 mcg; experience with doses >1,000 mcg daily is limited.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricOral: There are no dosage adjustments provided in the manufacturer's labeling; however, baclofen is primarily renally eliminated; use with caution; dosage reduction may be necessary.Intrathecal: Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, baclofen is primarily renally eliminated; use with caution; dosage reduction may be necessary.Dosing: Hepatic Impairment: PediatricOral, Intrathecal: There are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Baclofen: Drug information")Note: Gradual dose reduction is advised unless discontinuation is due to significant adverse effects or overdose-related emergencies; chronic oral baclofen therapy should be discontinued over at least 1 to 2 weeks or longer if withdrawal symptoms occur (Ref). Abrupt discontinuation of oral or intrathecal baclofen may result in severe adverse effects, including multiple organ-system failure and death.HiccupsHiccups (off-label use):Oral: Initial: 5 to 10 mg 3 times daily; may increase dose based on response and tolerability; usual maximum dose: 45 mg/day in divided doses (Ref).Muscle spasm and/or musculoskeletal painMuscle spasm and/or musculoskeletal pain (adjunctive therapy) (off-label use):Note: For skeletal muscle spasm and/or pain (eg, low back pain, neck pain) with muscle spasm, usually in combination with a nonsteroidal anti-inflammatory drug and/or acetaminophen (Ref). In general, muscle relaxants should be used temporarily (eg, for a few days or intermittently for a few days when needed) (Ref).Oral: Initial: 5 to 10 mg 3 times daily as needed (Ref).SpasticitySpasticity: Oral:Granules: Initial: 5 mg 3 times daily; may increase by 5 mg per dose every 3 days based on response and tolerability; maximum dose: 80 mg per day (20 mg 4 times per day).Solution, tablet: Initial: 5 mg 1 to 3 times daily; may increase by 5 mg per dose every 3 days based on response and tolerability; usual maximum dose: 80 mg/day in divided doses. Some patients may require doses up to 120 mg/day (Ref).Suspension: Initial: 5 mg (1 mL) 3 times daily; may increase by 5 mg (1 mL) per dose every 3 days based on response and tolerability; usual maximum dose: 80 mg (16 mL) per day (20 mg [4 mL] 4 times per day).Intrathecal:Note: Use extreme caution when filling the pump; follow manufacturer instructions.Screening dose: Initial bolus: 50 mcg over ≥1 minute then observe patient for 4 to 8 hours. A positive response consists of a significant decrease in muscle tone, frequency, and/or severity of spasms. If response is inadequate, may give 75 mcg as a second screening dose 24 hours after the first dose; observe patient for 4 to 8 hours. If response is still inadequate, may administer 100 mcg as a final screening dose 24 hours after the second dose. Patients not responding to screening dose of 100 mcg should not be considered for chronic infusion via implanted pump.Initial total daily continuous infusion dose via implanted pump:If screening dose provided positive response for >4 hours but <8 hours: Double the screening dose that gave a positive response and administer over 24 hours.If screening dose provided positive response for >8 hours: Infuse a dose equivalent to the screening dose over 24 hours.Initial titration after pump implantation: Do not increase dose in first 24 hours to allow steady state to be achieved; thereafter, initial dosage adjustments may be made by increasing daily dose by 10% to 30% (spasticity of spinal cord origin) or by 5% to 15% (spasticity of cerebral origin) once every 24 hours until satisfactory response.Maintenance dose and titration: Daily dose may be increased periodically (eg, during pump refills) by 10% to 40% (maximum increase: 40%) for spasticity of spinal cord origin or by 5% to 20% (maximum increase: 20%) for spasticity of cerebral origin. Dose may also be decreased 10% to 20% for adverse effects. Most patients have been adequately maintained on 300 to 800 mcg daily (spasticity of spinal cord origin) or 90 to 703 mcg daily (spasticity of cerebral origin). Experience with doses >1,000 mcg daily is limited.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function:Oral:The following dosage adjustments have been recommended (Ref): Note: Kidney function may be estimated using the co*ckcroft-Gault formula for dosage adjustment purposes.CrCl >80 mL/minute: No dosage adjustment necessary.CrCl 50 to 80 mL/minute: Initial: 5 mg every 12 hours; titrate cautiously to effect; do not exceed 50 mg/day or ~66% of the usual maximum daily dose, whichever is less.CrCl 30 to <50 mL/minute: Initial: 2.5 mg every 8 hours; titrate cautiously to effect; do not exceed 40 mg/day or ~50% of the usual maximum daily dose, whichever is less.CrCl <30 mL/minute: Avoid use; in some patients, even low initial doses for short duration have led to toxicity (Ref). If baclofen use cannot be avoided, initiate at a low dose (eg, 2.5 mg every 12 hours or less); titrate with extreme caution to effect; do not exceed 20 mg/day or ~33% of the usual maximum daily dose, whichever is less.Intrathecal: Mild to severe impairment: There are no specific dosage adjustments recommended. However, baclofen is primarily eliminated by the kidney; use with caution; dosage reduction may be necessary.Hemodialysis, intermittent (thrice weekly): Dialyzable (1 case report of 79% removal with a 4-hour session) (Ref):Oral, intrathecal: Avoid use. Numerous case reports and 1 population-based cohort study have demonstrated significant adverse events related to chronic maintenance dosing and unintentional overdoses (Ref). If baclofen use cannot be avoided, initiate at a low dose (eg, 2.5 mg orally every 12 hours or less); titrate with extreme caution to effect (Ref).Peritoneal dialysis:Oral, intrathecal: Avoid use. Baclofen clearance by peritoneal dialysis has not been characterized. Multiple case reports have reported hospitalization for encephalopathy (Ref). If baclofen use cannot be avoided, initiate at a low dose (eg, 2.5 mg orally every 12 hours or less); titrate with extreme caution to effect (Ref).CRRT:Oral, intrathecal: Avoid use. If baclofen use cannot be avoided, initiate at a low dose; titrate cautiously to effect (expert opinion). Note: CRRT data are primarily limited to the treatment of acute baclofen intoxication, which have demonstrated significant increases in baclofen clearance (Ref). However, because CRRT is often used short term and in acutely ill patients, dose increases in response to increased clearance are not recommended unless clinically indicated (eg, increased spasticity) (Ref).PIRRT (eg, sustained, low-efficiency diafiltration):Oral, intrathecal: Avoid use. Pharmaco*kinetics of baclofen in patients receiving PIRRT have not been well characterized (Ref).Dosing: Hepatic Impairment: AdultOral and intrathecal: There are no dosage adjustments provided in the manufacturer’s labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Packet, Oral: Lyvispah: 5 mg (90 ea); 10 mg (90 ea); 20 mg (90 ea) [contains saccharin sodium]Solution, Intrathecal: Generic: 10 mg/20 mL (20 mL); 40 mg/20 mL (20 mL); 20,000 mcg/20 mL (20 mL)Solution, Intrathecal [preservative free]: Gablofen: 10,000 mcg/20 mL (20 mL); 20,000 mcg/20 mL (20 mL) [antioxidant free]Gablofen: 40,000 mcg/20 mL (20 mL)Lioresal: 0.05 mg/mL (1 mL); 40 mg/20 mL (20 mL) [antioxidant free]Lioresal: 10 mg/20 mL (20 mL); 10 mg/5 mL (5 mL) [antioxidant free, pyrogen free]Generic: 10 mg/20 mL (20 mL); 40 mg/20 mL (20 mL); 20,000 mcg/20 mL (20 mL)Solution, Oral: Ozobax: 5 mg/5 mL (473 mL) [contains methylparaben, propylparaben; grape flavor]Generic: 5 mg/5 mL (473 mL)Solution Prefilled Syringe, Intrathecal [preservative free]: Gablofen: 50 mcg/mL (1 mL) [antioxidant free, latex free]Gablofen: 20,000 mcg/20 mL (20 mL) [antioxidant free]Gablofen: 10,000 mcg/20 mL (20 mL); 40,000 mcg/20 mL (20 mL) [antioxidant free, pyrogen free]Generic: 50 mcg/mL (1 mL)Suspension, Oral: Fleqsuvy: 25 mg/5 mL (120 mL, 300 mL) [contains fd&c red #40 (allura red ac dye), propylene glycol, quinoline yellow (d&c yellow #10), sodium benzoate]Tablet, Oral: Generic: 5 mg, 10 mg, 20 mgGeneric Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intrathecal: Lioresal Intrathecal: 500 mcg/mL (20 mL); 2000 mcg/mL (5 mL); 0.05 mg/mL (1 mL)Generic: 500 mcg/mL (20 mL); 0.05 mg/mL (1 mL); 2 mg/mL (5 mL, 20 mL)Tablet, Oral: Lioresal: 10 mg [DSC]Lioresal DS: 20 mg [DSC]Generic: 10 mg, 20 mgDosage Forms ConsiderationsFirst-Baclofen suspension is a compounding kit. Refer to manufacturer’s labeling for compounding instructions.Administration: PediatricOral: Administer without regard to meals. If nausea occurs, may administer with food or milk (Ref).Oral liquid: Baclofen is available as both an oral solution and oral suspension; concentration varies by product; use extra caution during product selection and preparation and verify correct product/concentration is chosen. When using oral liquid product, administer with a calibrated measuring device; do not use a household teaspoon (overdosage may occur).Oral suspension: Shake well prior to administration.Oral granules: Contents of packet may be emptied into the mouth and swallowed or may be mixed with up to 15 mL of liquid or soft food (eg, applesauce, yogurt, pudding). If mixing with food, entire mixture should be consumed within 2 hours of mixing. If multiple packets are needed to complete dose, each packet must be mixed with separate volume of liquid or food.Administration via feeding tube: Oral granules may be administered by NG tube ≥8 French, gastrostomy tubes (G tube) ≥12 French, percutaneous endoscopic gastrostomy (PEG) tube ≥14 French, or gastrojejunostomy (GJ) tube ≥16 French. Prior to administration, flush feeding tube with up to 15 mL of water using a catheter tip syringe. Empty contents of 1 packet into 15 mL of liquid (eg apple juice or milk) and mix until granules wetted. Draw up suspension of granules/liquid into dosing syringe and administer via feeding tube. Using same syringe, flush the feeding tube with 15 mL of water after administration. Repeat process if multiple packets are needed to complete a dose. If dosing syringe is allowed to stand for ≥15 minutes prior to administration, invert syringe 3 times to ensure baclofen is mixed; administration must be completed within 2 hours of initial mixing.Parenteral: Intrathecal: Screening dosage: Administer as a bolus injection by barbotage into the subarachnoid space over at least 1 minute, followed by maintenance infusion via implantable infusion pump; do not abruptly discontinue intrathecal baclofen administration. Do not administer intrathecal formulation IV, IM, SUBQ, or epidurally.Administration: AdultIntrathecal: For screening dosages, administer as a bolus injection (50 mcg/mL concentration) by barbotage into the subarachnoid space over at least 1 minute, followed by maintenance continuous infusion. Do not administer intrathecal formulation IV, IM, SUBQ, or epidurally.Oral:Granules: Contents of packet may be emptied into the mouth and swallowed or may be mixed with up to 15 mL of liquid or soft food (eg, applesauce, yogurt, pudding). If mixing with food, entire mixture should be consumed within 2 hours of mixing. If multiple packets are needed to complete dose, each packet must be mixed with separate volume of liquid or food.Solution, suspension: Administer without regards to meals. Shake suspension well; use a calibrated measuring device to administer; do not use a household teaspoon or tablespoon.Feeding tube: Oral granules may be administered by NG tube ≥8 French, gastrostomy tubes (G tube) ≥12 French, percutaneous endoscopic gastrostomy (PEG) tube ≥14 French, or gastrojejunostomy (GJ) tube ≥16 French. Prior to administration, flush feeding tube with up to 15 mL of water using a catheter tip syringe. Empty contents of 1 packet into 15 mL of liquid (eg, apple juice, milk) and mix until granules are wetted. Draw up suspension of granules/liquid into dosing syringe and administer via feeding tube. Using same syringe, flush the feeding tube with 15 mL of water after administration. Repeat process if multiple packets are needed to complete a dose. If dosing syringe is allowed to stand for ≥15 minutes prior to administration, invert syringe 3 times to ensure baclofen is mixed; administration must be completed within 2 hours of initial mixing.Storage/StabilityInjection: Do not store above 30°C (86°F). Does not require refrigeration. Do not freeze or heat sterilize. Discard any unused solution.Oral granules: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).Oral solution: Store refrigerated at 2°C to 8°C (36°F to 46°F). Dispense in a light-resistant container.Oral suspension: Store at 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F). Discard any unused portion 2 months after first opening.Tablets: Store at 20°C to 25°C (68°F to 77°F).UseOral: Tablets, granules (eg, Lyvispah), solution (eg, Ozobax), suspension (eg, Fleqsuvy): Management of reversible spasticity associated with multiple sclerosis or spinal cord lesions (FDA approved in ages ≥12 years and adults).Intrathecal: Management of severe spasticity of spinal cord origin (eg, spinal cord injury, multiple sclerosis) or cerebral origin (eg, cerebral palsy, traumatic brain injury); may also be considered as an alternative to destructive neurosurgical procedures (Gablofen, Lioresal: FDA approved in ages ≥4 years and adults). Note: Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long-term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy.Medication Safety IssuesSound-alike/look-alike issues:Baclofen may be confused with BactrobanLioresal may be confused with lisinopril, LotensinHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication (intrathecal administration) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.Administration issues:Different concentrations of the oral liquid are available; ensure appropriate strength and dose of oral liquid prior to administering, dispensing, and prescribing.Adverse Reactions (Significant): ConsiderationsCNS effectsCNS effects may include confusion, dizziness, drowsiness, sedation, asthenia, nausea, and vomiting (Ref). CNS effects may impair physical or mental abilities and be additive to alcohol and other CNS depressants (eg, opioids, benzodiazepines). Multiple cases describing neurotoxicity due to oral baclofen accumulation in adult patients with varying levels of renal impairment have been reported in the literature. In one study of 6,469 older adults on dialysis (360 receiving baclofen), 7.2% of patients started on baclofen were hospitalized for encephalopathy (median time to hospitalization of 3 days) compared to <0.1% of patients not receiving baclofen (Ref).Mechanism: Dose-related; related to the pharmacologic action. Reduces the release of excitatory neurotransmitters by binding to the GABA-B presynaptic receptors within the brain stem, dorsal horn of the spinal cord, and other CNS sites (Ref).Risk factors:• Oral doses >60 mg/day (Ref)• Oral (vs intrathecal) administration (Ref)• Severe kidney dysfunction (eGFR <30 mL/minute/1.73m2) (Ref)Withdrawal effectsIntrathecal baclofen: Abrupt withdrawal of intrathecal baclofen has been associated with altered mental status, exaggerated rebound spasticity, high fever, and muscle rigidity (which in rare cases has advanced to rhabdomyolysis, multiple organ-system failure, and death) (Ref).Oral baclofen: Abrupt withdrawal of oral baclofen has been associated with altered mental status, exaggerated rebound spasticity, hallucination, high fever, hypertension, hyperthermia, muscle rigidity, tachycardia, and seizure. Other symptoms include agitation, confusion, delusions, insomnia, and paranoid ideation (Ref). Neonatal withdrawal has also been reported in neonates whose mothers were treated with oral baclofen throughout pregnancy (Ratnayaka 2001).Mechanism: Withdrawal; related to the release of excitatory neurotransmitters (Ref).Onset: Rapid; symptoms appear within hours to a few days following interruption of intrathecal therapy (Ref) and within 12 to 72 hours after discontinuation of oral therapy (Ref). Neonatal withdrawal has been reported within hours to days after delivery.Risk factors:• Pump malfunction or removal (eg, battery failure, catheter displacement, infection, intrathecal mass) (Ref)• Preventable human errors (eg, programming or pump refill errors, oral baclofen administration or refill errors) (Ref)• Patients with spinal cord injuries at T-6 or above, communication difficulties, or history of withdrawal symptoms from intrathecal or oral baclofenAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Gastrointestinal: Nausea (≤12%), vomiting (≤11%)Nervous system: Asthenia (≤15%), confusion (≤11%), dizziness (2% to 15%), drowsiness (≤63%), headache (2% to 11%), hypotonia (2% to 35%)1% to 10%:Cardiovascular: Hypotension (≤9%), peripheral edema (2% to 3%)Dermatologic: Pruritus (4%), urticaria (≤1%)Gastrointestinal: Constipation (≤6%), diarrhea (≤2%), sialorrhea (3%), xerostomia (≤3%)Genitourinary: Difficulty in micturition (2%), impotence (≤2%), urinary frequency (≤6%), urinary incontinence (≤2%), urinary retention (≤8%)Nervous system: Abnormality in thinking (≤1%), agitation (≤1%), chills (≤1%), coma (≤2%), depression (2%), fatigue (2% to 4%), insomnia (≤7%), pain (≤4%), paresthesia (≤7%), seizure (≤10%), speech disturbance (≤4%), tremor (≤1%)Neuromuscular & skeletal: Back pain (≤2%)Ophthalmic: Amblyopia (≤2%)Respiratory: Dyspnea (≤1%), hypoventilation (≤4%), pneumonia (≤2%)Miscellaneous: Accidental injury (≤4%)<1%:Cardiovascular: Ankle edema (Bence 2014), bradycardia (Rifici 2011; Sechrist 2015), chest pain, hypertension, palpitations, syncope, vasodilationDermatologic: Alopecia, contact dermatitis, dermal ulcer, hyperhidrosis, skin rash (Pathak 2019; Saddichha 2011)Endocrine & metabolic: Weight gain (Hemingway 2001; Yang 2013)Gastrointestinal: Abdominal pain (Chen 1997), anorexia, dysgeusia, dysphagia, fecal incontinence, gastrointestinal hemorrhage, occult blood in stools, tongue irritationGenitourinary: Dysuria, hematuria, inhibited ejacul*tion (Saval 2008), nocturia, oliguria, vaginitisHematologic & oncologic: Carcinoma, leukocytosis (Gee 2016), petechial rashNervous system: Akathisia (Karol 2011), amnesia (Grande 2008; Zeman 2016), anxiety, ataxia (Porter 2017), dysarthria, dysautonomia, dystonia, euphoria (Das 2016; Ghosh 2017), excitement, hallucination, hyporeflexia, hypothermia (Singh 2009), hysteria, malaise, opisthotonus, personality disorder, slurred speechNeuromuscular & skeletal: Muscle rigidity, myalgiaOphthalmic: Accommodation disturbance, blurred vision, diplopia, miosis, mydriasis, nystagmus disorder, strabismusOtic: Tinnitus (Auffret 2014)Renal: NephrolithiasisRespiratory: Apnea (Locatelli 2019; Olivier 2016), hyperventilation, nasal congestionMiscellaneous: Fever (can be high fever with drug withdrawal)Frequency not defined:Endocrine & metabolic: Increased serum glucoseHepatic: Increased serum alkaline phosphatase, increased serum aspartate aminotransferaseNervous system: Withdrawal syndromePostmarketing:Cardiovascular: Deep vein thrombophlebitis (Carda 2008), pulmonary embolism (Carda 2008)Endocrine & metabolic: Decreased libido (Hornyak 2005), weight loss (Arima 2010)Gastrointestinal: Intestinal obstruction (Karthikeyan 2015), paralytic ileus (Morant 2006)Genitourinary: Erectile dysfunction (Denys 1998), org*sm disturbance (Hornyak 2005; Saval 2008), priapism, sexual disorder (McGehee 2006; Saval 2008)Nervous system: Delirium (Chauvin 2020), disorientation (Chauvin 2020), neonatal withdrawal (Ratnayaka 2001), suicidal ideation (Pelissier 2017; WeiBhaar 2012), transient ischemic attacks (Chauvin 2020)Neuromuscular & skeletal: Scoliosis (Panagopoulos 2020), scoliosis progression (Ginsburg 2007; Walker 2017)ContraindicationsHypersensitivity to baclofen or any component of the formulationIntrathecal formulation: IV, IM, SubQ, or epidural administrationWarnings/PrecautionsConcerns related to adverse effects:• Intrathecal mass: Cases (most from pharmacy compounded preparations) of intrathecal mass formation at the implanted catheter tip have been reported; patients may experience worsening or return of spasticity, pain, inadequate response to dose adjustments, and/or neurological deficit/dysfunction. Neurosurgical evaluation and/or an appropriate imaging study should be considered if a mass is suspected.• Urinary retention: May cause acute urinary retention (may be related to underlying disease); use with caution in patients with urinary obstruction.Disease-related concerns:• Autonomic dysreflexia: Use with caution in patients with a history of autonomic dysreflexia; presence of nociceptive stimuli or abrupt baclofen withdrawal may cause an autonomic dysreflexic episode.• Gastrointestinal disorders: Use with caution in patients with peptic ulcer disease, decreased GI motility, and/or GI obstructive disorders.• Psychiatric disease: Use with caution in patients with psychotic disorders, schizophrenia, or confusional states; may cause exacerbation of condition.• Renal impairment: Use with caution in patients with renal impairment; baclofen is eliminated primarily unchanged via the kidneys.• Respiratory disease: Use with caution in patients with respiratory disease.• Seizure disorder: Loss of seizure control has been reported in patients treated with baclofen; use with caution and monitor patients with a history of seizure disorder.Special populations:• Older adult: Use with caution in elderly patients; may be more sensitive to adverse CNS effects, especially at higher doses.• Neonates: Neonatal withdrawal symptoms (eg, increased muscle tone, jitteriness, tremor, seizure), beginning hours to days after delivery, have been reported in neonates born to mothers treated with baclofen throughout pregnancy.• Pediatric: Intrathecal: Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion.Dosage form specific issues:• Oral products: Multiple products available; ensure appropriate strength and dose of the oral formulation prior to administering, dispensing, and prescribing; oral suspension is a concentrated formulation.Other warnings/precautions:• Appropriate use: Intrathecal: For use only in an FDA-approved implantable pump for intrathecal baclofen administration; health care providers should be experienced with chronic intrathecal infusion therapy and resuscitative equipment should be readily available. Ensure patient is infection-free and then evaluate patient's response to bolus intrathecal injection (screening phase) prior to implanting pump. Monitor closely during the initial phase of pump use and when adjusting the dosing rate and/or the concentration in the reservoir. Educate patients and caregivers on proper home care of the pump and insertion site. Use extreme caution when filling an implantable pump; pumps should only be refilled through the reservoir refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Some pumps are equipped with a catheter access port that allows direct access to the intrathecal catheter; direct injection into this catheter access port or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose. Except in overdose related emergencies, intrathecal baclofen should be reduced slowly if discontinuation is necessary.• Appropriate use: Oral: Efficacy of oral baclofen has not been established in patients with Parkinson disease or cerebral palsy; therefore, use is not recommended. Use caution in patients with a history of stroke; poor tolerability to baclofen without significant benefit has been observed. Not indicated for spasticity associated with rheumatic disorders. Use with caution when spasticity is utilized to sustain upright posture and balance in locomotion, or when spasticity is necessary to obtain increased function.• Overdose: Intrathecal use: Monitor closely for signs and symptoms of overdose, which may appear suddenly or insidiously, especially during the initial screening and dose-titration phase of treatment, and during reintroduction of therapy after a period of interruption. Signs/symptoms of overdose may include drowsiness, dizziness, somnolence, hypothermia, respiratory depression, seizures, rostral progression of hypotonia, and loss of consciousness progressing to coma. If overdose is suspected, patient should be evaluated immediately in a hospital setting and the pump reservoir emptied.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAlcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).Risk C: Monitor therapyAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBotulinum Toxin-Containing Products: Muscle Relaxants (Centrally Acting) may enhance the adverse/toxic effect of Botulinum Toxin-Containing Products. Specifically, the risk for increased muscle weakness may be enhanced.Risk C: Monitor therapyBrexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyCNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapyDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDoxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants isnot recommended. Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationEsketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLacidipine: Baclofen may enhance the hypotensive effect of Lacidipine.Risk C: Monitor therapyLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMetoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPerampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPiribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil.Risk C: Monitor therapyPramipexole: CNS Depressants may enhance the sedative effect of Pramipexole.Risk C: Monitor therapyProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole.Risk C: Monitor therapyRotigotine: CNS Depressants may enhance the sedative effect of Rotigotine.Risk C: Monitor therapyRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationTolperisone: May enhance the adverse/toxic effect of Muscle Relaxants (Centrally Acting). Management: Monitor for increased sedation or CNS effects if tolperisone is combined with other centrally acting muscle relaxants. Consider decreasing the tolperisone dose if these agents are combined. Risk D: Consider therapy modificationTrimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyUrapidil: Baclofen may enhance the hypotensive effect of Urapidil.Risk C: Monitor therapyValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationPregnancy ConsiderationsLate-onset neonatal withdrawal may occur following in utero exposure. Feeding difficulties, high-pitched cry, hyperthermia, hypertonicity, loose stools, tremors, and seizures have been reported in newborns following maternal use of oral baclofen throughout pregnancy (Duncan 2013; Freeman 2016; Ratnayaka 2001). Use of intrathecal baclofen in pregnant females has been described (Dalton 2008; Hara 2018; Méndez-Lucena 2016; Tandon 2010). Maternal plasma concentrations following administration of intrathecal baclofen are significantly less than those with oral doses; exposure to the fetus is expected to be limited and adverse neonatal events have not been noted in available reports (Morton 2009).Monitoring ParametersMonitor for signs and symptoms of baclofen withdrawal (eg, altered mental status, exaggerated rebound spasticity, hallucinations, high fever, hypertension, hyperthermia, muscle rigidity, tachycardia, seizure, agitation, confusion, delusions, insomnia, paranoid ideation). Consider EEG in patients with epilepsy if clinically indicated (decreased seizure threshold has been reported). Monitor closely for signs and symptoms of overdose (eg, drowsiness, dizziness, somnolence, hypothermia, respiratory depression, seizures, rostral progression of hypotonia, loss of consciousness progressing to coma), which may appear suddenly or insidiously, especially during the initial screening and dose-titration phase of treatment, and during reintroduction of therapy after a period of interruption.Mechanism of ActionInhibits the transmission of both monosynaptic and polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals, with resultant relief of muscle spasticityPharmaco*kinetics (Adult data unless noted)Onset of action: Intrathecal bolus: 30 minutes to 1 hour; Continuous infusion: 6 to 8 hours after infusion initiation.Peak effect: Intrathecal bolus: 4 hours (effects may last 4 to 8 hours); Continuous infusion: 24 to 48 hours.Absorption (dose dependent): Oral: Rapid; absorption from the GI tract is thought to be dose dependent; in pediatric patients (age range: 2 to 17 years) with cerebral palsy, absorption from GI tract highly variable and delayed (reported time lag: 0.59 ± 0.28 hours) (He 2014).Bioavailability: Oral: 74% (Agarwal 2015).Protein binding: 30%.Distribution: Volume of distribution: Pediatric patients (age range: 2 to 17 years: Oral: Highly variable: 1.16 L/kg with 43.5% interindividual variability (He 2014).Metabolism: Hepatic (15% of dose) (He 2014).Half-life elimination:Oral:Pediatric patients with cerebral palsy (age range: 2 to 17 years): 4.5 hours (He 2014).Adults: Granules: 5.5 hours; Solution: 5.7 hours; Suspension: ~5.6 hours; Tablets: 3.75 ± 0.96 hours (Brunton 2011).Intrathecal: CSF elimination half-life: 1.51 hours over the first 4 hours.Time to peak, serum: Oral: 1 hour (0.5 to 4 hours) (Brunton 2011); Suspension: 1 hour.Excretion: Urine (>70% as unchanged drug) and feces (Brunton 2011).Extemporaneous PreparationsNote: Baclofen is commercially available as 1 mg/mL or 5 mg/mL oral suspension (First-Baclofen compounding kit [1 mg/mL or 5 mg/mL]; Fleqsurvy 5 mg/mL) or as a 1 mg/mL oral solution (Ozobax). Compounded oral suspension may be available in multiple concentrations (eg, up to 10 times more concentrated); use caution to avoid confusion; verify concentration.5 mg/mL Oral Suspension (ASHP Standard Concentration) (ASHP 2017)A 5 mg/mL oral suspension may be made with tablets. Crush thirty 20 mg tablets in a mortar and reduce to a fine powder. Add a small amount of glycerin and mix to a uniform paste. Mix while adding Simple Syrup, NF in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add a sufficient quantity of vehicle to make 120 mL. Label “shake well” and “refrigerate.” Stable for 35 days (Johnson 1993).Johnson CE, Hart SM. Stability of an extemporaneously compounded baclofen oral liquid. Am J Hosp Pharm. 1993;50(11):2353-2355.826696110 mg/mL Oral Suspension: Note: Commercially available suspension is more dilute (eg, up to 10 times more dilute); use caution to avoid confusion; verify concentrations.A 10 mg/mL oral suspension may be made with tablets. Crush one-hundred-twenty 10 mg tablets in a mortar and reduce to a fine powder. Add small portions (60 mL) of a 1:1 mixture of Ora-Sweet and Ora-Plus and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “refrigerate.” Stable for 60 days (Allen 1996).Allen LV Jr, Erickson MA 3rd. Stability of baclofen, captopril, diltiazem hydrochloride, dipyridamole, and flecainide acetate in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1996;53(18):2179-2184.8879325Pricing: USPack (Lyvispah Oral)5 mg (per each): $11.0010 mg (per each): $11.0020 mg (per each): $22.00Solution (Baclofen Intrathecal)10 mg/20 mL (per mL): $7.08 - $11.6040 mg/20 mL (per mL): $28.38 - $46.39Solution (Baclofen Oral)5 mg/5 mL (per mL): $1.31Solution (Gablofen Intrathecal)10000 mcg/20 mL (per mL): $14.1820000 mcg/20 mL (per mL): $28.3540000 mcg/20 mL (per mL): $56.71Solution (Lioresal Intrathecal)0.05 mg/mL (per mL): $39.5610 mg/20 mL (per mL): $14.1810 mg/5 mL (per mL): $56.7140 mg/20 mL (per mL): $56.71Solution (Ozobax Oral)5 mg/5 mL (per mL): $2.07Solution Prefilled Syringe (Baclofen Intrathecal)50 mcg/mL (per mL): $52.80Solution Prefilled Syringe (Gablofen Intrathecal)50 mcg/mL (per mL): $105.5010000 mcg/20 mL (per mL): $15.2320000 mcg/20 mL (per mL): $30.4640000 mcg/20 mL (per mL): $61.00Suspension (Fleqsuvy Oral)25 mg/5 mL (per mL): $6.60Tablets (Baclofen Oral)5 mg (per each): $0.34 - $1.2410 mg (per each): $0.14 - $2.4720 mg (per each): $0.16 - $5.13Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalBaclan (IN, KR);Baclofen-ratiopharm (LU);Baclofene (FR);Baclon (FI, LK, TW);Baclopar (IE);Baclosal (IL, LV);Baclosan (RU);Baclosol (VN);Bacmax (IN);Bacofen (KR);Bacron (KR);Bamifen (VN);Barapa (KR);Bathecal (AU);Clofen (AU);Colmifen (MT, SG);Curofen (KR);Diafen (PY, UY);Espast (PE);Flexibac (LK);Gabalon (JP);Gablofen (NL);Liobac (TH);Liofen (IN);Lionova (DK, NO, SE);Liorel (BD);Lioresal (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CN, CO, CY, CZ, DE, DK, EE, ES, ET, FI, FR, GB, GH, GM, GN, GR, GY, HK, HR, HU, ID, IE, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KW, LB, LK, LR, LU, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, NZ, OM, PH, PK, PL, PT, PY, QA, RO, RU, SA, SC, SD, SE, SG, SI, SL, SN, SR, SY, TH, TN, TR, TT, TZ, UG, VE, YE, ZA, ZM, ZW);Lioresyl (CL);Liosal (BD);Lyflex (GB, IE);Miorel (GR);Mulax (TW);Mylinax (CR, DO, GT, HN, NI, PA, SV);Mylobac (EG);Myorel (LK);Onelaxant-R (PH);Pacifen (NZ, TW);Prex (KR);Skelofen (BD);Slaken (BD);Solofen (TW);Spinax (CN, TW);Stelax (AU, HK);Trilaxant (PH);Yylofen (VN);Zufen (CN)For country code abbreviations (show table)Agarwal SK, Kriel RL, Cloyd JC, et al. A pilot study assessing pharmaco*kinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers. J Child Neurol. 2015;30(1):37-41. doi:10.1177/0883073814535504 [PubMed 25028414]Aisen ML, Dietz M, McDowell F, Kutt H. Baclofen toxicity in a patient with subclinical renal insufficiency. Arch Phys Med Rehabil. 1994;75(1):109-111. [PubMed 8291951]Alden TD, Lytle RA, Park TS, Noetzel MJ, Ojemann JG. Intrathecal baclofen withdrawal: a case report and review of the literature. Childs Nerv Syst. 2002;18(9-10):522-525. doi:10.1007/s00381-002-0634-8 [PubMed 12382179]Al-Khodairy AT, Vuagnat H, Uebelhart D. Symptoms of recurrent intrathecal baclofen withdrawal resulting from drug delivery failure: a case report. Am J Phys Med Rehabil. 1999;78(3):272-277. doi:10.1097/00002060-199905000-00018 [PubMed 10340425]Alstermark C, Amin K, Dinn SR, et al. Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors. J Med Chem. 2008;51(14):4315-4320. doi:10.1021/jm701425k [PubMed 18578471]Alvis BD, Sobey CM. Oral baclofen withdrawal resulting in progressive weakness and sedation requiring intensive care admission. Neurohospitalist. 2017;7(1):39-40. doi:10.1177/1941874416637404 [PubMed 28042369]American Pain Society (APS). Principles of Analgesic Use. 7th ed. American Pain Society; 2016.Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]Arima H, Oiso Y. Positive effect of baclofen on body weight reduction in obese subjects: a pilot study. Intern Med. 2010;49(19):2043-2047. doi:10.2169/internalmedicine.49.3918 [PubMed 20930428]ASHP. Standardize 4 Safety Initiative Compounded Oral Liquid Version 1.01. July 2017. https://www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/s4s-ashp-oral-compound-liquids.ashx?la=en&hash=4C2E4F370B665C028981B61F6210335AD5D0D1D6.Auffret M, Rolland B, Deheul S, et al; CAMTEA Team. Severe tinnitus induced by off-label baclofen. Ann Pharmacother. 2014;48(5):656-659. doi:10.1177/1060028014525594 [PubMed 24577148]Baclofen tablet [prescribing information]. Memphis, TN: Northstar Rx LLC; October 2020.Baclofen tablets [prescribing information]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; April 2021.Baclofen tablets [prescribing information]. Amityville, NJ: Innogenix LLC; June 2021.Based on expert opinion.Bence C, Cottencin O, Deheul S, Gautier S, Bordet R, Rolland B. Baclofen-induced edema in alcohol use disorders. J Clin Pharmacol. 2014 ;54(4):478-481. doi:10.1002/jcph.233 [PubMed 24293402]Berweck S, Lütjen S, Voss W, et al. Use of intrathecal baclofen in children and adolescents: interdisciplinary consensus table 2013. Neuropediatrics. 2014;45(5):294-308. [PubMed 25188830]Boster AL, Adair RL, Gooch JL, et al. Best practices for intrathecal baclofen therapy: dosing and long-term management. Neuromodulation. 2016;19(6):623-631. doi:10.1111/ner.12388 [PubMed 27433993]Boz C, Velioglu S, Bulbul I, Ozmenoglu M. Baclofen is effective in intractable hiccups induced by brainstem lesions. Neurol Sci. 2001;22(5):409. [PubMed 11917982]Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill Medical; 2011.Carda S, Cazzaniga M, Taiana C, Pozzi R. Intrathecal baclofen bolus complicated by deep vein thrombosis and pulmonary embolism. A case report. Eur J Phys Rehabil Med. 2008;44(1):87-88. [PubMed 18385632]Chauvin KJ, Blake PG, Garg AX, et al. Baclofen has a risk of encephalopathy in older adults receiving dialysis. Kidney Int. 2020;S0085-2538(20)30552-4. doi:10.1016/j.kint.2020.04.047 [PubMed 32450156]Chen KS, Bullard MJ, Chien YY, Lee SY. Baclofen toxicity in patients with severely impaired renal function. Ann Pharmacother. 1997;31(11):1315-1320. doi:10.1177/106002809703101108 [PubMed 9391686]Chen YC, Chang CT, Fang JT, Huang CC. Baclofen neurotoxicity in uremic patients: is continuous ambulatory peritoneal dialysis less effective than intermittent hemodialysis? Ren Fail. 2009;25(2):297-305. doi:10.1081/jdi-120018730 [PubMed 12739836]Choo YM, Kim GB, Choi JY, et al. Severe respiratory depression by low-dose baclofen in the treatment of chronic hiccups in a patient undergoing CAPD. Nephron. 2000;86(4):546-547. doi:10.1159/000045866 [PubMed 11124626]Chou CL, Chen CA, Lin SH, Huang HH. Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hiccups. South Med J. 2006;99(11):1308-1309. doi:10.1097/01.smj.0000247632.84949.27 [PubMed 17195438]Chou R, Deyo R, Friedly J, et al. Systemic pharmacologic therapies for low back pain: a systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med. 2017;166(7):480-492. doi:10.7326/M16-2458 [PubMed 28192790]Committee on Safety of Medicines (CSM), Medicines Control Agency. Reminder: severe withdrawal reactions with baclofen. Curr Probl Pharmacovigilance. 1997;23:1-4. https://webarchive.nationalarchives.gov.uk/20090218060434/http://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con2023229.pdfDalton CM, Keenan E, Jarrett L, Buckley L, Stevenson VL. The safety of baclofen in pregnancy: intrathecal therapy in multiple sclerosis. Mult Scler. 2008;14(4):571-572. doi: 10.1177/1352458507085552 [PubMed 18562512]Dapas F, Hartman SF, Martinez L, et al. Baclofen for the treatment of acute low-back syndrome. A double-blind comparison with placebo. Spine (Phila Pa 1976). 1985;10(4):345-349. doi:10.1097/00007632-198505000-00010 [PubMed 2931831]Dario A, Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity. Drug Saf. 2004;27(11):799-818. doi:10.2165/00002018-200427110-00004 [PubMed 15350152]Das S, Palappalllil DS, Purushothaman ST, Rajan V. An unusual case of baclofen abuse. Indian J Psychol Med. 2016;38(5):475-476. doi:10.4103/0253-7176.191383 [PubMed 27833235]Denys P, Mane M, Azouvi P, Chartier-Kastler E, Thiebaut JB, Bussel B. Side effects of chronic intrathecal baclofen on erection and ejacul*tion in patients with spinal cord lesions. Arch Phys Med Rehabil. 1998;79(5):494-496. doi:10.1016/s0003-9993(98)90061-2 [PubMed 9596387]Duncan SD, Devlin LA. Use of baclofen for withdrawal in a preterm infant. J Perinatol. 2013;33(4):327-328. doi:10.1038/jp.2012.107 [PubMed 23536044]El-Husseini A, Sabucedo A, Lamarche J, Courville C, Peguero A. Baclofen toxicity in patients with advanced nephropathy: proposal for new labeling. Am J Nephrol. 2011;34(6):491-495. doi:10.1159/000333247 [PubMed 22041434]Eriksson G, Swahn CG. Concentrations of baclofen in serum and breast milk from a lactating woman. Scand J Clin Lab Invest. 1981;41(2):185-187. doi:10.3109/00365518109092032 [PubMed 7313501]Fleqsuvy (baclofen) [prescribing information]. Wilmington, MA: Azurity Pharmaceuticals Inc; February 2022.Freeman EH, Delaney RM. Neonatal baclofen withdrawal: A case report of an infant presenting with severe feeding difficulties. J Pediatr Nurs. 2016;31(3):346-349. doi:10.1016/j.pedn.2015.12.004. [PubMed 26810267]Gablofen (baclofen) [prescribing information]. Bethlehem, PA: Primal Critical Care Inc; October 2020.Galvez-Jimenez N. Symptom-based management of amyotrophic lateral sclerosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 6, 2022.Gee SW, Outsen S, Becknell B, Schwaderer AL. Baclofen toxicity responsive to hemodialysis in a pediatric patient with acute kidney injury. J Pediatr Intensive Care. 2016;5(1):37-40. doi:10.1055/s-0035-1568151. [PubMed 31110881]Ghosh S, Bhuyan D. Baclofen abuse due to its hypomanic effect in patients with alcohol dependence and comorbid major depressive disorder. Clin Psychopharmacol Neurosci. 2017;15(2):187-189. doi:10.9758/cpn.2017.15.2.187 [PubMed 28449569]Ginsburg GM, Lauder AJ. Progression of scoliosis in patients with spastic quadriplegia after the insertion of an intrathecal baclofen pump. Spine (Phila Pa 1976). 2007;32(24):2745-2750. doi:10.1097/BRS.0b013e31815a5219 [PubMed 18007255]Goyal V, Laisram N, Wadhwa RK, Kothari SY. Prospective randomized study of oral diazepam and baclofen on spasticity in cerebral palsy. J Clin Diagn Res. 2016;10(6):RC01-RC5. doi:10.7860/JCDR/2016/17067.7975 [PubMed 27504360]Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg. 2008;106(4):1284-1287, table of contents. doi:10.1213/ane.0b013e318165e1c6 [PubMed 18349207]Grant JA, Steiner EM, Johnson RH. Treatment of persistent hiccups. J Neurol Neurosurg Psychiatry. 1991;54(5):468. doi:10.1136/jnnp.54.5.468 [PubMed 1865216]Greenberg MI, Hendrickson RG. Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. J Toxicol Clin Toxicol. 2003;41(1):83-85. doi:10.1081/clt-120018277 [PubMed 12645974]Guelaud C, Similowski T, Bizec JL, Cabane J, Whitelaw WA, Derenne JP. Baclofen therapy for chronic hiccup. Eur Respir J. 1995;8(2):235-237. doi:10.1183/09031936.95.08020235 [PubMed 7758557]Hadjiyannacos D, Vlassopoulos D, Hadjiconstantinou V. Treatment of intractable hiccup in haemodialysis patients with baclofen. Am J Nephrol. 2001;21(5):427-8. doi:10.1159/000046290 [PubMed 11684810]Hara T, Nakajima M, Sugano H, et al. Pregnancy and breastfeeding during intrathecal baclofen therapy - a case study and review. NMC Case Rep J. 2018;5(3):65-68. doi:10.2176/nmccrj.cr.2017-0191 [PubMed 30023142]He Y, Brunstrom-Hernandez JE, Thio LL, et al. Population pharmaco*kinetics of oral baclofen in pediatric patients with cerebral palsy. J Pediatr. 2014;164(5):1181-1188.Hemingway C, McGrogan J, Freeman JM. Energy requirements of spasticity. Dev Med Child Neurol. 2001;43(4):277-278. doi:10.1017/s0012162201000524 [PubMed 11305407]Hornyak JE, McGehee MJ, Kelly B, Lin C. Oral baclofen as a cause of sexual dysfunction: A report of 2 cases. Archives of Physical Medicine and Rehabilitation. 2005;86(9):E39, Poster 197. https://www.archives-pmr.org/action/showPdf?pii=S0003-9993%2805%2900809-9Isaac Z. Management of non-radicular neck pain in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. doi:10.1056/NEJM200007133430208 [PubMed 10891521]Karol DE, Muzyk AJ, Preud'homme XA. A case of delirium, motor disturbances, and autonomic dysfunction due to baclofen and tizanidine withdrawal: a review of the literature. Gen Hosp Psychiatry. 2011;33(1):84.e1-e2. doi:10.1016/j.genhosppsych.2010.10.003 [PubMed 21353141]Karthikeyan VS, Senthilkumaran K, Easwaran B, Rajbhaskar R. Intestinal pseudo-obstruction following oral baclofen: An unusual complication. J Pharmacol Pharmacother. 2015;6(3):169-171. doi:10.4103/0976-500X.162010 [PubMed 26312004]Katsinelos P, Pilpilidis J, Xiarchos P, et al. Baclofen therapy for intractable hiccups induced by ultraflex esophageal endoprosthesis. Am J Gastroenterol. 2000;95(10):2986-2987. doi:10.1111/j.1572-0241.2000.03216.x [PubMed 11051387]Khazneh E, Shamlawi A, Jebrin K, Hamdan Z, Sawalmeh O. Single-dose baclofen-induced neurotoxicity in a patient with end stage renal disease: case report. BMC Nephrol. 2018;19(1):352. doi:10.1186/s12882-018-1167-z [PubMed 30537935]Lee J, Shin HS, Jung YS, Rim H. Two cases of baclofen-induced encephalopathy in hemodialysis and peritoneal dialysis patients. Ren Fail. 2013;35(6):860-862. doi:10.3109/0886022X.2013.794679 [PubMed 23682655]Lin HH, Barton N, Wiegand TJ. Baclofen distribution into breast milk - a potential for toxicity? J Med Toxicol. 2014;10:86.Lioresal Intrathecal (baclofen) [prescribing information]. Roswell, GA: Saol Therapeutics Inc; January 2019.Lioresal Intrathecal (baclofen) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; May 2020.Lioresal tablets (baclofen) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; May 2020.Locatelli F, Formica F, Galbiati S, et al. Polysomnographic analysis of a pediatric case of baclofen-induced central sleep apnea. J Clin Sleep Med. 2019;15(2):351-354. doi:10.5664/jcsm.7644 [PubMed 30736882]Lois F, Wallemacq P, de Tourtchaninoff M, et al. Prolonged unconsciousness in a patient on automated peritoneal dialysis. Eur J Emerg Med. 2006;13(6):361-363. doi:10.1097/01.mej.0000217992.32235.ff [PubMed 17091060]Lubsch L, Habersang R, Haase M, Luedtke S. Oral baclofen and clonidine for treatment of spasticity in children. J Child Neurol. 2006;21(12):1090-1092. doi:10.1177/7010.2006.00134 [PubMed 17156708]Lyvispah (baclofen) [prescribing information]. Roswell, GA: Saol Therapeutics Inc; November 2021.Marino RA. Baclofen therapy for intractable hiccups in pancreatic carcinoma. Am J Gastroenterol. 1998;93(10):2000. doi: 10.1111/j.1572-0241.1998.02000.x [PubMed 9772082]McGehee M, Hornyak JE, Lin C, Kelly BM. Baclofen-induced sexual dysfunction. Neurology. 2006;67(6):1097-1098. doi:10.1212/01.wnl.0000237332.25528.ac [PubMed 17000991]Medical Advisory Secretariat. Intrathecal baclofen pump for spasticity: an evidence-based analysis. Ont Health Technol Assess Ser. 2005;5(7):1-93. [PubMed 23074476]Méndez-Lucena C, Chacón Peña J, García-Moreno JM. Intrathecal baclofen for dystonia treatment during pregnancy: a case report. Neurologia. 2016;31(2):131-132. doi:10.1016/j.nrl.2014.04.008 [PubMed 24851698]Meulendijks D, Khan S, Koks CH, Huitema AD, Schellens JH, Beijnen JH. Baclofen overdose treated with continuous venovenous hemofiltration. Eur J Clin Pharmacol. 2015;71(3):357-361. doi:10.1007/s00228-014-1802-y [PubMed 25567218]Milla PJ, Jackson AD. A controlled trial of baclofen in children with cerebral palsy. J Int Med Res. 1977;5(6):398-404. doi:10.1177/030006057300100203 [PubMed 338390]Mirijello A, Addolorato G, D'Angelo C, et al. Baclofen in the treatment of persistent hiccup: a case series. Int J Clin Pract. 2013;67(9):918-921. doi:10.1111/ijcp.12184 [PubMed 23834241]Mohammed I, Hussain A. Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: a case report. BMC Clin Pharmacol. 2004;4:6. doi:10.1186/1472-6904-4-6 [PubMed 15301690]Morant A, Noé E, Boyer J, et al. Paralytic ileus: a complication after intrathecal baclofen therapy. Brain Inj. 2006;20(13-14):1451-1454. doi:10.1080/02699050601082016 [PubMed 17378237]Morton CM, Rosenow J, Wong C, Kirschner KL. Intrathecal baclofen administration during pregnancy: a case series and focused clinical review. PM R. 2009;1(11):1025-1029. doi:10.1016/j.pmrj.2009.07.010 [PubMed 19942189]Olek MJ, Narayan RM, Frohman EM, Frohman TC. Symptom management of multiple sclerosis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 6, 2022.Olivier PY, Joyeux-Faure M, Gentina T, et al. Severe central sleep apnea associated with chronic baclofen therapy: A case series. Chest. 2016;149(5):e127-e131. doi:10.1016/j.chest.2015.10.001 [PubMed 27157226]O'Rourke F, Steinberg R, Ghosh P, Khan S. Withdrawal of baclofen may cause acute confusion in elderly patients. BMJ. 2001;323(7317):870. [PubMed 11597980]Ozobax (baclofen) [prescribing information]. Athens, GA: Metacel Pharmaceuticals LLC; May 2020.Panagopoulos D, Apostolopoulou K, Themistocleous M. Severe neuromuscular scoliosis implicated by dysfunction of intrathecal baclofen pump: Case report and review of the literature. World Neurosurg. 2020;134:390-395. doi:10.1016/j.wneu.2019.11.027 [PubMed 31733394]Pathak LK, Athavale A, Martinez I. Baclofen-induced toxicity in renal disease with neurotoxicity and skin rash. Proc (Bayl Univ Med Cent). 2019;32(3):425-426. doi:10.1080/08998280.2019.1618659 [PubMed 31384209]Peces R, Navascués RA, Baltar J, Laurés AS, Alvarez-Grande J. Baclofen neurotoxicity in chronic haemodialysis patients with hiccups. Nephrol Dial Transplant. 1998;13(7):1896-1897. [PubMed 9681766]Pelissier F, de Haro L, Cardona F, et al. Self-poisoning with baclofen in alcohol-dependent patients: national reports to French Poison Control Centers, 2008-2013. Clin Toxicol (Phila). 2017;55(4):275-284. doi:10.1080/15563650.2017.1284330 [PubMed 28152635]Porter LM, Merrick SS, Katz KD. Baclofen toxicity in a patient with hemodialysis-dependent end-stage renal disease. J Emerg Med. 2017;52(4):e99-e100. doi:10.1016/j.jemermed.2016.09.025 [PubMed 27789113]Quality Standards Subcommittee of the American Academy of Neurology (AAN) and the Practice Committee of the Child Neurology Society, Delgado MR, Hirtz D, Aisen M, et al. Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2010;74(4):336-343. doi: 10.1212/WNL.0b013e3181cbcd2f [PubMed 20101040]Ratnayaka BD, Dhaliwal H, Watkin S. Drug points: Neonatal convulsions after withdrawal of baclofen. BMJ. 2001;323(7304):85. doi:10.1136/bmj.323.7304.85 [PubMed 11451783]Refer to manufacturer's labeling.Reis PV, Vieira CR, Midões AC, Rebelo V, Barbosa P, Gomes A. Intrathecal baclofen infusion pumps in the treatment of spasticity: A retrospective cohort study in a Portuguese Centre. Acta Med Port. 2019;32(12):754-759. doi:10.20344/amp.10482 [PubMed 31851884]Rifici C, D'Aleo G, D'Aleo P, Bramanti P, Saltuari L, Kofler M. Cardiovascular alterations heralded by intrathecal baclofen bolus. NeuroRehabilitation. 2011;28(4):389-393. doi:10.3233/NRE-2011-0668 [PubMed 21725173]Riva-baclofen (baclofen) [product monograph]. Blainville, Canada: Laboratoire Riva Inc; July 2020.Roberts JK, Westphal S, Sparks MA. Iatrogenic Baclofen neurotoxicity in ESRD: recognition and management. Semin Dial. 2015;28(5):525-529. doi:10.1111/sdi.12400. [PubMed 26096760]Saddichha S, Jayaram N, Manjunatha N, Benegal V. Baclofen-induced morbiliform rashes: a case series. J Clin Pharmacol. 2011;51(12):1733-1734. doi:10.1177/0091270010385936 [PubMed 21119092]Salim SA, Thomas L, Achanti A, et al. Baclofen-induced neurotoxicity in patients with compromised renal function: Review. Int J Clin Pharmacol Ther. 2018;56(10):467-475. doi:10.5414/CP203243 [PubMed 12769509]Saulino M, Anderson DJ, Doble J, et al. Best practices for intrathecal baclofen therapy: Troubleshooting. Neuromodulation. 2016;19(6):632-641. doi:10.1111/ner.12467 [PubMed 27434299]Saval A, Chiodo AE. Sexual dysfunction associated with intrathecal baclofen use: a report of two cases. J Spinal Cord Med. 2008;31(1):103-105. doi:10.1080/10790268.2008.11753989 [PubMed 18533420]Scheinberg A, Hall K, Lam LT, O'Flaherty S. Oral baclofen in children with cerebral palsy: a double-blind cross-over pilot study. J Paediatr Child Health. 2006;42(11):715-20. doi:10.1111/j.1440-1754.2006.00957.x [PubMed 17044900]Sechrist C, Kinsman S, Cain N. Profound bradycardia after intrathecal baclofen injection in a patient with hydranencephaly. Pediatr Neurol. 2015;53(6):532-534. doi:10.1016/j.pediatrneurol.2015.08.010 [PubMed 26411756]Seker MM, Aksoy S, Ozdemir NY, et al. Successful treatment of chronic hiccup with baclofen in cancer patients. Med Oncol. 2012;29(2):1369-1370. doi:10.1007/s12032-011-9910-3 [PubMed 21442315]Siegfried RN, Jacobson L, Chabal C. Development of an acute withdrawal syndrome following the cessation of intrathecal baclofen in a patient with spasticity. Anesthesiology. 1992;77(5):1048-1050. doi:10.1097/00000542-199211000-00034 [PubMed 1443727]Singh NK, Agarwal A, Salazar L, Henkle JQ. Osborn waves in hypothermia induced by baclofen overdose. BMJ Case Rep. 2009;2009:bcr10.2008.1142. doi:10.1136/bcr.10.2008.1142 [PubMed 21686448]Su W, Yegappan C, Carlisle EJ, Clase CM. Reduced level of consciousness from baclofen in people with low kidney function. BMJ. 2009;339:b4559. doi:10.1136/bmj.b4559 [PubMed 20044395]Swigar ME, Bowers MB. Baclofen withdrawal and neuropsychiatric symptoms: a case report and review of other case literature. Compr Psychiatry. 1986;27(4):396-400. doi:10.1016/0010-440x(86)90016-7 [PubMed 3731773]Tandon SS, Hoskins I, Azhar S. Intrathecal baclofen pump - a viable therapeutic option in pregnancy. Obstet Med. 2010;3(3):119-120. doi:10.1258/om.2010.100016 [PubMed 27576877]Turkyilmaz A, Eroglu A. Use of baclofen in the treatment of esophageal stent-related hiccups. Ann Thorac Surg. 2008;85(1):328-330. doi:10.1016/j.athoracsur.2007.07.059 [PubMed 18154840]van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM; Cochrane Back Review Group. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane Collaboration. Spine (Phila Pa 1976). 2003;28(17):1978-1992. doi:10.1097/01.BRS.0000090503.38830.AD [PubMed 12973146]Vlavonou R, Perreault MM, Barrière O, et al. Pharmaco*kinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations. J Clin Pharmacol. 2014;54(5):584-592. doi:10.1002/jcph.247 [PubMed 24414993]Walker KR, Novotny SA, Krach LE. Does intrathecal baclofen therapy increase prevalence and/or progression of neuromuscular scoliosis? Spine Deform. 2017;5(6):424-429. doi:10.1016/j.jspd.2017.03.006 [PubMed 29050720]Weißhaar GF, Hoemberg M, Bender K, et al. Baclofen intoxication: a "fun drug" causing deep coma and nonconvulsive status epilepticus--a case report and review of the literature. Eur J Pediatr. 2012;171(10):1541-1547. doi:10.1007/s00431-012-1780-y [PubMed 22729246]Wolf E, Kothari NR, Roberts JK, Sparks MA. Baclofen toxicity in kidney disease. Am J Kidney Dis. 2018;71(2):275-280. doi:10.1053/j.ajkd.2017.07.005 [PubMed 28899601]Wu VC, Lin SL, Lin SM, Fang CC. Treatment of baclofen overdose by haemodialysis: a pharmaco*kinetic study. Nephrol Dial Transplant. 2005;20(2):441-443. doi:10.1093/ndt/gfh297 [PubMed 15615812]Yang TF, Wang JC, Chiu JW, Lai CJ, Chan RC, Lee SS. Ultrasound-guided refilling of an intrathecal baclofen pump--a case report. Childs Nerv Syst. 2013;29(2):347-349. doi: 10.1007/s00381-012-1953-z [PubMed 23129445]Zeman A, Hoefeijzers S, Milton F, Dewar M, Carr M, Streatfield C. The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report. Cortex. 2016;74:9-19. doi:10.1016/j.cortex.2015.10.005 [PubMed 26599496]Zhang C, Zhang R, Zhang S, Xu M, Zhang S. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial. Trials. 2014;15:295. doi:10.1186/1745-6215-15-295 [PubMed 25052238]Topic 12983 Version 602.0

CloseTestosterone: Drug informationTestosterone: Drug information(For additional information see "Testosterone: Patient drug information" and see "Testosterone: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Special AlertsREMS Drugs COVID-19 Safety AlertMarch 2020Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.ALERT: US Boxed WarningBlood pressure increases (oral testosterone undecanoate; SUBQ testosterone enanthate)Testosterone undecanoate and testosterone enanthate can cause blood pressure (BP) increases that can increase the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke and cardiovascular death, with greater risk for MACE in patients with cardiovascular risk factors or established cardiovascular disease. Before initiating, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled. Starting approximately 3 weeks (testosterone undecanoate) or 6 weeks (testosterone enanthate) after initiating therapy or changing the dose, periodically monitor for and treat new-onset hypertension or exacerbations of preexisting hypertension and reevaluate whether the benefits of testosterone undecanoate or testosterone enanthate outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease while on treatment. Due to this risk, use oral testosterone undecanoate or subcutaneous testosterone enanthate only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies.Secondary exposure (transdermal gel, transdermal solution):Virilization has been reported in children who were secondarily exposed to topical testosterone gel and solution. Children should avoid contact with unwashed or unclothed application sites in men using topical testosterone.Advise patients to strictly adhere to recommended instructions for use.Pulmonary oil microembolism (intramuscular testosterone undecanoate):Serious pulmonary oil microembolism (POME) reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of testosterone undecanoate injection. These reactions can occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose.Following each injection, observe patients in the health care setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis.Because of the risks of serious POME reactions and anaphylaxis, testosterone undecanoate is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Aveed REMS Program.Brand Names: USAndroderm;AndroGel;AndroGel Pump;Aveed;Depo-Testosterone;Fortesta;Jatenzo;Kyzatrex;Natesto;Striant [DSC];Testim;Testopel;Tlando;Vogelxo;Vogelxo Pump;XyostedBrand Names: CanadaAndroderm [DSC];AndroGel;Delatestryl;Depo-Testosterone;Natesto;PMS-Testosterone Undecanoate;TARO-Testosterone;TARO-Testosterone Cypionate;TestimPharmacologic CategoryAndrogenDosing: AdultNote: Striant (buccal formulation) has been discontinued in the United States for >1 year.Note: Testosterone enanthate IM formulation and testosterone enanthate SUBQ formulation are not interchangeable. Oral testosterone undecanoate products are not interchangeable.Hormone therapy for transgender malesHormone therapy for transgender males (assigned female at birth) (off-label use):IM(testosterone enanthate or testosterone cypionate): 100 to 200 mg every 2 weeks or 50 to 100 mg every week (ES [Hembree 2017]).SUBQ(testosterone enanthate or testosterone cypionate): 50 to 100 mg every week (ES [Hembree 2017]; Spratt 2017).Topical:Gel (1% or 1.62%): 50 to 100 mg daily (ES [Hembree 2017]; Tangpricha 2022).Transdermal system (Androderm): 2 to 8 mg/day (Safer 2019).Dosage adjustment: May adjust dose after ≥3 months based on clinical response and serum testosterone levels (ES [Hembree 2017]).Hypogonadism, maleHypogonadism, male (primary or hypogonadotropic): Initial dosage and usual dosage range are based on dosage form as follows:Testosterone Dosing Regimens for Male HypogonadismAdministration routePreparationInitial dosageUsual dosage rangea Striant (buccal formulation) has been discontinued in the United States for >1 year.b Dosing for this formulation is from the following sources: AUA (Mulhall 2018), ES (Bhasin 2018).c Canadian product.dAndroGel 1% may also be applied to the abdomen.e For the testosterone 1% gel and Vogelxo pump formulations, 1 pump actuation = 12.5 mg.f Maximum dose according to manufacturers of Testim and Vogelxo.g For the AndroGel 1.62% pump formulation, 1 pump actuation = 20.25 mg.h Administer the 6 mg/day dosage as one 2 mg/day patch and one 4 mg/day patch.BuccalBuccal system (Striant)a30 mg applied twice daily (every 12 hours) to the gum region above the incisor toothIMSolution (testosterone enanthate, testosterone cypionate)75 to 100 mg once weekly or 150 to 200 mg every 2 weeksb50 to 100 mg once weekly or 100 to 200 mg every 2 weeksbSolution (testosterone undecanoate)750 mg; repeat 750 mg dose after 4 weeks, and then every 10 weeks thereafterIntranasalGel (Natesto)11 mg (2 pump actuations; 1 actuation per nostril) 3 times daily (6 to 8 hours apart)OralCapsule (Jatenzo)237 mg twice daily158 to 396 mg twice dailyCapsule (Kyzatrex)200 mg twice daily100 mg once daily or 100 to 400 mg twice daily (maximum: 800 mg/day)Capsule (Tlando)225 mg twice dailyCapsule (testosterone undecanoate)c120 to 160 mg/day in 2 divided doses for 2 to 3 weeks40 to 120 mg/daySUBQ (injection)Solution (Xyosted)75 mg once weekly50 to 100 mg once weeklySUBQ (implantation)Pellet (Testopel)150 to 450 mg every 3 to 6 monthsTopical1% Gel (eg, AndroGel 1%, Testim, Vogelxo)50 mg applied once daily in the morning to the shoulders and/or upper armsd,e50 to 100 mg/day (maximum: 100 mg/day)e,f1.62% Gel (eg, AndroGel 1.62%)40.5 mg applied once daily in the morning to the shoulders and upper armsg20.25 to 81 mg/day (maximum: 81 mg/day)g2% Gel (eg, Fortesta)40 mg (4 pump actuations) applied once daily in the morning to the thighs10 to 70 mg/day (1 to 7 pump actuations) (maximum: 70 mg/day)Transdermal solution60 mg (2 pump actuations) applied once daily in the morning to the axillae30 to 120 mg/day (1 to 4 pump actuations)Transdermal system (Androderm)4 mg/day (as one 4 mg/day patch; do not use two 2 mg/day patches)2 to 6 mg/dayhDosage adjustment: Adjust therapy within usual dosage range every 3 to 12 months if needed based on symptoms and testosterone levels; target total testosterone in the midnormal laboratory range (eg, 350 to 600 ng/dL) (AUA [Mulhall 2018]; ES [Bhasin 2018]). Dose adjustment is not necessary if symptoms resolve with testosterone levels below the target range (AUA [Mulhall 2018]).Dosing conversion for transdermal system (Androderm): The 2.5 and 5 mg/day patches have been discontinued in the United States; patients may be switched from the 2.5 mg/day patch, 5 mg/day patch, or the combination (ie, 7.5 mg/day) as follows:From 2.5 mg/day patch to 2 mg/day patch.From 5 mg/day patch to 4 mg/day patch.From 7.5 mg daily (one 2.5 mg/day patch and one 5 mg/day patch) to 6 mg daily (one 2 mg/day patch and one 4 mg/day patch).Note: Patch change should occur at the next scheduled dosing. Measure early morning testosterone concentrations ~2 weeks after switching therapy.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied). May enhance edema formation. Testosterone cypionate is contraindicated in serious renal disease.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied). May enhance edema formation. Testosterone cypionate is contraindicated in serious hepatic disease.Dosing: Pediatric(For additional information see "Testosterone: Pediatric drug information")Note: Striant (buccal formulation) has been discontinued in the United States for >1 year. Dosage and duration of therapy depend upon age, sex, diagnosis, patient's response to therapy, and appearance of adverse effects; in general total doses >400 mg/month are not required due to the prolonged action of the drug.Constitutional delay of growth and pubertyConstitutional delay of growth and puberty (CDGP):IM:Children ≥12 years and Adolescents ≤17 years: Note: Typically not recommended for use before 14 years of age (Palmert 2012; Sperling 2014): Initial: Enanthate or cypionate: 50 mg/dose every 2 to 4 weeks for 3 to 6 months; may increase dose in 25 to 50 mg increments for another 3 to 6 months to effect; maximum dose: 100 mg; typical duration of therapy: 12 months; if no response or inadequate response after 1 year of treatment, diagnosis should be reconsidered and additional testing performed (Palmert 2012; Sperling 2014); Note: Other regimens have suggested high initial doses and taper downward as puberty progresses.Adolescents ≥18 years: Enanthate: 50 to 200 mg every 2 to 4 weeks for a limited duration (eg, 4 to 6 months)Subcutaneous implant: Pellet: Children ≥12 years and Adolescents: Usual range: 150 to 450 mg every 3 to 6 months; usual duration: 4 to 6 months; dosing typically on the lower end of range; various regimens have been usedMale hypogonadism or hypogonadotropic hypogonadismMale hypogonadism or hypogonadotropic hypogonadism:IM: Enanthate or cypionate:Children ≥12 years and Adolescents ≤17 years:Initiation of pubertal growth: 25 to 75 mg every 3 to 4 weeks, gradually titrate dose every 6 to 9 months to 100 to 150 mg monthly; some experts suggest increasing the interval to every 2 weeks at this point; typical duration of initiation therapy 3 to 4 years (Han 2010; Sperling 2014; Wales 2012)Maintenance therapy: 200 to 250 mg every 3 to 4 weeks; once expected adult height and adequate virilization achieved, may convert to other testosterone replacement dosage form (eg, patch, gel, etc) (Han 2010; Sperling 2014; Wales 2012)Adolescents ≥18 years: 50 to 400 mg every 2 to 4 weeks (manufacturer's labeling); 75 to 100 mg/week or 150 to 200 mg every 2 weeks (Endocrine Society [Bhasin 2010])IM: Undecanoate: Aveed: Adolescents ≥18 years: Initial dose: 750 mg, followed by 750 mg administered 4 weeks later, then 750 mg administered every 10 weeks thereafter.Subcutaneous implant: Pellet:Fixed dosing: Children ≥12 years and Adolescents: Usual range: 150 to 450 mg every 3 to 6 months; various regimens have been usedWeight-direct dosing: Limited data available: Children ≥12 years and Adolescents <17 years: 8 to 10 mg/kg/dose every 6 months (Zacharin 1997)Topical: Adolescents ≥18 years:Buccal: Striant: 30 mg twice daily (every 12 hours) applied to the gum region above the incisor tooth; discontinue if serum testosterone concentrations are consistently outside of the normal range.Dermal:Gel:AndroGel 1%: 50 mg applied once daily in the morning to the shoulder and upper arms or abdomen. Dosage may be increased to a maximum of 100 mg. Dose adjustment based on serum testosterone levels:Less than normal range: Increase dose from 50 mg to 75 mg or from 75 mg to 100 mg once dailyGreater than normal range: Decrease dose. Discontinue if consistently above normal at 50 mg daily.AndroGel 1.62%: 40.5 mg applied once daily in the morning to the shoulder and upper arms; dose range: 20.25 to 81 mg. Maximum daily dose: 81 mg/day. Dose adjustment based on serum testosterone levels:>750 ng/dL: Decrease dose by 20.25 mg/day350 to 750 ng/dL: Maintain current dose<350 ng/dL: Increase dose by 20.25 mg/dayFortesta: 40 mg once daily in the morning. Apply to the thighs. Dosing range: 10 to 70 mg/day. Dose adjustment based on serum testosterone levels:≥2,500 ng/dL: Decrease dose by 20 mg/day≥1,250 to <2,500 ng/dL: Decrease dose by 10 mg/day≥500 and <1,250 ng/dL: Maintain current dose<500 ng/dL: Increase dose by 10 mg/dayTestim: 50 mg applied once daily (preferably in the morning) to the shoulder and upper arms. If serum testosterone concentrations are less than the normal range, dosage may be increased from 50 mg to 100 mg once daily; maximum daily dose: 100 mg/day.Vogelxo: 50 mg applied once daily to the shoulder and/or upper arms. Dosage may be increased up to a maximum daily dose: 100 mg/day. Dose adjustment based on serum testosterone levels: If level less than normal range: Increase dose from 50 mg to 100 mg once daily.Solution: Axiron: 60 mg once daily; dosage range: 30 to 120 mg/day. Apply to the axilla at the same time each morning; do not apply to other parts of the body. Dose adjustment based on serum testosterone levels:>1,050 ng/dL: Decrease 60 mg/day dose to 30 mg/day; if levels >1,050 ng/dL persist after dose reduction discontinue therapy<300 ng/dL: Increase 60 mg/day dose to 90 mg/day, or increase 90 mg/day dose to 120 mg/dayTransdermal system: Androderm:Initial: 4 mg/day (as one 4 mg/day patch; do not use two 2 mg/day patches). Dose adjustment based on testosterone levels:>930 ng/dL: Decrease dose to 2 mg/day400 to 930 ng/dL: Continue 4 mg/day<400 ng/dL: Increase dose to 6 mg/day (as one 4 mg/day and one 2 mg/day patch)Dosing conversion of transdermal patches: If needed, patients may be switched from the 2.5 mg/day, 5 mg/day, and 7.5 mg/day patches as follows. Patch change should occur at their next scheduled dosing. Measure early morning testosterone concentrations ~2 weeks after switching therapy:From 2.5 mg/day patch to 2 mg/day patchFrom 5 mg/day patch to 4 mg/day patchFrom 7.5 mg/day patch to 6 mg/day patch (one 2 mg/day and one 4 mg/day patch)Intranasal: Testosterone gel: Natesto: 11 mg (2 pump actuations; 1 actuation per nostril) intranasally 3 times daily (6 to 8 hours apart). Total daily dose: 33 mgDose adjustment based on testosterone levels:Less than normal range: Consider alternative treatment if consistently <300 ng/mLGreater than normal range: Discontinue if consistently >1,050 ng/mLMultiple pituitary hormone deficiencyMultiple pituitary hormone deficiency (with microphallus): Limited data available: Infants: IM: Enanthate or cypionate: 25 mg every 4 weeks for 3 months; may repeat for another second course if necessary (Kliegman 2016).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricAll patients: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution; may enhance edema formation. Testosterone cypionate is contraindicated in serious renal disease.Dosing: Hepatic Impairment: PediatricAll patients: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution; may enhance edema formation. Testosterone cypionate is contraindicated in serious hepatic disease.Dosing: Older AdultRefer to adult dosing. Some data suggest a slightly lower testosterone target may be reasonable in older patients (eg, the lower end of the normal testosterone range) (AUA [Mulhall 2018]).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral, as undecanoate: Jatenzo: 158 mg, 198 mg, 237 mg [contains cremophor rh40, fd&c yellow #6 (sunset yellow)]Kyzatrex: 100 mg, 150 mg, 200 mg [contains cremophor rh40]Tlando: 112.5 mg [contains cremophor rh40]Gel, Nasal: Natesto: 5.5 mg/actuation (7.32 g)Gel, Transdermal: AndroGel: 25 mg/2.5 g (1%) (2.5 g) [contains alcohol, usp]AndroGel: 20.25 mg/1.25 g (1.62%) (1.25 g [DSC]); 40.5 mg/2.5 g (1.62%) (2.5 g [DSC])AndroGel: 50 mg/5 g (1%) (5 g [DSC]) [contains alcohol, usp]AndroGel Pump: 20.25 mg/actuation (1.62%) (75 g)Fortesta: 10 mg/actuation (2%) (60 g) [contains propylene glycol, trolamine (triethanolamine)]Testim: 50 mg/5 g (1%) (5 g) [contains alcohol, usp, propylene glycol, tromethamine]Vogelxo: 50 mg/5 g (1%) (5 g) [contains alcohol, usp, tromethamine]Vogelxo Pump: 12.5 mg/actuation (1%) (75 g) [contains alcohol, usp, tromethamine]Generic: 25 mg/2.5 g (1%) (2.5 g); 20.25 mg/1.25 g (1.62%) (1.25 g); 40.5 mg/2.5 g (1.62%) (2.5 g); 10 mg/actuation (2%) (60 g); 12.5 mg/actuation (1%) (75 g); 20.25 mg/actuation (1.62%) (75 g); 50 mg/5 g (1%) (5 g)Miscellaneous, Buccal: Striant: 30 mg (60 ea [DSC])Patch 24 Hour, Transdermal: Androderm: 2 mg/24 hr (1 ea, 60 ea); 4 mg/24 hr (1 ea, 30 ea)Pellet, Implant: Testopel: 75 mg (10 ea, 100 ea)Solution, Transdermal: Generic: 30 mg/actuation (90 mL)Solution, Intramuscular, as cypionate: Depo-Testosterone: 100 mg/mL (10 mL); 200 mg/mL (1 mL, 10 mL) [contains benzyl alcohol, benzyl benzoate]Generic: 100 mg/mL (10 mL); 200 mg/mL (1 mL, 10 mL)Solution, Intramuscular, as enanthate: Generic: 200 mg/mL (5 mL)Solution, Intramuscular, as undecanoate: Aveed: 750 mg/3 mL (3 mL) [contains benzyl benzoate, castor oil (ricine oil)]Solution Auto-injector, Subcutaneous [preservative free]: Xyosted: 50 mg/0.5 mL (0.5 mL); 75 mg/0.5 mL (0.5 mL); 100 mg/0.5 mL (0.5 mL) [contains sesame oil]Generic Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral, as undecanoate: Generic: 40 mgGel, Nasal: Natesto: 5.5 mg/actuation (1 ea)Gel, Transdermal: AndroGel: 25 mg/2.5 g (1%) (2.5 g); 50 mg/5 g (1%) (5 g); 12.5 mg/actuation (1%) (1.25 g, 2.5 g, 75 g) [contains alcohol, usp]Testim: 50 mg/5 g (1%) (5 g) [contains alcohol, usp, tromethamine]Generic: 25 mg/2.5 g (1%) (2.5 g); 50 mg/5 g (1%) (5 g)Patch 24 Hour, Transdermal: Androderm: 2.5 mg/24 hr ([DSC]); 5 mg/24 hr ([DSC]) [contains alcohol, usp]Solution, Intramuscular, as cypionate: Depo-Testosterone: 100 mg/mL (10 mL) [contains benzyl alcohol, benzyl benzoate]Generic: 100 mg/mL (10 mL)Solution, Intramuscular, as enanthate: Delatestryl: 200 mg/mL (5 mL) [contains chlorobutanol (chlorobutol), sesame oil]Product AvailabilityStriant (buccal formulation) has been discontinued in the United States for >1 year.Kyzatrex capsules: FDA approved July 2022; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Kyzatrex is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Consult the prescribing information for additional information.Controlled SubstanceC-IIIMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product and as follows, must be dispensed with this medication:AndroGel 1%: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021015s045lbl.pdf#page=23AndroGel 1.62%: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022309s020lbl.pdf#page=25Aveed: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022219s014lbl.pdf#page=23Axiron: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022504s016lbl.pdf#page=15Fortesta: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021463s025lbl.pdf#page=21Kyzatrex: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213953s000lbl.pdf#page=22Testim: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021454s030s031lbl.pdf#page=21Testosterone cypionate injection: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216318s000lbl.pdf#page=14Testosterone Gel (Perrigo): http://www.fda.gov/downloads/Drugs/DrugSafety/UCM294248.pdfTestosterone Gel (Teva): https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202763s000mg.pdfVogelxo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204399s012lbl.pdf#page=23Xyosted: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209863s000lbl.pdf#page=16Administration: AdultIM: Administer by deep IM injection into the gluteal muscle.Testosterone undecanoate: Inject into the gluteus medius; alternate injection between left and right buttock. Avoid intravascular injection, may lead to pulmonary oil microembolism; avoid the superior gluteal arteries and sciatic nerve.Intranasal gel (Natesto): Administer intranasally 3 times daily, 6 to 8 hours apart, preferably at the same time each day. Prime pump prior to first use by inverting then depressing pump 10 times (discard this portion of product into sink). Blow nose prior to application. To administer the dose, insert actuator into nostril until pump reaches base of nose; tilt so the tip is in contact with the lateral wall of nostril. Depress slowly until pump stops, then remove from nose while wiping tip to transfer gel to lateral side of nostril. Following administration, press on the nostrils at a point just below the bridge of the nose and lightly massage. Refrain from blowing nose or sniffing for 1 hour after administration. If gel gets on hands, wash with warm soap and water. Temporarily discontinue with episodes of severe rhinitis; if severe rhinitis symptoms persist consider an alternative therapy.Oral, buccal application (Striant): One mucoadhesive for buccal application (buccal system) should be applied to a comfortable area above the incisor tooth twice daily. Gently push the curved side against the upper gum. Hold buccal system firmly in place by pushing down on outside of the upper lip for 30 seconds to ensure adhesion. The buccal system should adhere to gum until it is removed. Rotate to alternate sides of mouth with each application. If the buccal system falls out within the first 8 hours of dosing, replace with a new buccal system and continue for a total of 12 hours from the placement of the first system; if the buccal system falls out of position after 8 hours of dosing, a new buccal system should be applied and it may remain in place for 12 hours, then continue with the next regularly scheduled dosing. System will soften and mold to shape of gum as it absorbs moisture from mouth. Do not chew or swallow the buccal system. The buccal system will not dissolve; gently remove by sliding downwards from gum; avoid scratching gum. Remove prior to routine morning and evening oral care, prior to application of new system.Oral, capsule (Jatenzo, Kyzatrex, Tlando): Administer once in the morning and once in the evening with meals. In patients taking Kyzatrex once daily, administer in the morning with a meal.40 mg capsule [Canadian product]: Administer once in the morning and once in the evening with meals. Should be swallowed whole; do not crush or chew.SUBQ implant (Testopel): Using strict sterile technique, must be surgically implanted.SUBQ injection (Xyosted): Administer in the abdominal region only. Do not administer IM or IV.SUBQ injection (testosterone cypionate, testosterone enanthate) (off-label route): Hormone therapy for transgender males (assigned female at birth) (off-label use): Administer dose using a 1 mL syringe with a 20- or 25-gauge needle. Administer in the abdomen or thigh (Spratt 2017).Topical gel and solution: General information: Alcohol-based gels and solutions are flammable; avoid fire, flames, or smoking until dry. Testosterone may be transferred to another person following skin-to-skin contact with the application site. Strict adherence to application instructions is needed in order to decrease secondary exposure. Thoroughly wash hands after application and cover application site with clothing (ie, shirt) once gel or solution has dried, or clean application site thoroughly with soap and water prior to contact in order to minimize transfer. In addition to skin-to-skin contact, secondary exposure has also been reported following exposure to secondary items (eg, towel, shirt, sheets). If secondary exposure occurs, the other person should thoroughly wash the skin with soap and water as soon as possible. The application sites and doses of topical testosterone products are not interchangeable.Product-specific administration instructions:AndroGel 1%: Apply at the same time each morning to clean, dry, intact skin to an area of the shoulder, upper arms, and/or abdomen that will be covered by a short sleeve t-shirt. Do not apply to other parts of the body such as the genitals, chest, back, axillae, or knees. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Alternatively, a portion may be squeezed onto palm of hand and applied, repeating the process at the same or other site until entire packet has been applied. Avoid swimming, showering or washing the application site for ≥5 hours following application. Cover application site with clothing (eg, t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times (and discard this portion of product) prior to initial use. Each actuation delivers 12.5 mg of testosterone (4 actuations = 50 mg; 6 actuations = 75 mg; 8 actuations = 100 mg). When using the pump, the gel may be delivered into the palm of the hand prior to application or applied directly to the application site.AndroGel 1.62%: Apply at the same time each morning to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to other parts of the body such as the abdomen, genitals, chest, axillae, or knees. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Alternatively, a portion may be squeezed onto palm of hand and applied, repeating the process at the same or other site until entire packet has been applied. Avoid swimming, showering or washing the application site for ≥2 hours following application. Cover application site with clothing (eg t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times (and discard this portion of product) prior to initial use. Each actuation delivers 20.25 mg of testosterone (2 actuations = 40.5 mg; 3 actuations = 60.75 mg; 4 actuations = 81 mg). When using the pump, the gel may be delivered into the palm of the hand prior to application or applied directly to the application site.Fortesta: Apply to clean dry intact skin once daily in the morning to skin of front and inner thighs. Do not apply to genitals or other parts of the body. Use one finger to rub gel evenly onto skin of each thigh. Avoid showering, washing the site, or swimming for ≥2 hours after application. Prior to first dose, prime the pump by holding canister upright and fully depressing the pump 8 times (discard this portion of the product). Each pump actuation delivers testosterone 10 mg. The total dose should be divided between thighs (example, 10 mg/day: apply 10 mg to one thigh only; 20 mg/day: apply 10 mg to each thigh; 30 mg/day: apply 20 mg to one thigh and 10 mg to the other thigh; etc). Once application site is dry, cover with clothing.Testim: Apply once daily (preferably in the morning) to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to the genitals or abdomen. Upon opening the tube, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Avoid swimming, showering or washing the application site for ≥2 hours following application. Cover application site with clothing (eg t-shirt) once the gel has dried.Transdermal solution: Apply using the applicator to clean, dry, intact skin on an area of the axilla at the same time each morning. Do not apply to other parts of the body (eg, abdomen, genitals, shoulders, upper arms). Avoid washing the site or swimming for 2 hours after application. Prior to first use, prime the applicator pump by depressing it 3 times (discard this portion of the product). After priming, position the nozzle over the applicator cup and depress pump fully one time; ensure liquid enters cup. Each pump actuation delivers testosterone 30 mg. No more than 30 mg (one pump) should be added to the cup at one time. The total dose should be divided between axilla (example, 30 mg/day: apply to one axilla only; 60 mg/day: apply 30 mg to each axilla; 90 mg/day: apply 30 mg to each axilla, allow to dry, then apply an additional 30 mg to one axilla; etc). To apply dose, keep applicator upright and wipe into the axilla; if solution runs or drips, use cup to wipe. Do not rub into skin with fingers or hand. If more than one 30 mg dose is needed, repeat process. Apply roll-on or stick antiperspirants or deodorants ≥2 minutes prior to testosterone. Once application site is dry, cover with clothing. After use, rinse applicator under running water and pat dry with a tissue.Vogelxo: Apply once daily at the same time each morning to clean dry intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to the genitals or to the abdomen. Upon opening the tube or packet, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). If two doses (testosterone 100 mg) are needed, apply one dose (50 mg) to upper arm and or/shoulder, then apply the second dose (50 mg) to the opposite upper arm and/or shoulder. Avoid showering, washing the site, or swimming for at least 2 hours following application. Cover application site with clothing (eg, t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times by fully depressing the pump mechanism (actuation) and discard this portion of product. Each actuation delivers testosterone 12.5 mg (4 actuations = 50 mg; 8 actuations = 100 mg).Transdermal patch (Androderm): Apply to skin immediately upon removal from the protective pouch. Apply at the same time each night to clean, dry area of skin on the back, abdomen, upper arms, or thigh. Do not apply to bony areas or parts of the body that are subject to prolonged pressure while sleeping or sitting. Do not apply to oily, damaged, or irritated skin. Do not apply to the scrotum. Rotate administration sites, allowing 7 days between applying to the same site. Avoid showering, washing the site, or swimming for ≥3 hours after application. Following patch removal, mild skin irritation may be treated with OTC hydrocortisone cream. A small amount of triamcinolone acetonide 0.1% cream may be applied under the system to decrease irritation; do not use ointment (triamcinolone ointment decreases testosterone absorption). Dispose of any used or unused patches by folding adhesive ends together, replace in pouch or sealed container, and discard properly in trash away from children and pets.Administration: PediatricParenteral: IM:Cypionate, enanthate: Warming injection to room temperature and shaking vial will help redissolve crystals that have formed after storage. Administer by deep IM injection into the gluteal muscle.Undecanoate: Inject into the gluteus medius; alternate injection between left and right buttock. Avoid intravascular injection, may lead to pulmonary oil microembolism; avoid the superior gluteal arteries and sciatic nerve.Subcutaneous implant (Testopel): Using strict sterile technique, must be surgically implanted.Topical: Buccal: Striant: One mucoadhesive for buccal application (buccal system) should be applied to a comfortable area above the incisor tooth. Apply flat side of system on fingertip. Gently push the curved side against upper gum. Rotate to alternate sides of mouth with each application. Hold buccal system firmly in place for 30 seconds to ensure adhesion. The buccal system should adhere to gum for 12 hours. If the buccal system falls out with the first 8 hours of dosing, replace with a new system and continue for a total of 12 hours from the placement of the first system. If the system falls out of position after 8 hours of dosing, a new buccal system should be placed and remain for 12 hours, then continue with the next regularly scheduled dose. System will soften and mold to shape of gum as it absorbs moisture from mouth. Do not chew or swallow the buccal system; check to ensure buccal system is in place following toothbrushing, use of mouthwash, and consumption of food or beverages. The buccal system will not dissolve; gently remove by sliding downwards from gum; avoid scratching gum.Dermal:Gels and solution: Apply to clean, dry, intact skin. Application sites should be allowed to dry for a few minutes prior to dressing. Hands should be washed with soap and water after application. Do not apply testosterone gel or solution to the genitals. Alcohol-based gels and solutions are flammable; avoid fire or smoking until dry. Testosterone may be transferred to another person following skin-to-skin contact with the application site. Strict adherence to application instructions is needed in order to decrease secondary exposure. Thoroughly wash hands after application and cover application site with clothing (ie, shirt).AndroGel 1%: Apply at the same time each morning to clean, dry, intact skin to an area of the shoulder, upper arms, and/or abdomen that will be covered by a short sleeve t-shirt. Do not apply to other parts of the body such as the genitals, chest, back, axillae, or knees. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Alternatively, a portion may be squeezed onto palm of hand and applied, repeating the process at the same or other site until entire packet has been applied. Avoid swimming, showering, or washing the application site for ≥5 hours following application. Cover application site with clothing (eg, t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times (and discard this portion of product) prior to initial use. Each actuation delivers 12.5 mg of testosterone (4 actuations = 50 mg; 6 actuations = 75 mg; 8 actuations = 100 mg). When using the pump, the gel may be delivered into the palm of the hand prior to application or applied directly to the application site.AndroGel 1.62%: Apply at the same time each morning to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to other parts of the body such as the abdomen, genitals, chest, axillae, or knees. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Alternatively, a portion may be squeezed onto palm of hand and applied, repeating the process at the same or other site until entire packet has been applied. Avoid swimming, showering, or washing the application site for ≥2 hours following application. Cover application site with clothing (eg, t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times (and discard this portion of product) prior to initial use. Each actuation delivers 20.25 mg of testosterone (2 actuations = 40.5 mg; 3 actuations = 60.75 mg; 4 actuations = 81 mg). When using the pump, the gel may be delivered into the palm of the hand prior to application or applied directly to the application site.Axiron: Apply using the applicator to clean, dry, intact skin on the axilla at the same time each morning. Do not apply to other parts of the body (eg, abdomen, genitals, shoulders, upper arms). Avoid washing the site or swimming for 2 hours after application. Prior to first use, prime the applicator pump by depressing it 3 times (discard this portion of the product). After priming, position the nozzle over the applicator cup and depress pump fully one time; ensure liquid enters cup. Each pump actuation delivers testosterone 30 mg. No more than 30 mg (one pump) should be added to the cup at one time. The total dose should be divided between axilla (eg, 30 mg/day: Apply to one axilla only; 60 mg/day: Apply 30 mg to each axilla; 90 mg/day: Apply 30 mg to each axilla, allow to dry, then apply an additional 30 mg to one axilla; etc). To apply dose, keep applicator upright and wipe into the axilla; if solution runs or drips, use cup to wipe. Do not rub into skin with fingers or hand. If more than one 30 mg dose is needed, repeat process. Apply roll-on or stick antiperspirants or deodorants ≥2 minutes prior to testosterone. Once application site is dry, cover with clothing. After use, rinse applicator under running water and pat dry with a tissue. The application site and dose of this product are not interchangeable with other topical testosterone products.Fortesta: Apply to clean, dry, intact skin of front and inner thighs. Do not apply to other parts of the body. Use one finger to rub gel evenly onto skin of each thigh. Avoid showering, washing the site, or swimming for ≥2 hours after application. Prior to first dose, prime the pump by holding canister upright and fully depressing the pump 8 times (discard this portion of the product). Each pump actuation delivers testosterone 10 mg. The total dose should be divided between thighs (eg, 10 mg/day: Apply 10 mg to one thigh only; 20 mg/day: Apply 10 mg to each thigh; 30 mg/day: Apply 20 mg to one thigh and 10 mg to the other thigh; etc). Once application site is dry, cover with clothing. The application site and dose of this product are not interchangeable with other topical testosterone products.Testim: Apply once daily (preferably in the morning) to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to the genitals or abdomen. Upon opening the tube, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Avoid swimming, showering, or washing the application site for ≥2 hours following application. Cover application site with clothing (eg, t-shirt) once the gel has dried.Vogelxo: Apply once daily at the same time each morning to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to the genitals or to the abdomen. Upon opening the tube or packet, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). If two doses (testosterone 100 mg) are needed, apply one dose (50 mg) to upper arm and or/shoulder, then apply the second dose (50 mg) to the opposite upper arm and/or shoulder. Avoid showering, washing the site, or swimming for at least 2 hours following application. Cover application site with clothing (eg, t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times by fully depressing the pump mechanism (actuation) and discard this portion of product. Each actuation delivers testosterone 12.5 mg (4 actuations = 50 mg; 8 actuations = 100 mg).Transdermal patch: Androderm: Apply to skin immediately upon removal from the protective pouch. Apply at the same time each night to clean, dry area of skin on the back, abdomen, upper arms, or thigh. Do not apply to bony areas or parts of the body that are subject to prolonged pressure while sleeping or sitting. Do not apply to oily, damaged, or irritated skin. Do not apply to the scrotum. Rotate administration sites, allowing 7 days between applying to the same site. Avoid showering, washing the site, or swimming for ≥3 hours after application. Following patch removal, mild skin irritation may be treated with OTC hydrocortisone cream. A small amount of triamcinolone acetonide 0.1% cream may be applied under the system to decrease irritation; do not use ointment (triamcinolone ointment decreases testosterone absorption). Dispose of any used or unused patches by folding adhesive ends together, replace in pouch or sealed container and discard properly in trash away from children and pets.Intranasal: Intranasal gel (Natesto): Administer intranasally 3 times daily, 6 to 8 hours apart, preferably at the same time each day. Prime pump prior to first use by inverting then depressing pump 10 times (discard this portion of product into sink). Blow nose prior to application. To administer the dose, insert actuator into nostril until pump reaches base of nose; tilt so the tip is in contact with the lateral wall of nostril. Depress slowly until pump stops, then remove from nose while wiping tip to transfer gel to lateral side of nostril. Following administration, press on the nostrils at a point just below the bridge of the nose and lightly massage. Refrain from blowing nose or sniffing for 1 hour after administration. If gel gets on hands, wash with warm soap and water. Temporarily discontinue with episodes of severe rhinitis; if severe rhinitis symptoms persist, consider an alternative therapy.Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 3]).Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.For IM preparation, double gloves, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator) are recommended. Double gloving and a protective gown are required during IM administration. NIOSH recommends double gloving, a protective gown, and (if liquid that could splash) eye/face protection for administration of a topical product; if there is potential for inhalation, respiratory protection is recommended (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).Use: Labeled IndicationsDelayed puberty: IM injection (enanthate); pellet: To stimulate puberty in carefully selected males with delayed puberty.Hypogonadism, male (primary or hypogonadotropic): Buccal; Capsule (oral); Gel (nasal, transdermal); IM injection (cypionate, enanthate, undecanoate); Patch (transdermal); Pellet; Solution (transdermal); SUBQ injection (Xyosted): Treatment of testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals; gonadotropin or luteinizing hormone-releasing hormone deficiency; or pituitary-hypothalamic injury from tumors, trauma, or radiation.Limitations of use: Safety and efficacy in males with age-related hypogonadism (or late-onset hypogonadism) not associated with structural or genetic etiologies have not been established; some products are specifically contraindicated in this population (varies per manufacturer's labeling). However, the Endocrine Society suggests that testosterone therapy may be offered to patients with symptoms of testosterone deficiency and consistently and unequivocally low morning testosterone concentrations (regardless of etiology). In males >65 years of age, treatment should only be initiated on an individual basis and after consultation with the patient regarding risks and benefits (ES [Bhasin 2018]).Use: Off-Label: AdultHormone therapy for transgender males (assigned female at birth)Medication Safety IssuesSound-alike/look-alike issues:Testosterone may be confused with testolactoneAndroGel 1% may be confused with AndroGel 1.62%Bio-T-Gel may be confused with T-GelHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.Older adult: High-Risk Medication:Beers Criteria: Testosterone is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to its potential for cardiac problems; use is contraindicated in patients with prostate cancer. Avoid unless testosterone is used for confirmed hypogonadism with clinical symptoms (Beers Criteria [AGS 2019]).Other safety concerns:Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.Adverse Reactions (Significant): ConsiderationsBreast cancerData to clearly establish or quantify a risk of breast cancer with testosterone therapy (TTh) remains elusive; however, it is plausible (Ref). Additionally, upregulation of over 200 genes associated with breast cancer–unique expression was found after 2 years of TTh (Ref). Further studies in the transgender population are needed, but a retrospective study looking at a median exposure duration of 13 years found the breast cancer risk increased toward cisgender female levels during feminizing treatment and the characteristics of breast cancer resembled a female pattern (Ref). Additionally, considerations of risk should be noted in transgender women (ie, BRCA +) (Ref). Medical evidence for reactivation of breast cancer is not found in the literature; however, mastectomy does not negate future risk of cancer development in residual breast tissue (Ref).Mechanism: Proposed mechanisms include aromatization of testosterone to estrogens in peripheral tissues and the activation of androgen receptors which leads to cellular growth and proliferation, particularly in mammary tissues (Ref).Onset: Delayed; onset in case reports range from 5 weeks to 15 years (Ref).Risk factors:• History of breast cancer (contraindication to initiation of testosterone) (Ref)• Transmen secondary to inadequate population screening (Ref)• Klinefelter syndrome (Ref)Cardiovascular eventsTestosterone undecanoate (TU) and testosterone enanthate (TE) may cause or exacerbate hypertension that can increase the risk of major adverse cardiovascular events (MACE). In a study comparing a new oral TU formulation to a testosterone topical product, a mean increase in systolic blood pressure (SBP) of 3 to 5 mmHg was observed with TU while diastolic blood pressure (DBP) was unchanged. No participants discontinued testosterone therapy (TTh) secondary to increase in blood pressure; antihypertensive therapy was initiated in 5.9% of TU participants (Ref). In a retrospective review of 5 years, no significant changes in either SBP or DBP was found with TU or TE (Ref). Available studies are inconclusive regarding the risk of developing MACE, such as nonfatal acute myocardial infarction (MI), ischemic stroke/transient ischemic attacks, or cardiovascular death following testosterone use (Ref). Some studies have suggested an increased risk of cardiovascular events among males prescribed testosterone therapy (Ref); although, the overall evidence does not demonstrate an increased or decreased cardiovascular risk (Ref).Mechanism: Blood pressure increases: Not clearly established; potentially secondary to fluid retention and peripheral edema. Increase in edema may be associated with heart failure or other edematous states (Ref). Trends in SBP increases have not been linked to any specific mechanism (Ref).Onset: Cardiovascular events: Delayed; one study demonstrated the highest risk in the first 6 months to 2 years of continuous use (Ref).Risk factors:• Blood pressure increases:- History of hypertension/taking antihypertensive medication (Ref)- History or current treatment of edematous states (Ref)- Preexisting diabetes mellitus• Cardiovascular events:- History of cardiovascular disease (avoid use in patients with a history of MI or stroke in the last 6 months) (Ref)- Presence of cardiovascular disease risk factors (eg, edematous states, hypertension) (Ref)HepatotoxicityHepatic effects and hepatotoxicity, including abnormal hepatic function tests, cholestasis, jaundice, nodular regeneration, chronic vascular injury (peliosis hepatitis), hepatic adenoma, and hepatocellular neoplasm, have been limited to oral alkylated testosterone (eg, methyltestosterone) (Ref). Although the development of these events is ~1% (Ref), methyltestosterone should not be used in clinical practice secondary to the detrimental hepatic effects (Ref). Oral testosterone undecanoate has not been associated with clinically significant liver changes as it is predominately absorbed through the intestinal lymphatic system rather the liver. Furthermore, the small number of patients that experienced an increase in AST or ALT had transient changes <2 x ULN that returned to baseline with continued treatment (Ref).Mechanism: Time-related; idiosyncratic. Androgens may stimulate genes that are important in cell growth and development, as well as decrease bile salt transporter proteins (Ref).Onset: Delayed; most adenomas occur with long-term use (5 to 15 years), but changes may occur within 2 years of therapy initiation (Ref).Risk factors:• Long-term use (Ref)• Risk factors for liver disease (ie, Fanconi syndrome, iron overload, chronic hepatitis C) (Ref)• Oral products that do not bypass the liver (methyltestosterone) (Ref)Polycythemia/erythrocytosisTestosterone therapy (TTh) has been associated with polycythemia/erythrocytosis, especially during the first year of therapy. The resulting increased hematocrit or increased hemoglobin increases blood viscosity and platelet adhesiveness and decreases venous return which are potential risks for thromboembolic events and/or ischemic sequelae (Ref). Increases in hemoglobin of 5% to 7% have been observed (Ref). Baseline hematocrit value >50% is a contraindication to TTh, while values >54% are an indication to discontinue therapy (Ref).Mechanism: Exact mechanism unknown; however, several hypotheses have been cited including the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors (Ref).Onset: Delayed; dependent upon formulation and pharmaco*kinetics. Increases in hemoglobin/hematocrit have occurred as early as 1 month after TTh initiation and are most often observed within 1 year of initiation (Ref).Risk factors:• Males 60 to 75 years of age (Ref)• Short-acting IM formulation (Ref)Prostate cancerTestosterone therapy (TTh) may increase the risk for benign prostatic hypertrophy (BPH) and/or prostate carcinoma; however, evidence is conflicting (Ref).Risk factors:• BPH:- Severe (AUA/International Prostate Symptom Score >19) lower urinary tract symptoms (contraindicated) (Ref)• Prostate cancer (withhold therapy pending urological evaluation):- Palpable prostate nodule or induration (Ref)- PSA >4 ng/mL (Ref)- PSA >3 ng/mL in patients at high risk of prostate cancer (Ref)Pulmonary oil microembolismIntramuscular injection of testosterone undecanoate (TU) has been associated with pulmonary oil microembolism (POME) (Ref). The current US annual spontaneously reported adverse event rate for POME is <0.1%. Most events (95%) resolved; 76% resolved in ≤30 minutes. Furthermore, >60% had spontaneous resolution that required no medical intervention (Ref). Older observational data suggest the rate may be as high as 2.1% (Ref). Cough is the consistent symptom with increase blood pressure and heart rate, diaphoresis, red eyes, and “asthma-like symptoms” also reported (Ref). TU is only available under the Aveed Risk Evaluation and Mitigation Strategies Program (REMS). Subcutaneous injection with oil-based testosterone enanthate and cypionate in transgender patients did not report any POME events (Ref).Mechanism: Non–dose-related; occurs due to oil vehicle delivery into venous circulation (Ref).Onset: Rapid; within 1 hour (most reports observed coughing within minutes of injection). POME is independent of duration of therapy, as events have been association with the initial injection and subsequent injections (Ref).Risk factors:• Oil-based formulations (Ref)• IM route (Ref)• Respiratory hypersensitivity (Ref)• Incorrect injection technique (Ref)Secondary exposureWhen using topical preparations of testosterone, there is risk of transfer (secondary) exposure of testosterone (Ref). Secondary exposure has resulted in virilization of females, children (Ref), and fetuses (Ref). Degree of signs and symptoms are variable but may include acne vulgaris or irregular menses in females, precocious puberty in children (Ref), and cl*toromegaly in fetuses (Ref). Of note, the fetal genitalia appear to be more susceptible to testosterone effects rather than the skeletal system (Patel 2010). Secondary exposure signs and symptoms regress when exposure is discontinued, but return to baseline is not absolute (Ref).Mechanism: Non–dose-related; contact with site of topically applied testosterone to unintended recipient (Ref).Risk factors:• Topical testosterone formulations (Ref)Venous thromboembolismAn established correlation between testosterone therapy and venous thromboembolism (VTE) including deep vein thrombosis and pulmonary embolism, are conflicting; data from randomized, placebo-controlled trials with VTE as a primary endpoint are lacking. A large case-crossover study showed increased risk of VTE with short-term therapy (<3 months) (Ref), while two other large observational studies (Ref) had conflicting conclusions. In a study with 67 females on testosterone therapy, there was an increased risk of VTE (Ref).Mechanism: Non–dose-related; elevated hematocrit levels may increase viscosity, platelet accumulation, and thromboxane A2 concentration (Ref). However, there are case reports of VTE without elevated hematocrit levels (Ref).Onset: Delayed; the highest risk for development of VTE appears to be within the first 3 months of therapy initiation (Ref). However, in another study, the median time to development of VTE was 6 months and was equated to the risk of VTE in females taking hormone replacement therapy, where the risk is highest in the first year of therapy (Ref).Risk factors:• Thrombophilia (contraindication) (Ref)• Prior thrombotic event (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Cardiovascular: Hypertension (including exacerbation of hypertension: ≤13%) (table 1)HypertensionTestosterone: Adverse Reaction: HypertensionDrug (Testosterone)PlaceboDoseDosage FormNumber of Patients (Testosterone)Number of Patients (Placebo)13%N/A75 mg weekly, then titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/dSUBQ injection150N/A5%N/A225 mg dailyOral capsule138N/A4%N/A237 mg twice daily, then titrated to 158 mg, 198 mg, 316 mg, or 396 mg twice daily to achieve testosterone concentrations in the eugonadal rangeOral capsule166N/A3%N/A50 mg1% topical gel77N/A3%N/A100 mg1% topical gel78N/A2%0%N/A1.62% topical gel234402%N/A100 mg daily to 400 mg twice dailyOral capsule155N/A1%N/AN/ABuccal117N/A0%N/A75 mg1% topical gel40N/ADermatologic: Skin blister (application site: 12%)Genitourinary: Prostate specific antigen increase (1% to 18%) (table 2)Prostate Specific Antigen IncreaseTestosterone: Adverse Reaction: Prostate Specific Antigen IncreaseDrug (Testosterone)PlaceboDoseDosage FormNumber of Patients (Testosterone)Number of Patients (Placebo)Comments18%N/AN/A1% topical gel162N/AN/A12%N/A75 mg weekly, then titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/dSUBQ injection150N/AN/A11%0%N/A1.62% topical gel23440N/A6%N/A11 mg three times dailyNasal gel69N/AN/A5%N/A750 mg at initiation, at 4 weeks, and every 10 weeks thereafterIntramuscular injection153N/AN/A3%N/A100 mg daily to 400 mg twice dailyOral capsule155N/AProstate specific antigen increase >1.4 ng/mL3%N/A75 mg weekly, then titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/dSUBQ injection133N/AN/A2%N/A237 mg twice daily, then titrated to 158 mg, 198 mg, 316 mg, or 396 mg twice daily to achieve testosterone concentrations in the eugonadal rangeOral capsule161N/AN/A2%N/AN/ABuccal117N/AN/A1%N/A100 mg daily to 400 mg twice dailyOral capsule155N/AProstate specific antigen increase >4 ng/mL1%N/AN/ATopical gel149N/AN/AHematologic & oncologic: Increased hematocrit (1% to 14%)Local: Application-site pruritus (37%)1% to 10%:Cardiovascular: Peripheral edema (3%), peripheral vascular diseaseDermatologic: Acne vulgaris (1% to 8%), alopecia (1%), bulla (application site), contact dermatitis (2% to 4%), crusted skin (nasal scab; intranasal: 4% to 6%), erythema of skin (1%), excoriation of skin (nasal; intranasal), hyperhidrosis (1%), pruritus (≤2%), skin rash, xeroderma (2%)Endocrine & metabolic: Decreased HDL cholesterol (3%), decreased libido (1% to 3%), gynecomastia (1% to 3%), hot flash (1%), increased plasma estradiol concentration (3%), increased serum prolactin (6%), increased thyroid stimulating hormone level, weight gain (1% to 2%)Gastrointestinal: Abdominal pain (2%), ageusia (buccal: 1%), bitter taste (buccal: 4%), decreased appetite, diarrhea (3% to 4%), dysgeusia (<3%), dyspepsia (>2%), eructation (>2%), gastric ulcer with hemorrhage (1%), gastroesophageal reflux disease, gastrointestinal hemorrhage, gingival pain (buccal: 3%; includes gingival tenderness), gingival swelling (buccal: 2%), gingivitis (buccal: ≤9%), increased appetite (≤3%), nausea (≤2%), oral irritation (buccal: ≤9%), oral mucosa changes (buccal; includes buccal mucosa roughening and gum blister: 1%), toothache (buccal: ≤1%), vomiting (3% to 4%)Genitourinary: Benign prostatic hypertrophy (≤2%), breast hypertrophy (1%), difficulty in micturition (1%), dysuria, ejacul*tory disorder (1%), hematuria (2%), impotence (<3%), mastalgia (1% to 3%), pelvic pain, prostate carcinoma (1%), prostate induration (1%), prostatic disease (3% to 5%), prostatitis (3%), spontaneous erections (1%), testicular atrophy, testicular disease (including testicular tenderness and non-palpable testes: 3%), urinary frequency (≤2%), urinary incontinence, urinary tract infection (3%)Hematologic & oncologic: Anemia (3%), increased hemoglobin (1% to 5%), polycythemia (≤3%)Hepatic: Abnormal hepatic function tests (1%), increased serum bilirubin (≤6%)Local: Application-site burning (1% to 3%), application-site edema (1%), application-site erythema (5% to 7%), application-site induration (3%), application-site irritation (7% to 8%), application-site rash, application-site vesicles (6%), bleeding at injection site (3% to 6%), bruising at injection site (4% to 7%), erythema at injection site (1% to 3%), local skin exfoliation (application site), pain at injection site (5%)Nervous system: Abnormal dreams (1%), abnormality in thinking, aggressive behavior (1%), altered sense of smell (1% to 6%), anosmia, anxiety (1%), asthenia (≤3%), body pain, chills, confusion, depression (≤3%), emotional lability (≤3%), fatigue (1% to 2%), headache (1% to 6%), insomnia (1% to 2%), irritability (2%), nervousness (1% to 3%), outbursts of anger (1%), paresthesia, stinging sensation (lips; buccal: 1%), vertigoNeuromuscular & skeletal: Abnormal bone growth, arthralgia (≤2%), back pain (3%), hemarthrosis, increased creatine phosphokinase in blood specimen (3% to 4%), limb pain (4%), musculoskeletal pain (2%)Renal: PolyuriaRespiratory: Bronchitis (intranasal: 4%), cough (2% to 3%), dry nose (intranasal: 2% to 4%), epistaxis (intranasal: 4% to 7%), nasal congestion (intranasal: 2% to 4%), nasal discomfort (intranasal: 4% to 6%), nasal mucosa swelling (buccal: 1%), nasopharyngitis (1% to 9%), rhinorrhea (intranasal: 4% to 8%), sinusitis (4%), sleep apnea (2%), upper respiratory tract infection (4%)<1%:Dermatologic: FolliculitisGastrointestinal: Gingival erythema, oral inflammation, stomatitis, xerostomiaGenitourinary: Breast tenderness, nipple tenderness (sensitivity)Hematologic & oncologic: Prolonged partial thromboplastin time, prolonged prothrombin timeHypersensitivity: AnaphylaxisInfection: InfectionNervous system: Suicidal ideation, suicidal tendenciesNeuromuscular & skeletal: MyalgiaOphthalmic: Increased lacrimationRenal: Increased serum creatinineFrequency not defined:Dermatologic: Lip blister (ulceration)Endocrine: HyperlipidemiaGastrointestinal: Constipation, decreased gastrointestinal motility, gingival recessionHematologic & oncologic: PetechiaHepatic: Hepatic adenomaLocal: Induration at injection siteNervous system: Dizziness, hostilityMiscellaneous: FeverPostmarketing:Cardiovascular: Acute myocardial infarction (Loo 2019), angina pectoris, chest pain, circulatory shock, coronary artery disease, coronary occlusion, deep vein thrombosis, edema, heart failure, peripheral venous insufficiency, pulmonary embolism (including pulmonary oil microembolism [POME]) (Pastuszak 2020), syncope, tachycardia, thromboembolism, thrombosis, vasodilation, venous thromboembolismDermatologic: Allergic dermatitis, androgenetic alopecia (Griggs 2018), diaphoresis, hair discoloration, papular rash, wound secretionEndocrine & metabolic: Calcium retention, change in HDL, diabetes mellitus, electrolyte disorder (calcium, chloride, nitrogen, phosphorus, potassium, sodium), fluid retention, hirsutism, hyperparathyroidism, hypertriglyceridemia, hypoglycemia, increased libido, increased serum glucose, inorganic phosphate retention, potassium retention, sodium retentionGastrointestinal: Cholestasis (LiverTox 2012), mesenteric ischemia (portal vein thrombosis, mesenteric venous occlusion) (Poirier-Blanchette 2021), oral mucosa ulcer, upper abdominal painGenitourinary: Azoospermia (Jan 2012), breast induration, erectile dysfunction, frequent erections, genitourinary infection (prostate), malignant neoplasm of prostate, oligospermia, org*sm disturbance (male), pollakiuria, priapism (Ichioka 2006), prostatic intraepithelial neoplasia, spermatocele, testicular pain, virilization (in children secondarily exposed to topical testosterone)Hematologic & oncologic: Clotting factors suppression (factors II, V, VII, X), thrombocytopeniaHepatic: Cholestatic jaundice, hepatocellular neoplasm (LiverTox 2012), hepatotoxicity (idiosyncratic; Chalasani 2021), increased gamma-glutamyl transferase, jaundice (LiverTox 2012), peliosis hepatitis (LiverTox 2012)Hypersensitivity: Anaphylactic shock, angioedema, hypersensitivity angiitis, lip edema, nonimmune anaphylaxisLocal: Abscess at injection site, discomfort at injection site, fibrosis at injection site, hematoma at injection site, inflammation at injection site, injection-site infection (cellulitis), irritation at injection siteNervous system: Amnesia, cerebral infarction, cerebrovascular accident, cerebrovascular insufficiency, drug abuse, ischemic stroke (Loo 2019), Korsakoff syndrome (nonalcoholic), malaise, migraine, restlessness, reversible ischemic neurological deficit, sleep disorder, transient ischemic attacks (Loo 2019), voice disorderNeuromuscular & skeletal: Musculoskeletal chest pain, osteoporosis, systemic lupus erythematosusOphthalmic: Increased intraocular pressure, retinopathy (central serous chorioretinopathy) (Grieshaber 2007), vitreous detachmentOtic: Hearing loss (sudden) (Tikka 2016), tinnitusRenal: Nephrolithiasis, renal colic, renal painRespiratory: Asthma, chronic obstructive pulmonary disease, dyspnea, flu-like symptoms, hyperventilation, pharyngeal edema, pharyngolaryngeal pain, respiratory distress, rhinitis, snoringContraindicationsBreast cancer (males); prostate cancer (known or suspected); pregnancy.Natesto, Striant, transdermal solution: Additional contraindications: Breastfeeding patients; patients who may become pregnant.Aveed: Additional contraindications: Hypersensitivity to testosterone undecanoate, castor oil, benzyl benzoate.Depo-Testosterone: Additional contraindications: Hypersensitivity to testosterone cypionate, serious cardiac, hepatic, or renal disease.Testosterone enanthate (IM injection): Additional contraindications: Hypersensitivity to any component of the formulation; patients who may become pregnant.Testosterone enanthate (SUBQ injection): Additional contraindications: Hypersensitivity to any component of the formulation; males with hypogonadal conditions that are not associated with structural or genetic etiologies (eg, age-related hypogonadism); patients who may become pregnant.Testosterone undecanoate (oral): Additional contraindications: Hypersensitivity to any component of the formulation; males with hypogonadal conditions that are not associated with structural or genetic etiologies (eg, age-related hypogonadism).Canadian labeling: Additional contraindications (not in the US labeling): Androderm: Hypersensitivity to any component of the formulation; skin contact in pregnant or breastfeeding patients; not indicated for use in females.Documentation of allergenic cross-reactivity for androgens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Hypercalcemia: May cause hypercalcemia in patients with prolonged immobilization or cancer.Disease-related concerns:• Depression: Use with caution in patients with depression; testosterone may increase risk of depression and suicidal ideation. Evaluate patients with new onset or worsening depression, anxiety, mood changes, or suicidal ideation or behavior.• Hepatic impairment: Use with caution in patients with hepatic impairment; testosterone may cause fluid retention; testosterone cypionate is contraindicated in serious hepatic impairment.• Renal impairment: Use with caution in patients with renal impairment; testosterone may cause fluid retention; testosterone cypionate is contraindicated in serious renal impairment.• Sleep apnea: May potentiate sleep apnea in some patients, especially those with risk factors (eg, obesity or chronic lung disease). Withhold initial treatment in patients with untreated obstructive sleep apnea (ES [Bhasin 2018]).Special populations:• Older adults: Patients >65 years of age may be at greater risk for prostatic hyperplasia, prostate cancer, fluid retention, and transaminase elevations. Testosterone replacement in patients >65 years of age is not routinely recommended and should only be considered on a case by case basis if conditions or symptoms suggestive of low testosterone are present along with consistently and unequivocally low morning testosterone concentrations (ES [Bhasin 2018]).• Pediatric: May accelerate bone maturation (without producing compensatory gain in linear growth) and premature closure of the epiphyses in children; in prepubertal children perform radiographic examination of the hand and wrist every 6 months to determine the rate of bone maturation and to assess the effect of treatment on the epiphyseal centers. Use with caution in males with delayed puberty. Some formulations/products are not approved for use in patients <18 years of age.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.• Castor oil: Some products may contain castor oil.• Gel, intranasal: Use of the intranasal gel is not recommended in patients with sinus disease, mucosal inflammatory disorders (eg, Sjogren syndrome), or with a history of nasal disorders, nasal or sinus surgery, nasal fracture within the previous 6 months, or nasal fracture that caused a deviated anterior nasal septum. Safety and efficacy have not been established in patients with a BMI >35 kg/m2.• Gel, topical: Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure; these products are not interchangeable.• Injection: Testosterone cypionate should not be used interchangeably with testosterone propionate due to differences in duration of action.• Pellet: Pellet insertion has been associated with infection and/or pellet extrusion at or around the implantation site, occurring concurrently or separately. Most reported cases occurred <1 month after implantation. Symptoms may include induration, inflammation, fibrosis, bleeding, bruising, drainage, pain, itching, and pellet extrusion; further treatment may be warranted if infection or extrusion occurs.• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer’s labeling.• Sesame oil: Some products may contain sesame oil.• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI.• Transdermal solution: Transdermal solution is not interchangeable with other topical testosterone products. Use in patients with BMI >35 kg/m2 has not been established.Other warnings/precautions:• Abuse/misuse/diversion: Anabolic steroids may be abused, typically at doses higher than recommended and in combination with other anabolic androgenic steroids; abuse may be associated with serious cardiovascular and psychiatric adverse reactions. Inform patients of the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids; if abuse is suspected, check serum testosterone levels (testosterone levels may be in the normal or subnormal range in males abusing synthetic testosterone derivatives). Consider the possibility of abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.• Dependence: Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented; however, dependence may occur when used outside of approved dosage/indications.Warnings: Additional Pediatric ConsiderationsSome dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Agents with Blood Glucose Lowering Effects: Androgens may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects.Risk C: Monitor therapyAjmaline: Androgens may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased.Risk C: Monitor therapyC1 inhibitors: Androgens may enhance the thrombogenic effect of C1 inhibitors.Risk C: Monitor therapyCorticosteroids (Systemic): May enhance the fluid-retaining effect of Androgens. Risk C: Monitor therapyCycloSPORINE (Systemic): Androgens may enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic).Management: Consider avoiding concomitant use of androgens and cyclosporine. If concomitant use is unavoidable, monitor serum cyclosporine concentrations and for signs and symptoms of hepatotoxicity. Cyclosporine dose reductions may be required. Risk D: Consider therapy modificationDehydroepiandrosterone: May enhance the adverse/toxic effect of Testosterone. Risk X: Avoid combinationHypertension-Associated Agents: May enhance the hypertensive effect of Androgens. Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): Androgens may enhance the anticoagulant effect of Vitamin K Antagonists.Management: Monitor for increased effects of vitamin K antagonists if an androgen is initiated/dose increased, or decreased effects if androgen is discontinued/dose decreased. Significant reductions in vitamin K antagonist dose are likely required. Risk D: Consider therapy modificationReproductive ConsiderationsUse of some products is contraindicated in persons who may become pregnant.Large doses of testosterone may suppress spermatogenesis; the impact on fertility may be irreversible. Treatment of hypogonadotropic hypogonadism with testosterone is not recommended for males desiring fertility within 6 to 12 months (ES [Bhasin 2018]).Testosterone is a component of therapy for transgender males. Menstruation may be suppressed but ovulation may occur. Although treatment may cause temporary or permanent infertility, unintended pregnancies have been reported. Consider contraception in transgender males having sex with males. Successful planned pregnancies have been reported following cessation of testosterone therapy (ACOG 2021; Cheung 2019; ES [Hembree 2017]; Light 2014; Taub 2020). All available forms of contraception can be considered for patients receiving gender affirming testosterone therapy after evaluating the appropriateness of the method based on patient preferences and medical conditions (Bonnington 2020; Krempasky 2020).Abuse of anabolic steroids may cause irregular menstruation and female infertility (ACOG 2011).Testosterone has been evaluated for the treatment of hypoactive sexual desire disorder, primarily in postmenopausal patients. There are no FDA-approved formulations available for this indication. Transdermal products at 1% of the male dose may be an option in patients diagnosed following a formal biopsychosocial assessment, however robust long-term (>24 months) safety data are not available. Compounded testosterone products or off label use of pellets, IM injection and oral formulations is not recommended. Additional study is needed (Parish 2021).Pregnancy ConsiderationsUse is contraindicated during pregnancy.Exposure to a fetus may cause virilization of varying degrees. Because of the potential for secondary exposure, all persons should avoid skin-to-skin contact to areas where testosterone has been applied topically on another person.Some products contain benzyl alcohol, which can cross the placenta.Breastfeeding ConsiderationsTestosterone is present in breast milk.Information related to the presence of testosterone in breast milk is available from case reports:- Distribution of testosterone in breast milk was evaluated following use of the subcutaneous pellet in a breastfeeding woman. Prior to therapy, milk concentrations of testosterone were 96 pg/mL. Following SubQ implantation of the 100 mg pellet, milk samples ranged from 88 pg/mL (day 2) to 100 pg/mL (day 7 [morning]). Reported maternal serum samples ranged from <100 pg/mL (baseline), 2,830 pg/mL (day 2), and 1,480 pg/mL (day 7 [morning]). Adverse events were not observed in the breastfeeding male infant after 7 months of continuous maternal therapy (Glaser 2009).- A case report describes milk concentrations of testosterone in a lactating male who initiated gender affirming testosterone therapy when the infant was 13 months of age. SUBQ testosterone cypionate 50 mcg was administered weekly; milk and infant serum testosterone were measured prior to the first dose and over the first month of therapy. Milk concentrations were 0.462 ng/dL (baseline), 20.85 ng/dL (14 days after therapy initiated), and 12.36 ng/dL (28 days after the first dose of testosterone). Infant serum concentrations were <7 ng/dL at all time points. In comparison, the total testosterone concentration in the parent serum were 14 ng/dL at baseline and increased to 430 ng/dL after 28 days. It was not stated how much milk was ingested by the infant (Oberhelm 2020).Because of the potential for secondary exposure, all persons should avoid skin-to-skin contact to areas where testosterone has been applied topically on another person.High levels of endogenous maternal testosterone, such as those caused by certain ovarian cysts, suppress milk production. Maternal serum testosterone levels generally fall following pregnancy and return to normal once breastfeeding is stopped (Betzold 2004; Hoover 2002). Some products are specifically contraindicated while breastfeeding. Because testosterone may suppress milk production, reinitiating treatment in transgender males after pregnancy is not recommended until chestfeeding is complete (ACOG 2021).Monitoring ParametersPrior to treatment initiation: Confirm hypogonadism by measuring serum total testosterone on at least 2 separate mornings following overnight fasting. LFTs, lipid panel, hemoglobin and hematocrit (withhold initial treatment with hematocrit >48% or >50% in males living at higher altitudes) (ES [Bhasin 2018]). Evaluate cardiovascular risk factors. PSA and prostate exam in males 55 to 69 years of age or ≥40 years of age and at increased risk for prostate cancer (withhold treatment pending urological evaluation in patients with palpable prostate nodule or induration or PSA >4 ng/mL or if PSA >3 ng/mL in males at high risk of prostate cancer (ES [Bhasin 2018]); BP.During treatment:BP (3 to 6 weeks after initiation or dosage adjustments, and periodically thereafter), LFTs, lipid panel, hemoglobin and hematocrit (at 3 to 6 months, at 12 months, then annually); discontinue therapy if hematocrit exceeds 54% (ES [Bhasin 2018]). Monitor urine and serum calcium and signs of virilization in females treated for breast cancer. Serum glucose (may be decreased by testosterone, monitor patients with diabetes). Evaluate males for response to treatment and adverse events 3 to 12 months after initiation and then annually; monitor for cardiovascular events closely during therapy. Monitor for symptoms of pain, edema, warmth, and erythema in the lower extremity (evaluate for deep vein thrombosis) and acute shortness of breath (evaluate for pulmonary embolism).Bone mineral density:Prepubertal children: Radiologic examination of wrist and hand every 6 months.Males with hypogonadism and osteoporosis or low trauma fracture: Monitor after 1 to 2 years of therapy (ES [Bhasin 2018]).Prostate-specific antigen (PSA): In males 55 to 69 years of age or ≥40 years of age and at increased risk for prostate cancer, PSA and prostate exam at 3 to 12 months, then as recommended based on current prostate cancer screening guidelines. Withhold treatment pending urological evaluation if there is a confirmed increase in PSA of >1.4 ng/mL from baseline, a confirmed PSA >4.0 ng/mL, or prostatic abnormality or substantial worsening of LUTS (ES [Bhasin 2018]).Testosterone (free): Free testosterone should be measured in patients with conditions associated with increased or decreased SHBG, or in patients with total testosterone concentrations in the borderline zone around the lower limit of the normal range (eg 200 to 400 ng/dL) (ES [Bhasin 2018]).Testosterone (total):General recommendations: 3 to 6 months after initiation (formulation-dependent), at 12 months, then every 6 to 12 months (AUA [Mulhall 2018]; ES [Bhasin 2018]).Formulation-specific monitoring:Buccal: Striant: Examine application area of gums; total serum testosterone 4 to 12 weeks after initiating treatment, prior to morning dose. Discontinue therapy if the total serum testosterone is consistently outside of the normal range.Injection:Testosterone cypionate injection, testosterone enanthate IM injection: Measure testosterone level midway between injections (ES [Bhasin 2018]).Testosterone enanthate SUBQ injection (Xyosted): Measure total testosterone trough levels after 6 weeks of dosing, after 6 weeks following a dose adjustment, and periodically during therapy. Trough concentrations should be measured 7 days after the most recent dose.Testosterone undecanoate (Aveed): Monitor for 30 minutes after injection; appropriate treatment should be available in the event of a serious POME reaction or anaphylaxis. Measure testosterone level just prior to each subsequent injection and adjust dosing interval to maintain nadir levels in low-mid range (ES [Bhasin 2018]). Alternatively, may measure halfway between each 10-week injection (AUA [Mulhall 2018]).Intranasal: Natesto: Measure testosterone periodically, beginning 1 month after initiating therapy. Discontinue therapy if the total serum testosterone is consistently outside of the normal range.Oral capsule:Jatenzo: Measure testosterone 6 hours after the morning dose beginning 7 days after initiation of therapy or after dosage adjustments and then periodically thereafter.Kyzatrex: Measure testosterone 3 to 5 hours after morning dose beginning 7 days after initiating therapy or after dosage adjustments and then periodically thereafter.Tlando: Measure testosterone 8 to 9 hours after morning dose beginning 3 to 4 weeks after initiating therapy and periodically thereafter. Discontinue therapy if total serum testosterone is consistently outside the normal range.40 mg capsule [Canadian product]: Measure testosterone 5 hours after a dose.Pellet (for subcutaneous implant): Testopel: Measure testosterone at the end of the dosing interval (ES [Bhasin 2018]).Topical: Note: Serum concentrations may vary substantially with topical gel or solution; single measurements may not consistently correspond to average testosterone levels and may not adequately guide dosage adjustments (Muram 2016; Swerdloff 2015).AndroGel 1%: Morning (pre-dose) serum testosterone levels ~14 days after start of therapy or dose adjustments.AndroGel 1.62%: Morning (pre-dose) serum testosterone levels after 14 and 28 days of starting therapy or dose adjustments and periodically thereafter.Androderm: Morning serum testosterone levels (following application the previous evening) ~14 days after start of therapy or dose adjustments.Fortesta: Serum testosterone levels can be measured 2 hours after application and after 14 and 35 days of starting therapy or dose adjustments.Testim: Morning (pre-dose) serum testosterone levels ~14 days after start of therapy or dose adjustments.Transdermal solution: Serum testosterone levels can be measured 2 to 8 hours after application and after 14 days of starting therapy or dose adjustments.Vogelxo: Morning (pre-dose) serum testosterone ~14 days after initiation of therapy. Hormone therapy for transgender males (assigned female at birth) (off-label use): Routine cancer and laboratory screening as in nontransgender individuals for all tissues present; serum testosterone levels every 3 months during the first year and then annually or biannually. Ensure testosterone levels remain within normal range for males throughout treatment (eg, 320 to 1,000 ng/dL) (ES [Hembree 2017]).Reference RangeTotal testosterone normal reference range for males (CDC-certified labs) (Travison 2017):2.5th and 97.5th percentile: 264 to 916 ng/dL5th and 95th percentile: 303 to 852 ng/dLNote: Due to diurnal fluctuations, diagnostic measurements should be obtained on at least 2 separate mornings while patient is fasting. Results from laboratories that are not CDC certified or otherwise standardized according to an accuracy-based quality control program may vary considerably (ES [Bhasin 2018]).Total testosterone therapeutic goal: 350 to 600 ng/dL (midnormal range for most labs) is a reasonable target for most patients on testosterone therapy to minimize potential for over- or under-treatment (AUA [Mulhall 2018]; ES [Bhasin 2018]). Some data suggest a slightly lower testosterone target may be reasonable in older patients (eg, the lower end of the normal testosterone range) (AUA [Mulhall 2018]).Free testosterone: The normal free testosterone reference range varies by laboratory and a CDC harmonized standard has not yet been established; therefore, the Endocrine Society recommends referring to ranges established within each local laboratory (ES [Bhasin 2018]).Mechanism of ActionPrincipal endogenous androgen responsible for promoting the growth and development of the male sex organs and maintaining secondary sex characteristics in androgen-deficient malesPharmaco*kineticsDuration (route and ester dependent): IM: Cypionate and enanthate esters: 2 to 4 weeks; Undecanoate: 10 weeks; Transdermal gel: 24 hours.Absorption: Transdermal gel: ~10% of applied dose.Protein binding: 98%; bound to sex hormone-binding globulin (40%) and albumin.Metabolism: Hepatic; forms metabolites, including dihydrotestosterone (DHT) and estradiol (both active).Bioavailability: Oral capsule: Jatenzo: Absolute bioavailability not reported; relative bioavailability decreased 25% when taken with lower fat content meal (eg, 15 g) versus higher fat content meal (eg, ≥30 g); Tlando: Absolute bioavailability not reported; administration in fasting conditions resulted in approximately 65% lower Cmax and 38% lower AUC compared to administration with food (high fat meal); 40 mg capsule [Canadian product]: ~7% (absolute bioavailability).Half-life elimination: Variable: 10 to 100 minutes; Testosterone cypionate: ~8 days.Time to peak: IM (undecanoate): 7 days (median; range: 4 to 42 days); Intranasal: ~40 minutes; Transdermal system: 8 hours (range: 4 to 12 hours); Buccal system: 10 to 12 hours; Oral capsule: Jatenzo: ~2 to 4 hours; Kyzatrex: ~4 hours; Tlando: ~5 hours; 40 mg capsule [Canadian product]: 4 to 5 hours; SUBQ (Xyosted): 11.9 hours (median; range: 5.8 to 168.7 hours) following weekly administration for 12 weeks.Excretion: Urine (90%; 40 mg oral capsule [Canadian product]: 45% to 48%); feces (6%).Pricing: USCapsules (Jatenzo Oral)158 mg (per each): $9.63198 mg (per each): $9.63237 mg (per each): $19.25Capsules (Kyzatrex Oral)100 mg (per each): $2.00150 mg (per each): $2.00200 mg (per each): $2.00Capsules (Tlando Oral)112.5 mg (per each): $7.44Gel (AndroGel Pump Transdermal)20.25 MG/ACT (1.62%) (per gram): $9.94Gel (AndroGel Transdermal)25 MG/2.5GM (1%) (per gram): $9.97Gel (Fortesta Transdermal)10 MG/ACT (2%) (per gram): $8.28Gel (Natesto Nasal)5.5 mg/ACT (per gram): $45.10Gel (Testim Transdermal)50 MG/5GM (1%) (per gram): $4.74Gel (Testosterone Transdermal)10 MG/ACT (2%) (per gram): $6.83 - $7.8712.5 MG/ACT (1%) (per gram): $2.75 - $3.0020.25 MG/ACT (1.62%) (per gram): $1.42 - $9.4420.25 MG/1.25GM (1.62%) (per gram): $10.75 - $18.9425 MG/2.5GM (1%) (per gram): $5.8340.5 MG/2.5GM (1.62%) (per gram): $5.81 - $9.7450 MG/5GM (1%) (per gram): $2.75 - $3.88Gel (Vogelxo Pump Transdermal)12.5 MG/ACT (1%) (per gram): $3.56Gel (Vogelxo Transdermal)50 MG/5GM (1%) (per gram): $3.56Patch, 24-hour (Androderm Transdermal)2 mg/24 hrs (per each): $12.324 mg/24 hrs (per each): $24.64Pellet (Testopel Implant)75 mg (per each): $129.82Solution (Aveed Intramuscular)750 mg/3 mL (per mL): $653.57Solution (Depo-Testosterone Intramuscular)100 mg/mL (per mL): $9.26200 mg/mL (per mL): $25.20Solution (Testosterone Cypionate Intramuscular)100 mg/mL (per mL): $5.91 - $8.98200 mg/mL (per mL): $21.60 - $67.50Solution (Testosterone Enanthate Intramuscular)200 mg/mL (per mL): $17.93Solution (Testosterone Transdermal)30 mg/ACT (per mL): $3.37 - $6.88Solution Auto-injector (Xyosted Subcutaneous)50 mg/0.5 mL (per 0.5 mL): $173.2175 mg/0.5 mL (per 0.5 mL): $173.21100 mg/0.5 mL (per 0.5 mL): $173.21Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAndriol (EG, MX, UA);Androderm (AU, BB, NZ);AndroForte (AU);Androgel (AE, BE, BH, CU, CZ, EE, FR, HK, HN, HU, IT, LB, MY, NL, PL, RU, SA, SG, TH, TW, UA, VN);Andromen (EG);Andropatch (GR);Aquaviron (IN);Axiron (AU);Depo-Test (TH);Depo-Testosterone (BB, ZA);Hormon-M (TW);Intrinsa Patch (IE);Itnogen (ES);Jenasteron (KR);Nebido (AT, BE, BG, BH, DE, DK, EE, EG, FR, HK, HR, HU, ID, IE, IL, IS, KW, LB, LT, LU, LV, MY, NL, NO, PL, QA, RO, UA, VN);Omnadren (PL, UA);Primoteston Depot (AU, BF, BJ, CI, EC, ET, GH, GM, GN, KE, KR, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Primotestone Depot (AE);Proviron Depot (VE);Reandron (ES);Sustanon (BH, JO, SA);Testex (ES);Testim (BE, DK, ES, GB, HU, IE, IS, LU, LV, MT, NO, PL, SI, SK);Testocaps (LU);Testoderm (AT);Testogel (BG, DK, IE, IS, TR);Testom (RO);Testopatch (FR);Testosteron Ferring (AT);Testosteronum propionicum (PL);Testotop (LU);Testoviron (CY, JO, PK, SI, TR);Testoviron Depot (HK, LK, QA, SA);Testoviron-Depot (AR, CH, CO, DE, IL, PE, PT, PY, SE, UY);Tostran (GB, IE);Tostrex (ID);Tostrex Gel (KR);Virormone (AE, BH, CY, IQ, IR, JO, LY, OM, SA, SY, YE);Vivrone (PH);Y45 (BD)For country code abbreviations (show table)2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767. [PubMed 30693946]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]American College of Obstetricians and Gynecologists (ACOG) Committee on Gynecologic Practice and Committee on Health Care for Underserved Women. ACOG Committee Opinion No. 823: Health care for transgender and gender diverse individuals. Obstet Gynecol. 2021;137(3):e75-e88. doi:10.1097/AOG.0000000000004294 [PubMed 33595253]American College of Obstetricians and Gynecologists (ACOG) Committee on Gynecologic Practice. ACOG Committee Opinion No. 484: Performance enhancing anabolic steroid abuse in women. Obstet Gynecol. 2011;117(4):1016-1018. doi:10.1097/AOG.0b013e3182192281 [PubMed 21422881]American Urological Association (AUA). AUA Position statement on testosterone therapy. 2014. Available at https://www.auanet.org/guidelines/archived-documents/testosterone-therapy [PubMed AUA.1]Androderm (testosterone transdermal system) [prescribing information]. Madison, NJ: Allergan USA Inc; May 2020.Androderm (testosterone transdermal system) [product monograph]. Markham, Ontario, Canada: Allergan Inc; February 2018.AndroGel 1% (testosterone) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2019.AndroGel 1.62% (testosterone) [prescribing information]. North Chicago, IL: AbbVie Inc; November 2020.Aveed (testosterone undecanoate) [prescribing information]. Malvern, PA: Endo Pharmaceuticals Inc; August 2021.Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc. 2015;90(8):1038-1045. doi:10.1016/j.mayocp.2015.05.012 [PubMed 26205547]Barghouthi N, Turner J, Perini J. Breast cancer development in a transgender male receiving testosterone therapy. Case Rep Endocrinol. 2018;2018:3652602. doi:10.1155/2018/3652602 [PubMed 30693115]Basaria S, Coviello AD, Travison TG. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122. [PubMed 20592293]Betzold CM, Hoover KL, Snyder CL. Delayed lactogenesis II: a comparison of four cases. J Midwifery Womens Health. 2004;49(2):132-137. [PubMed 15010666]Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. doi:10.1210/jc.2018-00229 [PubMed 29562364]Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. [PubMed 20525905]Bonnington A, Dianat S, Kerns J, et al. Society of Family Planning clinical recommendations: contraceptive counseling for transgender and gender diverse people who were female sex assigned at birth. Contraception. 2020;102(2):70-82. doi:10.1016/j.contraception.2020.04.001 [PubMed 32304766]Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]Cervi A, Balitsky AK. Testosterone use causing erythrocytosis. CMAJ. 2017;189(41):E1286-E1288. doi:10.1503/cmaj.170683 [PubMed 29038321]Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966. [PubMed 24935270]Cheung AS, Wynne K, Erasmus J, Murray S, Zajac JD. Position statement on the hormonal management of adult transgender and gender diverse individuals. Med J Aust. 2019;211(3):127-133. doi:10.5694/mja2.50259 [PubMed 31271465]Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13(10):1327-1351. [PubMed 25139126]de Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ. 2019;365:l1652. doi:10.1136/bmj.l1652 [PubMed 31088823]Depo-Testosterone (testosterone cypionate) [prescribing information]. New York, NY: Pfizer; August 2018.Ederveen EGT, van Hunsel FPAM, Wondergem MJ, van Puijenbroek EP. Severe secondary polycythemia in a female-to-male transgender patient while using lifelong hormonal therapy: a patient's perspective. Drug Saf Case Rep. 2018;5(1):6. doi:10.1007/s40800-018-0075-2 [PubMed 29396819]Endocrine Society news release. Endocrine Society Calls for Large-Scale Studies to Evaluate Testosterone Therapy Risks. 2014. Endocrine Society website. https://www.endocrine.org/news-room/press-release-archives/2014/endocrine-society-calls-for-large-scale-studies-to-evaluate-testosterone-therapy-risks. Accessed February 5, 2015.Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805. [PubMed 24489673]Fortesta (testosterone) [prescribing information]. Malvern, PA: Endo Pharmaceuticals Inc; January 2022.Gava G, Mancini I, Cerpolini S, Baldassarre M, Seracchioli R, Meriggiola MC. Testosterone undecanoate and testosterone enanthate injections are both effective and safe in transmen over 5 years of administration. Clin Endocrinol (Oxf). 2018;89(6):878-886. doi:10.1111/cen.13821 [PubMed 30025172]Glaser RL, Newman M, Parsons M et al. Safety of maternal testosterone therapy during breast feeding. Int J Pharm Compound. 2009;13:314-317.Glintborg D, T'Sjoen G, Ravn P, Andersen MS. Management of endocrine disease: optimal feminizing hormone treatment in transgender people. Eur J Endocrinol. 2021;185(2):R49-R63. doi:10.1530/EJE-21-0059 [PubMed 34081614]Glueck CJ, Goldenberg N, Wang P. Testosterone therapy, thrombophilia, venous thromboembolism, and thrombotic events. J Clin Med. 2018;8(1):11. doi:10.3390/jcm8010011 [PubMed 30577621]Glueck CJ, Prince M, Patel N, et al. Thrombophilia in 67 patients with thrombotic events after starting testosterone therapy. Clin Appl Thromb Hemost. 2016;22(6):548-553. doi:10.1177/1076029615619486 [PubMed 26620418]Goodale T, Sadhu A, Petak S, Robbins R. Testosterone and the heart. Methodist Debakey Cardiovasc J. 2017;13(2):68-72. doi:10.14797/mdcj-13-2-68 [PubMed 28740585]Grieshaber MC, Staub JJ, Flammer J. The potential role of testosterone in central serous chorioretinopathy. Br J Ophthalmol. 2007;91(1):118-119. doi:10.1136/bjo.2006.098277 [PubMed 17179128]Griggs J, Almohanna H, Ahmed A, Tosti A. New-onset androgenic alopecia following human chorionic gonadotropic diet and testosterone pellet implantation. Int J Trichology. 2018;10(6):284-285. doi:10.4103/ijt.ijt_75_18 [PubMed 30783337]Han TS and Bouloux PM, "What Is the Optimal Therapy for Young Males With Hypogonadotropic Hypogonadism?" Clin Endocrinol (Oxf), 2010, 72(6):731-7. [PubMed 19912242]Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. Endocr Pract. 2017;23(12):1437. doi:10.4158/1934-2403-23.12.1437 [PubMed 29320642]Hoover KL, Barbalinardo LH, Platia MP. Delayed lactogenesis II secondary to gestational ovarian theca lutein cysts in two normal singleton pregnancies. J Hum Lact. 2002;18(3):264-268. [PubMed 12192962]Ichioka K, Utsunomiya N, Kohei N, Ueda N, Inoue K, Terai A. Testosterone-induced priapism in Klinefelter syndrome. Urology. 2006;67(3):622.e17-e18. doi:10.1016/j.urology.2005.09.041 [PubMed 16504257]"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278. doi:10.1542/peds.99.2.268 [PubMed 9024461]Jan Z, Pfeifer M, Zorn B. Reversible testosterone-induced azoospermia in a 45-year-old man attending an infertility outpatient clinic. Andrologia. 2012;44(Suppl 1):823-825. doi:10.1111/j.1439-0272.2011.01192.x [PubMed 21762190]Jatenzo (testosterone) oral [prescribing information]. Northbrook, IL: Clarus Therapeutics Inc; June 2019.Kliegman RM, Stanton BMD, St. Geme J, Schor NF, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, PA: Saunders Elsevier; 2016.Krempasky C, Harris M, Abern L, Grimstad F. Contraception across the transmasculine spectrum. Am J Obstet Gynecol. 2020;222(2):134-143. doi:10.1016/j.ajog.2019.07.043 [PubMed 31394072]Kyzantrex capsules [prescribing information]. Raleigh, NC: Marius Pharmaceuticals; July 2022.Light AD, Obedin-Maliver J, Sevelius JM, Kerns JL. Transgender men who experienced pregnancy after female-to-male gender transitioning. Obstet Gynecol. 2014;124(6):1120-1127. doi:10.1097/AOG.0000000000000540 [PubMed 25415163]LiverTox: clinical and research information on drug-induced liver injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. [PubMed 31643176]Loo SY, Azoulay L, Nie R, Dell'Aniello S, Yu OHY, Renoux C. Cardiovascular and cerebrovascular safety of testosterone replacement therapy among aging men with low testosterone levels: a cohort study. Am J Med. 2019 Sep;132(9):1069-1077.e4. doi:10.1016/j.amjmed.2019.03.022 [PubMed 30953635]Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ. 2016;355:i5968. doi:10.1136/bmj.i5968 [PubMed 27903495]Medras M, Filus A, Jozkow P, Wiowski J, Sicinska-Werner T. Breast cancer and long-term hormonal treatment of male hypogonadism. Breast Cancer Res Treat. 2006; 96(3): 263-265. [PubMed 16418796]Meyer RJ, Mann M. Pulmonary oil micro-embolism (POME) syndrome: a review and summary of a large case series. Curr Med Res Opin. 2015;31(4):837-841. doi:10.1185/03007995.2015.1012254 [PubMed 25686650]Miller MG, Rogol AD, Zumbrunnen TL. Secondary exposure to testosterone from patients receiving replacement therapy with transdermal testosterone gels. Curr Med Res Opin. 2012;28(2):267-269. doi:10.1185/03007995.2011.652255 [PubMed 22185432]Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. 2015;90(2):224-251. [PubMed 25636998]Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432. doi:10.1016/j.juro.2018.03.115 [PubMed 29601923]Muram D, Ni X. Utility of a single serum testosterone measurement to determine response to topical testosterone replacement in hypogonadal men. Curr Med Res Opin. 2016;32(2):263-9. doi: 10.1185/03007995.2015.1117434. [PubMed 26549704]Natesto (testosterone nasal gel) [prescribing information]. Englewood, CO: Aytu BioScience, Inc; December 2021.Oberhelman S, Chang A, Braith A, et al. Testosterone impacts on milk and infant in a lactating transgender individual, a case report. Breastfeed Med. 2020;15:A-24. doi:10.1089/bfm.2020.29162.abstractsOhlander SJ, Varghese B, Pastuszak AW. Erythrocytosis following testosterone therapy. Sex Med Rev. 2018;6(1):77-85. doi:10.1016/j.sxmr.2017.04.001 [PubMed 28526632]Osterberg EC, Bernie AM, Ramasamy R. Risks of testosterone replacement therapy in men. Indian J Urol. 2014;30(1):2-7. doi:10.4103/0970-1591.124197 [PubMed 24497673]Palmert MR and Dunkel L, "Clinical Practice. Delayed Puberty," N Engl J Med, 2012, 366(5):443-53. [PubMed 22296078]Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Womens Health (Larchmt). 2021;30(4):474-491. doi:10.1089/jwh.2021.29037 [PubMed 33797277]Pastuszak AW, Hu Y, Freid JD. Occurrence of pulmonary oil microembolism after testosterone undecanoate injection: a postmarketing safety analysis. Sex Med. 2020;8(2):237-242. doi:10.1016/j.esxm.2020.01.009 [PubMed 32184081]Patel A, Rivkees SA. Prenatal virilization associated with paternal testosterone gel therapy. Int J Pediatr Endocrinol. 2010:867471. doi:10.1155/2010/867471 [PubMed 20976267]Pelusi C, Costantino A, Martelli V, et al. Effects of three different testosterone formulations in female-to-male transsexual persons. J Sex Med. 2014;11(12):3002-3011. doi: 10.1111/jsm.12698. [PubMed 25250780]Petak SM, Nankin HR, Spark RF, et al, “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients − 2002 Update,” Endocr Pract, 2002, 8(6):440-56. [PubMed 15260010]Petering RC, Brooks NA. Testosterone therapy: review of clinical applications. Am Fam Physician. 2017 Oct 1;96(7):441-449. [PubMed 29094914]Poirier-Blanchette L, Koolian M, Schwartz BC. Testosterone replacement therapy causing extensive portal and mesenteric vein thrombosis. Am J Med. 2021;134(7):e426-e427. doi:10.1016/j.amjmed.2020.12.018 [PubMed 33444584]Rastrelli G, Vignozzi L, Corona G, Maggi M. Testosterone and benign prostatic hyperplasia. Sex Med Rev. 2019;7(2):259-271. doi:10.1016/j.sxmr.2018.10.006 [PubMed 30803920]Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. 2016;34(25):3069-3103. doi:10.1200/JCO.2016.67.1487 [PubMed 27217461]Safer JD, Tangpricha V. Care of the transgender patient. Ann Intern Med. 2019;171(1):ITC1-ITC16. doi:10.7326/AITC201907020 [PubMed 31261405]Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med. 2009;10(2):256-259. [PubMed 19188870]Sperling MA, ed. Pediatric Endocrinology. 4th ed. Canada: Elsevier; 2014.Spratt DI, Stewart II, Savage C, et al. Subcutaneous injection of testosterone is an effective and preferred alternative to intramuscular injection: demonstration in female-to-male transgender patients. J Clin Endocrinol Metab. 2017;102(7):2349-2355. doi:10.1210/jc.2017-00359 [PubMed 28379417]Striant (testosterone) [prescribing information]. Malvern, PA: Actient Pharmaceuticals LLC; October 2016.Swerdloff RS, Pak Y, Wang C, et al. Serum testosterone (T) level variability in T Gel-treated older hypogonadal men: treatment monitoring implications. J Clin Endocrinol Metab. 2015;100(9):3280-3287. doi: 10.1210/JC.2015-1542. [PubMed 26120790]Swerdloff RS, Wang C, White WB, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020;105(8):2515-2531. doi:10.1210/clinem/dgaa238 [PubMed 32382745]Tangpricha V, Safer JD. Transgender men: Evaluation and management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 12, 2022.Taro-Testosterone (testosterone undecanoate) [product monograph]. Brampton Ontario, Canada: Taro Pharmaceuticals Inc; October 2018.Taub RL, Ellis SA, Neal-Perry G, Magaret AS, Prager SW, Micks EA. The effect of testosterone on ovulatory function in transmasculine individuals. Am J Obstet Gynecol. 2020;223(2):229.e1-229.e8. doi:10.1016/j.ajog.2020.01.059 [PubMed 32044312]Testim (testosterone) [prescribing information]. San Antonio, TX: DPT Laboratories Ltd; August 2021.Testopel (testosterone) [prescribing information]. Malvern, PA: Endo Pharmaceuticals, Inc; August 2018.Testosterone enanthate injection [prescribing information]. Eatontown, NJ: West-Ward Pharmaceutical; November 2016.Testosterone topical solution [prescribing information]. Upper Saddle River, NJ: Dash Pharmaceuticals LLC; June 2021.Testosterone transdermal solution [prescribing information]. Warren NJ: Cipla; August 2020.Thomas SR, Evans PJ, Holland PA, Biswas M. Invasive breast cancer after initiation of testosterone replacement therapy in a man--a warning to endocrinologists. Endocr Pract. 2008;14(2):201-203. doi:10.4158/EP.14.2.201 [PubMed 18308658]Tikka T, Mistry N, Janjua A. Acute unilateral sensorineural hearing loss associated with anabolic steroids and polycythaemia: case report. J Laryngol Otol. 2016;130(3):309-313. doi:10.1017/S0022215115003187 [PubMed 26653249]Tlando (testosterone capsules) [prescribing information]. Ewing, NJ: Antares Pharma Inc; March 2022.Travison TG, Vesper HW, Orwoll E, et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab. 2017;102(4):1161-1173. doi:10.1210/jc.2016-2935 [PubMed 28324103]US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.Vigen R, O'Donnell CI, Barón AE. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels [published correction appears in JAMA. 2014;311(9):967]. JAMA. 2013;310(17):1829-1836. [PubMed 24193080]Vogelxo (testosterone) [prescribing information]. Maple Grove, MN: Upsher-Smith Laboratories LLC; April 2020.Wales JK. Disordered pubertal development. Arch Dis Child Educ Pract Ed. 2012, 97(1):9-16. [PubMed 21278425]Walker RF, Zakai NA, MacLehose RF, et al. Association of testosterone therapy with risk of venous thromboembolism among men with and without hypogonadism. JAMA Intern Med. 2020;180(2):190-197. doi:10.1001/jamainternmed.2019.5135 [PubMed 31710339]Wierckx K, Van Caenegem E, Schreiner T, et al. Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results from the European network for the investigation of gender incongruence. J Sex Med. 2014;11(8):1999-2011. doi: 10.1111/jsm.12571. [PubMed 24828032]Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(10):3489-3510. doi: 10.1210/jc.2014-2260. [PubMed 25279570]Xyosted (testosterone) [prescribing information]. Ewing, NJ: Antares Pharma, Inc; September 2018.Zacharin MR and Warne GL, "Treatment of Hypogonadal Adolescent Boys With Long Acting Subcutaneous Testosterone Pellets," Arch Dis Child, 1997, 76(6):495-9. [PubMed 9245845]Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20(3):217-219. doi:10.1111/j.1525-139X.2007.00280.x [PubMed 17555487]Topic 9981 Version 577.0

CloseAdalimumab (including biosimilars): Pediatric drug informationAdalimumab (including biosimilars): Pediatric drug information(For additional information see "Adalimumab (including biosimilars): Drug information" and see "Adalimumab (including biosimilars): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningSerious infections:Patients treated with adalimumab are at increased risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.Discontinue adalimumab if a patient develops a serious infection or sepsis. Reported infections include the following:Active tuberculosis (TB), including reactivation of latent TB. Patients with TB frequently have presented with disseminated or extrapulmonary disease. Test patients for latent TB before adalimumab use and during therapy. Initiate treatment for latent infection prior to adalimumab use.Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk of invasive fungal infections who develop severe systemic illness.Bacterial, viral, and other infections caused by opportunistic pathogens, including Legionella and Listeria.Carefully consider the risks and benefits of treatment with adalimumab prior to initiating therapy in patients with chronic or recurrent infection.Monitor patients closely for the development of signs and symptoms of infection during and after treatment with adalimumab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.Malignancy:Lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with tumor necrosis factor (TNF)–blockers, including adalimumab. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF-blockers, including adalimumab. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF-blocker cases have occurred in patients with Crohn disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF-blocker or a TNF-blocker in combination with these other immunosuppressants.Brand Names: USHumira;Humira Pediatric Crohns Start;Humira Pen;Humira Pen-CD/UC/HS Starter;Humira Pen-Pediatric UC Start;Humira Pen-Ps/UV/Adol HS Start;Humira Pen-Psor/Uveit StarterBrand Names: CanadaAbrilada;Amgevita;Amgevita SureClick;Hadlima;Hadlima PushTouch;Hulio;Humira;Hyrimoz;Idacio;Simlandi;YuflymaTherapeutic CategoryAntirheumatic, Disease Modifying;Gastrointestinal Agent, Miscellaneous;Monoclonal Antibody;Tumor Necrosis Factor (TNF) Blocking AgentDosing: PediatricNote: Amjevita (adalimumab-atto), Cyltezo (adalimumab-adbm), Hadlima (adalimumab-bwwd), Hulio (adalimumab-fkjp), and Hyrimoz (adalimumab-adaz) are approved as biosimilar agents to Humira. Approved ages and uses may vary (Ref).Crohn disease; moderate to severeCrohn disease; moderate to severe:Children ≥6 years and Adolescents:17 kg to <40 kg: SUBQ:Initial: 80 mg on day 1, then 40 mg administered 2 weeks later (day 15).Maintenance (beginning day 29): 20 mg every other week (Ref). Patients who continue to experience flares after 12 weeks of therapy may benefit from weekly dosing (Ref).≥40 kg: SUBQ:Initial: 160 mg (administered on day 1 or split and administered over 2 consecutive days), then 80 mg administered 2 weeks later (day 15).Maintenance (beginning day 29): 40 mg every other week (Ref). Weekly dosing should be considered for patients with loss of response or low trough concentrations (<7.5 mcg/mL) (Ref).Hidradenitis suppurativaHidradenitis suppurativa:Children ≥12 years and Adolescents:30 to <60 kg: SUBQ:Initial: 80 mg on day 1.Maintenance (beginning day 8): 40 mg every other week.≥60 kg: SUBQ:Initial: 160 mg (administered as full dose on day 1 or dose split and administered over 2 consecutive days), then 80 mg 2 weeks later (day 15).Maintenance (beginning day 29): 40 mg weekly or 80 mg every other week.Juvenile idiopathic arthritisJuvenile idiopathic arthritis (JIA):Fixed dosing:Children ≥2 years and Adolescents:10 kg to <15 kg: SUBQ: 10 mg every other week.15 to <30 kg: SUBQ: 20 mg every other week.≥30 kg: SUBQ: 40 mg every other week.BSA-directed dosing: Note: Dosing based on trials performed with Humira product.Children 2 to <4 years: SUBQ: 24 mg/m2/dose every other week; maximum dose: 20 mg/dose (Ref).Children and Adolescents 4 to 17 years: SUBQ: 24 mg/m2/dose every other week; maximum dose: 40 mg/dose (Ref).Ulcerative colitis; moderate to severeUlcerative colitis; moderate to severe:Fixed dosing: Children ≥5 years and Adolescents:20 to <40 kg: SUBQ:Initial: 80 mg on day 1, then 40 mg administered weekly for 2 weeks (a dose on day 8 and day 15).Maintenance (beginning day 29): 40 mg every other week or 20 mg every week.≥40 kg: SUBQ:Initial: 160 mg on day 1 (administered as full dose on day 1 or dose split and administered over 2 consecutive days), then 80 mg administered weekly for 2 weeks (a dose on day 8 and day 15).Maintenance (beginning day 29): 80 mg every other week or 40 mg every week.BSA-directed dosing: Children and Adolescents: SUBQ: Initial: 92 mg/m2 (maximum dose: 160 mg/dose), then 46 mg/m2 (maximum dose: 80 mg/dose) 2 weeks later, then on day 29, begin maintenance therapy: 23 mg/m2 every other week (maximum dose: 40 mg/dose) (Ref). Note: Trials performed with Humira product.UveitisUveitis (noninfectious intermediate, posterior, and panuveitis):Fixed dosing: Children ≥2 years and Adolescents:10 kg to <15 kg: SUBQ: 10 mg every other week.15 to <30 kg: SUBQ: 20 mg every other week.≥30 kg: SUBQ: 40 mg every other week.BSA-directed dosing: Children ≥4 years and Adolescents: SUBQ: 24 or 40 mg/m2/dose every 2 weeks; maximum dose 40 mg/dose (Ref). Dosing based on one prospective trial comparing 24 mg/m2/dose every 2 weeks of adalimumab (n=16, ages 6 to 12 years) to infliximab (n=17, ages 5 to 13 years) and on a retrospective trial of biologic response modifiers, including 5 patients who received adalimumab at 40 mg/m2/dose every 2 weeks. Note: Trials performed with Humira product.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Adalimumab (including biosimilars): Drug information")Note: Patient should be under the care of a clinician experienced with use of adalimumab for the specific indication. Pretreatment screening: Screen for latent tuberculosis (TB) and hepatitis B virus before starting therapy; additional pretreatment screening (eg, hepatitis C, varicella zoster virus) may be warranted. For patients with significant active or latent infection, consultation with infectious diseases or other appropriate specialists (eg, pulmonary or hepatology) is generally warranted before initiating therapy. Treatment of latent TB is required before starting adalimumab (Ref). Avoid use in patients with severe active infections (Ref). Pretreatment immunizations: Patients should receive appropriate immunizations prior to starting therapy when feasible. Biosimilar agents: In Canada, Abrilada, Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Simlandi, and Yuflyma are also approved as biosimilars to Humira; refer to Canadian product monograph(s) for biosimilar-specific indication details.Axial spondyloarthritis, including ankylosing spondylitisAxial spondyloarthritis, including ankylosing spondylitis:Note: Reserve for patients who do not have an adequate response to nonsteroidal anti-inflammatory drugs (NSAIDs); may continue NSAIDs and/or analgesics (Ref).SUBQ: 40 mg every other week.Crohn disease, moderate to severe, induction and maintenance of remissionCrohn disease, moderate to severe, induction and maintenance of remission:Note: Combination therapy with an immunomodulator is generally preferred (Ref).Initial: SUBQ: 160 mg (given over 1 or 2 days), then 80 mg 2 weeks later (day 15). Note: If switching from another anti-tumor necrosis factor agent, may use this induction regimen.Maintenance: SUBQ: 40 mg every other week beginning day 29.Hidradenitis suppurativa, moderate to severe, refractoryHidradenitis suppurativa, moderate to severe, refractory:Initial: SUBQ: 160 mg (given over 1 or 2 days), then 80 mg 2 weeks later (day 15).Maintenance: SUBQ: 40 mg every week beginning day 29 or 80 mg every other week beginning day 29 (Ref). Note: 40 mg every week regimen has been more extensively studied and is therefore preferred by some experts (Ref).Nonradiographic axial spondyloarthritisNonradiographic axial spondyloarthritis (off-label use):Note: Reserve for patients who do not have an adequate response to NSAIDs; may continue NSAIDs and/or analgesics (Ref).SUBQ: 40 mg every other week.Peripheral spondyloarthritis, nonpsoriaticPeripheral spondyloarthritis, nonpsoriatic (off-label use):Note: May continue methotrexate, other nonbiologic DMARDs, corticosteroids, NSAIDs, and/or analgesics (Ref).SUBQ: 40 mg every other week (Ref).Plaque psoriasis, moderate to severePlaque psoriasis, moderate to severe:Note: Generally used as systemic monotherapy; may continue adjuvant topical therapies (eg, emollients, corticosteroids) as needed. A clinician experienced with use of adalimumab for plaque psoriasis should be involved in treatment.Initial: SUBQ: 80 mg as a single dose.Maintenance: SUBQ: 40 mg every other week beginning 1 week after initial dose. Note: Some patients may require 40 mg every week (Ref).Psoriatic arthritisPsoriatic arthritis:Note: May continue methotrexate, other nonbiologic DMARDs, corticosteroids, NSAIDs, and/or analgesics.SUBQ: 40 mg every other week.Rheumatoid arthritisRheumatoid arthritis:Note: For use as an alternative to methotrexate in disease-modifying antirheumatic drug (DMARD)–naive patients with moderate to high disease activity, or as adjunctive therapy in patients who have not met treatment goals despite maximally tolerated methotrexate therapy (Ref). May use in combination with other nonbiologic DMARDs, glucocorticoids, NSAIDs, and/or analgesics. A clinician experienced, NSAIDs, and/or analgesics. A clinician experienced with use of adalimumab for rheumatoid arthritis should be involved in treatment.SUBQ: Initial: 40 mg every other week; for select patients with an inadequate response, may increase dose to 40 mg every week or 80 mg every other week.Sarcoidosis, refractorySarcoidosis, refractory (adjunctive agent) (off-label use):Note: For use as an adjunctive agent in patients in whom treatment goals have not been met despite glucocorticoids and other immunosuppressants (eg, methotrexate) (Ref). A clinician experienced with use of adalimumab should be involved in treatment.Initial: SUBQ: The optimal dosing strategy is not known; one example of an initial regimen is 40 to 120 mg on week 0, 40 to 80 mg on week 1, and 40 mg on week 2 (Ref).Maintenance: SUBQ: 40 mg every 1 to 2 weeks (Ref). The optimal frequency and duration of therapy are not known and must be individualized based on response; after a stable response is achieved (eg, after 6 months), one option is to gradually prolong the dosing interval (eg, to every 2 weeks) and discontinue after 3 months if response remains adequate (Ref).Ulcerative colitis, moderate to severe, induction and maintenance of remissionUlcerative colitis, moderate to severe, induction and maintenance of remission:Initial: SUBQ: 160 mg (given over 1 or 2 days), then 80 mg 2 weeks later (day 15).Maintenance: SUBQ: 40 mg every other week beginning day 29. If a disease flare occurs, some experts increase to 40 mg every week (Ref). Note: Only continue maintenance treatment in patients demonstrating clinical remission by 8 weeks (day 57) of therapy.Uveitis, noninfectiousUveitis, noninfectious:Note: Generally reserved for patients with an incomplete response to first-line agents and ≥1 other systemic therapies (Ref).Initial: SUBQ: 80 mg as a single dose.Maintenance: SUBQ: 40 mg every other week beginning 1 week after initial dose.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productPen-injector Kit, Subcutaneous [preservative free]: Humira Pen: 40 mg/0.8 mL (1 ea); 40 mg/0.4 mL (1 ea); 80 mg/0.8 mL (1 ea) [contains polysorbate 80]Humira Pen-CD/UC/HS Starter: 40 mg/0.8 mL (1 ea); 80 mg/0.8 mL (1 ea) [contains polysorbate 80]Humira Pen-Pediatric UC Start: 80 mg/0.8 mL (1 ea) [latex free; contains polysorbate 80]Humira Pen-Ps/UV/Adol HS Start: 40 mg/0.8 mL (1 ea) [contains polysorbate 80]Humira Pen-Psor/Uveit Starter: 80 MG/0.8ML & 40MG/0.4ML (1 ea) [contains polysorbate 80]Prefilled Syringe Kit, Subcutaneous [preservative free]: Humira: 10 mg/0.2 mL (1 ea [DSC]); 20 mg/0.4 mL (1 ea [DSC]); 40 mg/0.8 mL (1 ea); 10 mg/0.1 mL (1 ea); 20 mg/0.2 mL (1 ea); 40 mg/0.4 mL (1 ea) [contains polysorbate 80]Humira Pediatric Crohns Start: 40 mg/0.8 mL (1 ea [DSC]); 80 mg/0.8 mL (1 ea); 80 MG/0.8ML & 40MG/0.4ML (1 ea) [contains polysorbate 80]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productAuto-injector Kit, Subcutaneous: Simlandi: 40 mg/0.4 mL (1 ea, 2 ea) [contains polysorbate 80]Pen-injector Kit, Subcutaneous: Hulio: 40 mg/0.8 mL (2 ea) [contains polysorbate 80]Yuflyma: 40 mg/0.4 mL (1 ea, 2 ea, 4 ea, 6 ea) [contains polysorbate 80]Prefilled Syringe Kit, Subcutaneous: Hulio: 20 mg/0.4 mL (2 ea); 40 mg/0.8 mL (2 ea) [contains polysorbate 80]Simlandi: 40 mg/0.4 mL (1 ea, 2 ea); 80 mg/0.8 mL (1 ea, 2 ea) [contains polysorbate 80]Solution, Subcutaneous: Humira: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Solution Auto-injector, Subcutaneous: Abrilada: 40 mg/0.8 mL (0.8 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]Amgevita SureClick: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Hadlima PushTouch: 40 mg/0.8 mL (0.8 mL)Hyrimoz: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Idacio: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Solution Pen-injector, Subcutaneous: Humira: 40 mg/0.4 mL ([DSC]) [contains polysorbate 80]Solution Prefilled Syringe, Subcutaneous: Abrilada: 40 mg/0.8 mL (0.8 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]Amgevita: 20 mg/0.4 mL (0.4 mL); 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Hadlima: 40 mg/0.8 mL (0.8 mL)Humira: 20 mg/0.2 mL (0.2 mL); 40 mg/0.4 mL ([DSC]) [contains polysorbate 80]Hyrimoz: 20 mg/0.4 mL (0.4 mL); 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Idacio: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]Dosage Forms ConsiderationsThe 10 mg/0.1 mL, 20 mg/0.2 mL, 40 mg/0.4 mL, and 80 mg/0.8 mL formulations are citrate free.Product AvailabilityAbrilada (adalimumab-afzb): FDA approved November 2019; availability anticipated in 2023. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Amjevita (adalimumab-atto): FDA approved September 2016; anticipated availability is currently unknown. Amjevita is approved as biosimilar to Humira. Consult the prescribing information for additional information.Cyltezo (adalimumab-adbm): FDA approved August 2017; anticipated availability is currently unknown. Cyltezo is approved as biosimilar to Humira. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Hadlima (adalimumab-bwwd): FDA approved July 2019; anticipated availability is currently unknown. Hadlima is approved as biosimilar to Humira. Consult the prescribing information for additional information.Hulio (adalimumab-fkjp): FDA approved July 2020; availability anticipated July 2023. Hulio is approved as a biosimilar to Humira.Hyrimoz (adalimumab-adaz): FDA approved October 2018; availability anticipated in 2023. Hyrimoz is approved as biosimilar to Humira. Consult the prescribing information for additional information.Idacio (adalimumab-aacf): FDA approved December 2022; availability anticipated in July 2023. Idacio is approved as biosimilar to Humira. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Yusimry (adalimumab-aqvh): FDA approved December 2021; availability anticipated July 2023. Yusimry is approved as a biosimilar to Humira.Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Abrilada (adalimumab-afzb): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761118s006lbl.pdf#page=44Amjevita (adalimumab-atto): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761024s010lbl.pdf#page=46Cyltezo (adalimumab-adbm): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761058s008lbl.pdf#page=33Hadlima (adalimumab-bwwd): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761059s004lbl.pdf#page=40Hulio (adalimumab-fkjp): https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761154s000lbl.pdf#page=41Humira: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125057s417lbl.pdf#page=60Hyrimoz (adalimumab-adaz): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761071s010s012lbl.pdf#page=41Yusimry (adalimumab-aqvh): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761216s000lbl.pdf#page=38Administration: PediatricSubQ: Administer subcutaneously into thigh or lower abdomen (avoid areas within 2 inches of navel); rotate injection sites. If single dose requires multiple injections, administer each injection at a separate site at least 1 inch apart. Do not administer into skin that is red, tender, bruised, or hard. May leave at room temperature for ~15 to 30 minutes prior to use; do not remove cap or cover while allowing product to reach room temperature. Do not use if solution is discolored or contains particulate matter.Single-use vial: Intended for institutional use only; does not contain a preservative; discard unused portion.Prefilled pens/syringe: Citrate-free formulations are available and may be associated with less pain on injection. Needle cap of the prefilled syringe or needle cover may contain latex. Pinch area of skin prepped for injection and continue to hold until injection complete. Hold pen firmly against pinched skin and press button. A loud click is heard when injection has begun. Continue to hold pen against skin until injection complete (may take 10 seconds). When injection is complete, the yellow indicator will fully appear in the window view and stop moving. See product labeling for administration details.Administration: AdultSUBQ: For SUBQ injection at separate sites in the thigh or lower abdomen (avoiding areas within 2 inches of navel); rotate injection sites. May leave at room temperature for ~15 to 30 minutes prior to use; do not remove cap or cover while allowing product to reach room temperature. Do not use if solution is discolored or contains particulate matter. Do not administer to skin which is red, tender, bruised, hard, or that has scars, stretch marks, or psoriasis plaques. Needle cap of the prefilled syringe or needle cover for the adalimumab pen may contain latex. Prefilled pens and syringes are available for use by patients and the full amount of the syringe should be injected (self-administration); the vial is intended for institutional use only. Vials do not contain a preservative; discard unused portion. Citrate-free formulations may be associated with less pain on injection.Storage/StabilityStore at 2°C to 8°C (36°F to 46°F) in original container to protect from light; do not freeze. Do not use if frozen even if it has been thawed. Do not store in extreme heat or cold. If needed, may be stored at room temperature up to a maximum of 25°C (77°F) for up to 14 days; discard if not used within 14 days.UseTreatment of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) alone or in combination with methotrexate (Humira: FDA approved in ages 2 to 17 years weighing ≥10 kg); treatment and maintenance of remission in patients with moderately to severely active ulcerative colitis (Humira: FDA approved in ages ≥5 years and adults); treatment and maintenance of remission in patients with moderately to severely active Crohn disease (Humira: FDA approved in ages ≥6 years and adults); treatment of noninfectious intermediate, posterior, and panuveitis (Humira: FDA approved in ages ≥2 years weighing ≥10 kg and adults); treatment of moderate to severe hidradenitis suppurativa (Humira: FDA approved in ages ≥12 years weighing ≥30 kg and adults); treatment of moderately to severely active rheumatoid arthritis (RA) alone or in combination with methotrexate or other nonbiologic, disease-modifying antirheumatic drugs (DMARDs) (Humira: FDA approved in adults); treatment of active psoriatic arthritis alone or in combination with nonbiologic DMARDs (Humira: FDA approved in adults); treatment of active ankylosing spondylitis (Humira: FDA approved in adults); treatment of moderate to severe chronic plaque psoriasis when systemic therapy is required and other agents are less appropriate (Humira: FDA approved in adults).Note: Amjevita (adalimumab-atto), Cyltezo (adalimumab-adbm), Hadlima (adalimumab-bwwd), Hulio (adalimumab-fkjp), and Hyrimoz (adalimumab-adaz) are approved as biosimilar agents; market availability anticipated at a later date (see "Product Availability"). Approved ages and uses may vary (consult product labeling).Medication Safety IssuesSound-alike/look-alike issues:Adalimumab may be confused with sarilumab.Humira may be confused with Humulin, HumalogHumira Pen may be confused with HumaPen Memoir (used with HumaLOG)High alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.Adverse Reactions (Significant): ConsiderationsAutoimmune disorderAntibody development may occur with the use of tumor necrosis factor alpha inhibitors (TNFai), including adalimumab. Most frequently, autoantibodies include anti-nuclear antibody (ANA) and anti-double stranded DNA (dsDNA); less frequently, anti-ENA, anti-histone Ab, and anti-cardiolipin Ab (Ref). Frequency of autoantibody development varies depending on underlying disease, specific TNFai medication, and the duration of use; the clinical significance of asymptomatic antibody positivity is unclear (Ref). Antibody positivity may rarely result in the development of an autoimmune disorder, such as lupus-like syndrome (Ref). Symptoms may include arthralgia, myalgia, mucocutaneous symptoms (eg, skin rash), cytopenia, fatigue, fever, serositis and kidney injury (Ref). Development of an autoimmune disorder is associated with a poor treatment response of the original disease to TNFai therapy (Ref). It is unclear if the development of an autoimmune disorder is a TNFai class effect; several reports of rechallenge with the same TNFai or a different TNFai after treatment of the initial autoimmune disorder did not result in a recurrence (Ref).Mechanism: Unknown; Postulated mechanisms include bystander activation of autoreactive lymphocytes due to drug-specific immunity, nonspecific activation of lymphocytes, direct cytotoxicity with release of autoantigens, and disruption of central T-cell tolerance (Ref).Onset: Varied; ranged from 5 weeks to 2 years (Ref).Risk factors: • Longer disease duration (Ref)• Females (Ref)• Ulcerative colitis (Ref)Demyelinating diseaseNew-onset or exacerbation of central and peripheral nervous system demyelinating disease, such as multiple sclerosis, optic neuritis, acute transverse myelitis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy may occur with tumor necrosis factor alpha inhibitors (TNFai), although causality has not been proven (Ref). Symptomatic CNS demyelination associated with TNFai may be monophasic and/or clinically isolated (Ref). Partial or complete resolution may occur after discontinuation of TNFai (Ref); however, approximately one-third of TNFai associated demyelinating episodes evolve into clinically definite multiple sclerosis (Ref).Mechanism: Unknown; several mechanisms have been postulated, including the following: May trigger CNS demyelination directly by immune activation in genetically and/or immunologically predisposed individuals (Ref); may inhibit remyelination via TNF type-2 receptor (TNRF2) (Ref); may increase ingress of auto-reactive T cells in the CNS; may alter downstream cytokine responses; may neutralize TNF systemically but not within the CNS, creating an artificially high local concentration of brain TNF (known as sponge effect); may permit latent CNS viral infection; or may promote anti-drug antibodies and immune complexes that are contributory to demyelination events (Ref).Onset: Varied; mean time of exposure to TNFai before onset of symptoms: 18 months (Ref).Risk factors:• Preexisting or recent onset central or peripheral nervous system demyelinating diseaseDermatologic reactionsVarious cutaneous eruptions have been reported, including psoriasiform eruption (either new-onset or exacerbation), hidradenitis suppurativa, lupus-like syndrome, eczematous rash, pustular rash, lichenoid eruption, and hypersensitivity angiitis (Ref).Mechanism: Psoriasiform eruptions, lichenoid drug eruptions: Non–dose-related; possibly related to cytokine imbalance or imbalance between tumor necrosis factor (TNF)-alpha and interferon-alpha (Ref).Onset: Psoriasiform eruptions: Delayed: Mean 15.6 ± 10.7 months (Ref). Hidradenitis suppurativa: Delayed; median 12 months (range: 1 to 72) (Ref).Risk factors:• Adult females (psoriatic lesions) (Ref)• Smoking (psoriatic lesions) (Ref)• Males (palmoplantar pustulosis) (Ref)• Younger patients (<40 years of age) (palmoplantar pustulosis) (Ref)• Patients with inflammatory bowel disease compared to other inflammatory diseases (psoriasiform reactions more frequent and severe) (Ref).• Females (hidradenitis suppurativa) (Ref)• Cross-reactivity data among TNFai in patients who develop psoriatic lesions are conflicting (Ref)Heart failureNew-onset heart failure (HF) and worsening of heart failure have been reported with tumor necrosis factor-alpha inhibitors (TNFai), including adalimumab; however, data are conflicting, and risk is unclear (Ref). Rheumatoid arthritis (RA) may be a risk factor for HF development (Ref). Some data suggest that TNFai may reduce the risk of HF in the RA population by improving inflammation, lowering disease activity, and improving surrogate markers of cardiovascular disease (Ref).Mechanism: Not clearly established; postulated mechanisms include pro-inflammatory cytokine activation, accelerated atherosclerosis, and reduced physical activity related to the underlying rheumatologic disease (Ref). "Reverse-signaling" may occur, leading to cardiotoxic effects; TNF on cardiomyocytes of the failing heart may act as receptors, activating intracellular signaling pathways, potentiating the toxic effect of the cytokine (Ref).Onset: Varied; median 8.5 months (range: 5 to 17 months (data with infliximab) (Ref).Risk factors:• Preexisting heart failure• Higher disease activity (inflammation) (eg, disease activity score (DAS28), C-reactive protein, erythrocyte sedimentation rate) (Ref)Hepatitis B virus reactivationReactivation of hepatitis B virus (HBV) may occur with immunosuppressive or biologic therapy, including tumor necrosis factor-alpha inhibitors (TNFai) (Ref). Reactivation of HBV may occur in both patients who are HBsAg-positive and in patients who are HBsAg-negative/HBcAb-positive with detectable HBV DNA (Ref). Criteria for HBV reactivation includes (1) a rise in HBV DNA compared to baseline (or an absolute level of HBV DNA when a baseline is unavailable) and (2) reverse seroconversion (seroreversion) from HBsAg negative to HBsAg positive for patients who are HBsAg-negative and anti-HBc–positive (Ref).Mechanism: Inhibit stimulation of HBV specific T-lymphocytes, promoting reactivation (Ref).Onset: Varied; 2 weeks after initiation, up to a year after discontinuation (Ref).Risk factors:• Males (Ref)• Older age (Ref)• Presence of cirrhosis (Ref)• High baseline HBV-DNA level (Ref)• HBeAg or HBsAg seropositivity (Ref)• Absence of anti-HBs among patients with resolved HBV infection (Ref)• Chronic HBV (Ref)• Non-A HBV genotype (Ref)• Hepatitis C, hepatitis D, or HIV co-infection (Ref)HepatoxicityAdalimumab has been associated with increased serum transaminases and hepatotoxicity (Ref). Cholestatic hepatitis, reactivation of hepatitis B virus, and autoimmune hepatitis have been reported (Ref). Elevated aminotransferases between 2 to 3 times the upper limit of normal may occur that are usually transient and asymptomatic (Ref). Resolution of symptoms in patients who develop an autoimmune hepatitis may require initiation of corticosteroid therapy (Ref). Immunomodulatory use, in particular methotrexate, may decrease the risk of hepatotoxicity associated with tumor necrosis factor-alpha inhibitors (TNFai) (Ref). Patients often tolerate a different TNFai (Ref); although, hepatotoxicity may recur with an alternative agent in some cases (Ref). Hepatotoxicity is more commonly associated with infliximab, as compared to adalimumab and other TNFai (Ref).Mechanism: Unknown; idiosyncratic drug reaction (Ref), or autoimmunity due to development of autoantibodies (Ref).Onset: Varied; ranges from 4 weeks to 52 weeks (Ref). Autoimmune hepatitis has a longer latency period than non-immune cases (16 weeks vs 10 weeks, respectively) (Ref).InfectionTumor necrosis factor-alpha inhibitors (TNFai) may be associated with infection (including serious infection). In clinical trials, serious infections were numerically higher among patients treated with TNFai than among patients who received placebo. Meta-analyses and observational studies have reported inconsistency in risk. One study reported an increase in serious infection in patients treated with TNFai (Ref). Another study found no increase in risk (Ref). An observational study did not demonstrate an increased infection risk among patients receiving TNFai versus comparators (Ref). Infections may present as disseminated (rather than local) disease. Active tuberculosis (including reactivation of latent tuberculosis), invasive fungal infection (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial infection, viral infection, or other opportunistic infections (including legionellosis and listeriosis) have been reported.Mechanism: Dose-related; TNFa is important in the immune response against infections, suggesting that medications that inhibit TNFa may increase the risk of infections (Ref).Risk factors:• Higher doses (Ref)• Older age (Ref)• Chronic lung or kidney disease (Ref)• Concurrent immunosuppressants (eg, corticosteroids, methotrexate) (Ref)• History of an opportunistic infection• Chronic or recurrent infection• Conditions that predispose to infections (eg, advanced or poorly controlled diabetes)• Residence/travel in areas of endemic tuberculosis or mycoses (blastomycosis, coccidioidomycosis, histoplasmosis)Injection-site reactionsAdalimumab is associated with injection-site reactions and delayed reactions (Ref). Concurrent immunomodulators (eg, methotrexate, cyclosporine) reduce the development of anti-adalimumab antibodies and may reduce risk (Ref). Most reactions do not require discontinuation and do not recur (Ref). Cross-reactivity between tumor necrosis factor-alpha inhibitors is not well-described (Ref). Anti-infliximab antibodies do not crossreact with adalimumab; although, patients who develop anti-infliximab antibodies are more prone to develop anti-adalimumab antibodies (Ref). Adalimumab has been tolerated in patients with previous infusion reactions with infliximab (Ref). In contrast, there are reports of immediate hypersensitivity reactions with adalimumab in patients who had previous infliximab-related reactions (Ref).Mechanism: Unknown; T-cell mediated (Ref) or IgE-mediated (Ref).Onset: Varied; 12 to 24 hours following injection (but may occur immediately following injection). Injection-site reactions often occur within the first month of treatment and last up to 4 days (Ref).Risk factors:• Younger age (Ref)MalignancyLymphoma and other malignancies (some fatal) have been reported in children and adolescents receiving tumor necrosis factor-alpha inhibitors (TNFai), including adalimumab. Half of the malignancies reported in children and adolescents were lymphomas (Hodgkin lymphoma and non-Hodgkin lymphoma), while other cases varied and included rare malignancies usually associated with immunosuppression and malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants. Hepatosplenic T-cell lymphoma, a rare T-cell lymphoma, has been reported (some fatal), primarily in patients with Crohn disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males.Long-term observational studies and meta-analyses indicate no association between TNFai therapy and an overall increased risk of cancer (Ref). One study reported a significant increase in lymphomas in patients with rheumatoid arthritis (RA) receiving TNFai compared to the general population. However, there was no significant increased risk of lymphomas in patients receiving TNFai compared to those receiving csDMARD or with dose, increasing time since initiation, or cumulative duration (Ref). Another study reported no difference in the risk of solid tumors in patients with RA receiving TNFai compared to those receiving csDMARDs (Ref). Other studies reported no increased risk of malignancy recurrence in patients receiving TNFai (Ref).Mechanism: May contribute to protumor activity and suppress the anti-tumor response (Ref).Onset: Delayed; median 30 months (range: 1 to 84 months).TuberculosisPatients treated with tumor necrosis factor-alpha inhibitors (TNFai) are at risk for developing active tuberculosis (TB) (including reactivated tuberculosis) (Ref). A meta-analysis of randomized controlled trials (RTC) of TNFai versus control and registry/longitudinal cohort studies of TNFai versus other DMARDs found a significant increase in TB risk in patients with rheumatoid arthritis (RA) treated with TNFai. In the non-RTC studies, incidence rates with adalimumab were higher than etanercept. Preventive treatment for latent TB infection reduced TB risk (Ref). In the RCT studies, no difference in TB rates were found; however, this failure to detect a difference in TB rates between the two groups may be due to a short observational period (Ref).Mechanism: TNFai interfere with TNFa induction of the granuloma, which is a crucial defense mechanism in controlling TB (Ref). TNFai modulates T-cell number, function, and cytokine signaling, important for the control of TB infection (Ref).Onset: Varied; median 3 to ~73 months (Ref).Risk factors:• Residence in an area with high TB prevalence (Ref)• Known TB exposure or ongoing risk factors for TB exposure (eg, travel to areas with high TB prevalence, residence in correctional facilities, long-term care facilities, or homeless shelters, certain healthcare workers (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Dermatologic: Skin rash (12%) (table 1)Skin RashAdalimumab: Adverse Reaction: Skin RashDrug (Adalimumab)Placebo PopulationDoseIndicationNumber of Patients (Adalimumab)Number of Patients (Placebo)12%6%Adults40 mg every other weekRheumatoid Arthritis705690Hematologic & oncologic: Positive ANA titer (12%)Immunologic: Antibody development (3% to 26%)Infection: InfectionLocal: Injection-site reaction (5% to 20%; including bleeding at injection site, erythema at injection site, injection-site pruritus, pain at injection site, swelling at injection site) (table 2)Injection-Site ReactionAdalimumab: Adverse Reaction: Injection-Site ReactionDrug (Adalimumab)Placebo PopulationDoseIndicationNumber of Patients (Adalimumab)Number of Patients (Placebo)16%N/AChildren and adolescentsEither 24 mg/m2 up to maximum 40 mg every other week or 20 mg every other week (<30 kg), 40 mg every other week (≥30 kg) dependent on phase of studyJuvenile idiopathic arthritis171N/A5%N/AChildren and adolescentsHigh dose: 40 mg every other week (≥40 kg) or 20 mg every other week (<40 kg); low dose: 20 mg every other week (≥40 kg) or 10 mg every other week (<40 kg)Crohn disease192N/A8%1%Adults40 mg every other weekRheumatoid Arthritis70569020%14%N/AN/APooled placebo-controlled clinical trialsN/AN/ANervous system: Headache (12%)Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (children and adolescents: 15%)Respiratory: Sinusitis (11%), upper respiratory tract infection (17%)1% to 10%:Cardiovascular: Acute myocardial infarction (<5%), atrial fibrillation (<5%), cardiac arrhythmia (<5%), chest pain (<5%), coronary artery disease (<5%), deep vein thrombosis (<5%), hypertension (5%), hypertensive encephalopathy (<5%), palpitations (<5%), pericardial effusion (<5%), pericarditis (<5%), peripheral edema (<5%), syncope (<5%), tachycardia (<5%)Endocrine & metabolic: Dehydration (<5%), hypercholesterolemia (6%), hyperlipidemia (7%), ketosis (<5%), menstrual disease (<5%), parathyroid disease (<5%)Gastrointestinal: Abdominal pain (7%), cholecystitis (<5%), cholelithiasis (<5%), esophagitis (<5%), gastroenteritis (<5%), gastrointestinal hemorrhage (<5%), nausea (9%), vomiting (<5%)Genitourinary: Cystitis (<5%), hematuria (5%), pelvic pain (<5%), urinary tract infection (8%)Hematologic & oncologic: Adenoma (<5%), agranulocytosis (<5%), paraproteinemia (<5%), polycythemia (<5%)Hepatic: Hepatic necrosis (<5%), increased serum alkaline phosphatase (5%)Hypersensitivity: Hypersensitivity reaction (children and adolescents: 5% to 6%)Infection: Herpes simplex infection (≤4%), herpes zoster infection (≤4%), serious infection (4% to 5%)Nervous system: Confusion (<5%), myasthenia (<5%), paresthesia (<5%), subdural hematoma (<5%), torso pain (<5%), tremor (<5%)Neuromuscular & skeletal: Arthralgia (3%), arthritis (<5%, including pyogenic arthritis), arthropathy (<5%), back pain (6%), bone disease (<5%), bone fracture (<5%), limb pain (<5%), muscle cramps (<5%), osteonecrosis (<5%), synovitis (<5%), tendinopathy (<5%)Ophthalmic: Cataract (<5%)Renal: Nephrolithiasis (<5%)Respiratory: Asthma (<5%), bronchospasm (<5%), dyspnea (<5%), flu-like symptoms (7%), pharyngitis (≤4%), pleural effusion (<5%), pneumonia (≤4%), respiratory depression (<5%)Miscellaneous: Abnormal healing (<5%), accidental injury (10%)<1%: Neuromuscular & skeletal: Lupus-like syndrome (Schiff 2006)Frequency not defined:Dermatologic: Basal cell carcinoma of skin, cellulitis, erysipelas, malignant melanoma, skin granuloma (annulare; children and adolescents)Gastrointestinal: AppendicitisGenitourinary: Uterine hemorrhageHematologic & oncologic: Carcinoma (including breast, gastrointestinal, lung, skin, urogenital), malignant lymphoma, neutropenia (children and adolescents)Hepatic: Increased serum transaminasesInfection: Atypical mycobacterial infection, bacterial infection, fungal infection (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and infection due to an organism in genus Pneumocystis), influenza (H1N1), opportunistic infection (including Legionella and listeriosis), parasitic infection, postoperative infection, sepsis (including catheter related sepsis), viral infectionNeuromuscular & skeletal: Myositis (children and adolescents), septic arthritisRenal: PyelonephritisRespiratory: Bronchitis, nasopharyngitis, streptococcal pharyngitis (children and adolescents), tuberculosis (including reactivated tuberculosis; disseminated, miliary, lymphatic, peritoneal, and pulmonary)Postmarketing:Cardiovascular: Heart failure (Mansitó López 2021), pulmonary embolism, vasculitis (systemic), worsening of heart failureDermatologic: Alopecia, cutaneous lupus erythematosus (Gonzalez-Cuevas 2020), eczematous rash (Moustou 2009), erythema multiforme, fixed drug eruption, lichenoid eruption (Moustou 2009), Merkel cell carcinoma, psoriasiform eruption (Bae 2018a), psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pustular rash (Moustou 2009), Stevens-Johnson syndrome (Mounach 2013), urticaria (Grace 2020)Gastrointestinal: Diverticulitis of the gastrointestinal tract, gastrointestinal perforation (appendiceal perforations), intestinal perforation, pancreatitisHematologic & oncologic: Aplastic anemia, hepatosplenic T-cell lymphomas (children, adolescents, and young adults), leukopenia, pancytopenia, thrombocytopeniaHepatic: Autoimmune hepatitis (Adar 2010), cholestatic hepatitis (Latus 2013), hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2021)Hypersensitivity: Anaphylaxis (Steenholdt 2012), angioedema (Hansel 2019), hypersensitivity angiitis (Amarantee 2015), nonimmune anaphylaxisImmunologic: SarcoidosisInfection: Reactivation of HBV (Loomba 2017)Nervous system: Cerebrovascular accident, demyelinating disease (peripheral; including Guillain-Barré syndrome) (Kemanetzoglou 2017), demyelinating disease of the central nervous system (including multiple sclerosis) (Kemanetzoglou 2017)Ophthalmic: Optic neuritisRespiratory: Interstitial lung disease (including pulmonary fibrosis)Miscellaneous: Fever (Choi 2021)ContraindicationsThere are no contraindications listed in the manufacturer's US labeling.Canadian labeling: Known hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection); moderate-to-severe heart failure (NYHA class III/IV)Warnings/PrecautionsConcerns related to adverse effects:• Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioneurotic edema; medications for the treatment of hypersensitivity reactions should be available for immediate use.• Antibody formation: Formation of neutralizing anti-drug antibodies may occur with biologic tumor necrosis factor (TNF) inhibitors and may be associated with loss of efficacy (AAD-NPF [Menter 2019]).• Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop.• Demyelinating disease: Rare cases of new-onset or exacerbation of demyelinating disorders (eg, multiple sclerosis, optic neuritis, peripheral demyelinating disease, including Guillain-Barré syndrome) have been reported; there is a known association between intermediate uveitis and central demyelinating disorders. Consider discontinuing use in patients who develop peripheral or central nervous system demyelinating disorders during treatment. Use with caution in patients with preexisting or recent onset central or peripheral nervous system demyelinating disorders.• Heart failure: Worsening and new-onset heart failure (HF) has been reported with adalimumab and other TNF blockers. Use with caution in patients with HF or decreased left ventricular function. In a scientific statement from the American Heart Association, TNF blockers have been determined to be agents that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).• Hematologic disorders: Rare cases of pancytopenia and aplastic anemia have been reported with TNF-blockers. Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias; discontinue if significant hematologic abnormalities are confirmed. Use with caution in patients with a history of significant hematologic abnormalities.• Hepatitis B: Rare reactivation of hepatitis B (HBV) has occurred in chronic carriers of the virus, usually in patients receiving concomitant immunosuppressants (some have been fatal); evaluate for HBV prior to initiation in all patients. Monitor during and for several months following discontinuation of treatment in HBV carriers; interrupt therapy if reactivation occurs and treat appropriately with antiviral therapy; if resumption of therapy is deemed necessary, exercise caution and monitor patient closely.• Infections: [US Boxed Warning]: Patients receiving adalimumab are at increased risk for serious infections which may result in hospitalization and/or fatality; infections usually developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate, corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis (including reactivation of latent tuberculosis), invasive fungal (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial, viral or other opportunistic infections (including legionellosis and listeriosis) have been reported. Monitor closely for signs/symptoms of infection during and after treatment. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to initiating therapy in patients with chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infections who develop severe systemic illness. Caution should be exercised when considering use in the elderly, patients with a history of an opportunistic infection, patients taking concomitant immunosuppressants (eg, corticosteroids, methotrexate), or in patients with conditions that predispose them to infections (eg, advanced or poorly controlled diabetes) or residence/travel in areas of endemic tuberculosis or mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent infections. Do not initiate adalimumab in patients with an active infection, including clinically important localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely.• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies (some fatal) have been reported in children and adolescents receiving TNF-blocking agents, including adalimumab. Half of the malignancies reported in children and adolescents were lymphomas (Hodgkin and non-Hodgkin) while other cases varied and included rare malignancies usually associated with immunosuppression and malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants. [US Boxed Warning]: Hepatosplenic T-cell lymphoma (HSTCL), a rare T-cell lymphoma, has been reported (some fatal) primarily in patients with Crohn disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males. The impact of adalimumab on the development and course of malignancy is not fully defined. Compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis alone has been previously associated with an increased rate of lymphoma and leukemia. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.7/100 patient years), when compared to the control group (0.2/100 patient years).• Tuberculosis: [US Boxed Warnings]: Active tuberculosis (disseminated or extrapulmonary), including reactivation of latent tuberculosis, has been reported in patients receiving adalimumab. Evaluate patients for tuberculosis risk factors and latent tuberculosis infection (with a skin test) prior to and during therapy. Treatment for latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis during and after treatment. Consider antituberculosis treatment if an adequate course of treatment cannot be confirmed in patients with a history of latent or active tuberculosis or with risk factors despite negative skin test. Some patients who tested negative prior to therapy have developed active infection; tests for latent tuberculosis infection may be falsely negative while on adalimumab therapy. Use with caution in patients who have traveled to or resided in regions where tuberculosis is endemic. Monitor for signs and symptoms of tuberculosis in all patients.Disease-related concerns:• HIV: Use with caution in HIV-positive patients; TNF-α inhibitors may be appropriate in patients receiving highly active antiretroviral therapy, provided they have normal CD4 counts, no viral load, and no recent opportunistic infections (AAD-NPF [Menter 2019]).Special populations:• Older adult: Infection and malignancy has been reported at a higher incidence; use caution in elderly patients.• Pediatric: Malignancies have been reported among children and adolescents.• Surgery patients: Limited experience with patients undergoing surgical procedures while on therapy; consider long half-life with planned procedures. Monitor closely for infection.Dosage form specific issues:• Latex: The packaging (needle cover of prefilled syringe and autoinjector) may contain latex.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy; live vaccines should not be given concurrently. There are no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.Warnings: Additional Pediatric ConsiderationsPostmarketing reports of lymphomas and other malignancies were primarily in pediatric patients with Crohn disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. In an analysis of children and adolescents who had received TNF-blockers (etanercept and infliximab), the FDA identified 48 cases of malignancy. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin and non-Hodgkin lymphoma). Other malignancies, such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate). The role of TNF-blockers in the development of malignancies in children cannot be excluded. The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients (children and adults) using TNF-blockers. Average onset time to development of leukemia was within the first 1 to 2 years of TNF-blocker initiation.Reactivation of TB has been reported in pediatric patients receiving biologic response modifiers (infliximab and etanercept); prior to therapy, patients with no TB risk factors should be screened for latent TB infection (LTBI) with an age appropriate test (ie, <5 years of age: tuberculin skin test, and ≥5 years of age: IGRA [interferon gamma release assay]); if any TB risk factors are present or symptoms, both LTBI screening tests should be performed (AAP [Davies 2016])Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAbatacept: Anti-TNF Agents may enhance the immunosuppressive effect of Abatacept.Risk X: Avoid combinationAbrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationAnakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported.Risk X: Avoid combinationAnifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab.Risk X: Avoid combinationBaricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib.Risk X: Avoid combinationBCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBelimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combinationBiologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combinationBrincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCanakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased.Risk X: Avoid combinationCertolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol.Risk X: Avoid combinationCladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationCoccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modificationCOVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCycloSPORINE (Systemic): Adalimumab may decrease the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyDengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab.Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modificationDeucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationEfgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapyFilgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationInebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modificationLeflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modificationNatalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationOcrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyPidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus.Risk X: Avoid combinationPneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationRabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept.Risk X: Avoid combinationRubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modificationSphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapyTacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationTheophylline Derivatives: Adalimumab may decrease the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyThiopurine Analogs: Anti-TNF Agents may enhance the adverse/toxic effect of Thiopurine Analogs. Specifically, the risk for T-cell non-Hodgkin's lymphoma (including hepatosplenic T-cell lymphoma) may be increased.Risk C: Monitor therapyTocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Risk X: Avoid combinationTofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib.Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combinationTyphoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib.Risk X: Avoid combinationVaccines (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modificationVaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combinationVedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab.Risk X: Avoid combinationWarfarin: Adalimumab may decrease the serum concentration of Warfarin.Risk C: Monitor therapyYellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationReproductive ConsiderationsThe American Academy of Dermatology considers tumor necrosis factor (TNF) blocking agents for the treatment of psoriasis to be compatible for use in patients planning to father a child (AAD-NPF [Menter 2019]). Patients with psoriasis planning to become pregnant may continue treatment with adalimumab. Patients with well-controlled psoriasis who wish to avoid fetal exposure can consider discontinuing adalimumab 10 weeks prior to attempting to become pregnant (Rademaker 2018).Biologics, such as adalimumab, may be continued in patients with inflammatory bowel disease (eg, Crohn disease, ulcerative colitis) planning to become pregnant (Mahadevan 2019). Treatment algorithms are available for use of biologics in patients with Crohn disease who are planning to become pregnant (Weizman 2019).Pregnancy ConsiderationsAdalimumab crosses the placenta.Adalimumab is a humanized monoclonal antibody (IgG1). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).Following administration to pregnant patients with inflammatory bowel disease (eg, Crohn disease, ulcerative colitis), cord blood and newborn serum concentrations of adalimumab are greater than maternal serum at delivery (Julsgaard 2016; Mahadevan 2013). The mean time to adalimumab clearance was 4 months (range: 2.9 to 5 months) in a study in 36 infants exposed in utero. The estimated mean half-life of adalimumab in these infants was 26 days (Julsgaard 2016). One case report notes adalimumab was detectable in the infant serum for 19 months following in utero exposure (Labetoulle 2018).Based on available data, an increased risk of adverse maternal or fetal effects has not been observed following adalimumab exposure during pregnancy (Nielsen 2020). Adalimumab information from a pregnancy registry collected between 2004 and 2016 is available. Included were pregnant women with rheumatoid arthritis (RA) or Crohn disease (CD) treated with adalimumab at least during the first trimester (n=257), pregnant women with RA or CD not treated with adalimumab (disease untreated control, n=120), and pregnant women without RA or CD (healthy unexposed control, n=225); 42 cases lost to follow-up. The incidence of major birth defects was not significantly different between the study groups and no pattern of specific defects was observed. An increased risk of growth restriction or serious opportunistic infections was not associated with maternal adalimumab therapy when compared to the disease untreated controls. An increased risk of preterm delivery was observed in pregnant patients with RA or CD, regardless of adalimumab exposure (Chambers 2019). Information related to this class of medications is emerging, but based on available data, tumor necrosis factor alpha (TNFα) blocking agents are considered to have low to moderate risk when used in pregnancy (ACOG 776 2019).The risk of immunosuppression may be increased following third trimester maternal use of TNFα blocking agents; the fetus, neonate/infant should be considered immunosuppressed for 1 to 3 months following in utero exposure (AAD-NPF [Menter 2019]). Vaccination with live vaccines (eg, rotavirus vaccine) should be avoided for the first 6 months of life if exposure to a biologic agent occurs during the third trimester of pregnancy (eg, >27 weeks' gestation) (Mahadevan 2019).Maternal adalimumab serum concentrations remain stable as pregnancy progresses (Flanagan 2020; Seow 2017).Inflammatory bowel disease is associated with adverse pregnancy outcomes including an increased risk of miscarriage, premature delivery, delivery of a low birth weight infant, and poor maternal weight gain. Management of maternal disease should be optimized prior to pregnancy. Treatment decreases disease flares, disease activity, and the incidence of adverse pregnancy outcomes (Mahadevan 2019).Use of immune modulating therapies in pregnancy should be individualized to optimize maternal disease and pregnancy outcomes (ACOG 776 2019). The American Academy of Dermatology considers TNFα blocking agents for the treatment of psoriasis to be compatible with pregnancy (AAD-NPF [Menter 2019]). When treatment for inflammatory bowel disease is needed in pregnant women, appropriate biologic therapy can be continued without interruption. Serum levels should be evaluated prior to conception and optimized to avoid subtherapeutic concentrations or high levels which may increase placental transfer. Dosing can be adjusted so delivery occurs at the lowest serum concentration. For adalimumab, the final injection can be given 2 to 3 weeks prior to the estimated date of delivery (1 to 2 weeks if weekly dosing), then continued 48 hours postpartum (Mahadevan 2019).Data collection to monitor pregnancy and infant outcomes following exposure to adalimumab is ongoing. Women exposed to adalimumab during pregnancy for the treatment of an autoimmune disease (eg, inflammatory bowel disease) may contact the OTIS Autoimmune Diseases Study at 877-311-8972.Monitoring ParametersMonitor improvement of symptoms and physical function assessments. Latent TB screening prior to initiating and during therapy; signs/symptoms of infection (prior to, during, and following therapy); CBC with differential; signs/symptoms/worsening of heart failure; LFTs at baseline; HBV screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); signs and symptoms of hypersensitivity reaction; symptoms of lupus-like syndrome; signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss), including periodic skin examination.Reference RangeCrohn disease (ECCO/ESPGHAN [van Rheenen 2020]): Early proactive therapeutic monitoring is recommended to optimize dose and prevent underdosing in pediatric Crohn disease patients.Timing of serum sample: Prior to third injection (4 weeks after first dose).Therapeutic concentrations: 7.5 to 10 mcg/mL.Mechanism of ActionAdalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFα receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn disease and ulcerative colitis; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.Pharmaco*kinetics (Adult data unless noted)Onset of action: Response best determined after 3 to 4 months (AAD-NPF [Menter 2019]).Distribution: Vd: 4.7 to 6 L; Synovial fluid concentrations: 31% to 96% of serumBioavailability: Absolute: 64%Half-life elimination: Terminal: ~2 weeks (range: 10 to 20 days)Time to peak, serum: SubQ: 131 ± 56 hoursPharmaco*kinetics: Additional ConsiderationsOlder adult: In patients with rheumatoid arthritis (RA), there was a trend toward lower clearance with increasing age in patients 40 to >75 years of age.Pricing: USPen-injector Kit (Humira Pen Subcutaneous)40 mg/0.4 mL (per each): $3,845.9040 mg/0.8 mL (per each): $3,845.9080 mg/0.8 mL (per each): $7,691.82Pen-injector Kit (Humira Pen-CD/UC/HS Starter Subcutaneous)40 mg/0.8 mL (per each): $3,845.9180 mg/0.8 mL (per each): $7,691.83Pen-injector Kit (Humira Pen-Pediatric UC Start Subcutaneous)80 mg/0.8 mL (per each): $7,691.82Pen-injector Kit (Humira Pen-Ps/UV/Adol HS Start Subcutaneous)40 mg/0.8 mL (per each): $3,845.91Pen-injector Kit (Humira Pen-Psor/Uveit Starter Subcutaneous)80 MG/0.8ML &40MG/0.4ML (per each): $5,127.88Prefilled Syringe Kit (Humira Pediatric Crohns Start Subcutaneous)80 mg/0.8 mL (per each): $7,691.8380 MG/0.8ML &40MG/0.4ML (per each): $5,768.87Prefilled Syringe Kit (Humira Subcutaneous)10MG/0.1ML (per each): $3,845.9020 mg/0.2 mL (per each): $3,845.9040 mg/0.4 mL (per each): $3,845.9040 mg/0.8 mL (per each): $3,845.90Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAmgevita (AT, BE, FI, HR, NL, RO, TW);Amsparity (AT);Cyltezo (AT, BE, HU, LV, NL, PT);Exemptia (IN);Hadlima (AU);Halimatoz (NL);Hulio (HR, RO);Humira (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IQ, IR, IS, IT, JO, JP, KR, KW, LB, LT, LU, LV, LY, MT, MX, MY, NI, NL, NO, NZ, OM, PA, PE, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, SV, SY, TR, TW, UA, UY, VE, VN, YE, ZA);Hyrimoz (AT, AU, CZ, DE, EE, ES, HR, HU, LT, LV, NL, PL, PT, RO, SK);Idacid (TW);Idacio (HR, RO);Imraldi (BE, HR, NL, RO);Solymbic (AT);Trudexa (BE, BG, CH, CZ, DE, DK, EE, FI, FR, GB, GR, IT, PT, RU, SE, SK, TR)For country code abbreviations (show table)A-Rahim YI, Farrell RJ. Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 4, 2021.Abrilada (adalimumab) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; April 2021.Adalimumab. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; February 10, 2017. [PubMed 31643860]Adalimumab injection [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; January 2021.Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol. 2010;44(1):e20-e22. doi:10.1097/MCG.0b013e3181a745e7 [PubMed 19593165]Ai JW, Zhang S, Ruan QL, et al. The risk of tuberculosis in patients with rheumatoid arthritis treated with tumor necrosis factor-α antagonist: a metaanalysis of both randomized controlled trials and registry/cohort studies. J Rheumatol. 2015;42(12):2229-2237. doi:10.3899/jrheum.150057 [PubMed 26472414]Al Hashash J, Regueiro M. Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed November 2, 2021.Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Amarante CF, Acedo LM, Rabay FM, Campos Bdo E, Lira ML, Mandelbaum SH. Drug-induced lupus with leukocytoclastic vasculitis: a rare expression associated with adalimumab. An Bras Dermatol. 2015;90(3 suppl 1):121-124. doi:10.1590/abd1806-4841.20153834 [PubMed 26312693]American College of Obstetricians and Gynecologists (ACOG). Committee opinion no. 776: immune modulating therapies in pregnancy and lactation. Obstet Gynecol. 2019;133(4):e287-e295. [PubMed 30913201]Amgevita (adalimumab) [product monograph]. Mississauga, Ontario, Canada: Amgen Canada Inc; July 2021.Angel K, Provan SA, Gulseth HL, Mowinckel P, Kvien TK, Atar D. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension. 2010;55(2):333-338. doi:10.1161/HYPERTENSIONAHA.109.143982 [PubMed 20038753]Arts EE, Fransen J, den Broeder AA, Popa CD, van Riel PL. The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients. Ann Rheum Dis. 2015;74(6):998-1003. doi:10.1136/annrheumdis-2013-204531 [PubMed 24458537]Askling J, Baecklund E, Granath F, et al. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis. 2009;68(5):648-653. doi:10.1136/ard.2007.085852 [PubMed 18467516]Askling J, Fored CM, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64(10):1421-1426. doi:10.1136/ard.2004.033993 [PubMed 15829572]Averbukh LD, Wu GY. Role of biologics in the development of autoimmune hepatitis: a review. J Clin Transl Hepatol. 2018;6(4):402-409. doi:10.14218/JCTH.2018.00039 [PubMed 30637218]Bae JM, Kwon HS, Kim GM, Park KS, Kim KJ. Paradoxical psoriasis following anti-TNF therapy in ankylosing spondylitis: a population-based cohort study. J Allergy Clin Immunol. 2018;142(3):1001-1003.e2. doi:10.1016/j.jaci.2018.05.015 [PubMed 29859201]Bae JM, Lee HH, Lee BI, et al. Incidence of psoriasiform diseases secondary to tumour necrosis factor antagonists in patients with inflammatory bowel disease: a nationwide population-based cohort study. Aliment Pharmacol Ther. 2018;48(2):196-205. doi:10.1111/apt.14822 [PubMed 29869804]Barešić M, Reihl Crnogaj M, Zadro I, Anić B. Demyelinating disease (multiple sclerosis) in a patient with psoriatic arthritis treated with adalimumab: a case-based review. Rheumatol Int. 2021;41(12):2233-2239. doi:10.1007/s00296-021-04995-0 [PubMed 34557936]Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021;58(6):2004079. doi:10.1183/13993003.04079-2020 [PubMed 34140301]Baumgart DC, Grittner U, Steingräber A, Azzaro M, Philipp S. Frequency, phenotype, outcome, and therapeutic impact of skin reactions following initiation of adalimumab therapy: experience from a consecutive cohort of inflammatory bowel disease patients. Inflamm Bowel Dis. 2011;17(12):2512-2520. doi:10.1002/ibd.21643 [PubMed 21351201]Bavbek S, Ataman Ş, Akıncı A, Castells M. Rapid subcutaneous desensitization for the management of local and systemic hypersensitivity reactions to etanercept and adalimumab in 12 patients. J Allergy Clin Immunol Pract. 2015;3(4):629-632. doi:10.1016/j.jaip.2015.01.009 [PubMed 25725941]Bavbek S, Ataman Ş, Bankova L, Castells M. Injection site reaction to adalimumab: positive skin test and successful rapid desensitisation. Allergol Immunopathol (Madr). 2013;41(3):204-206. doi:10.1016/j.aller.2012.04.006 [PubMed 23063342]Ben-Horin S, Yavzori M, Katz L, et al. Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol. 2010;8(5):475-476. [PubMed 20005982]Benucci M, Manfredi M, Demoly P, Campi P. Injection site reactions to TNF-alpha blocking agents with positive skin tests. Allergy. 2008;63(1):138-139. doi:10.1111/j.1398-9995.2007.01536.x [PubMed 18053024]Björnsson ES, Gunnarsson BI, Gröndal G, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2015;13(3):602-608. doi:10.1016/j.cgh.2014.07.062 [PubMed 25131534]Björnsson HK, Gudbjornsson B, Björnsson ES. Infliximab-induced liver injury: clinical phenotypes, autoimmunity and the role of corticosteroid treatment. J Hepatol. 2022;76(1):86-92. doi:10.1016/j.jhep.2021.08.024 [PubMed 34487751]Boggs JME, Ramsay B, Lynch M. Paradoxical psoriasis caused by tumour necrosis factor inhibitor therapy. Clin Exp Dermatol. 2021;46(3):580-582. doi:10.1111/ced.14500 [PubMed 33151572]Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-2285. doi:10.1001/jama.295.19.2275 [PubMed 16705109]Burgos-Vargas R, Tse SM, Horneff G, et al. A randomized, double-blind, placebo-controlled multicenter study of adalimumab in pediatric patients with enthesitis-related arthritis. Arthritis Care Res (Hoboken). 2015;67(11):1503-1512. [PubMed 26223543]Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis. 2013;72(4):517-524. doi:10.1136/annrheumdis-2011-201244 [PubMed 22562972]Canu D, Seneschal J, Milpied B, Taieb A, Darrigade AS. TNFα inhibitor-induced urticaria: a class effect. Eur J Dermatol. 2019;29(5):543-544. doi:10.1684/ejd.2019.3625 [PubMed 31789277]Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep. 2000;49(RR-6):1-51. [PubMed 10881762]Centers for Disease Control and Prevention (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm [PubMed 6423951]Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966. [PubMed 24935270]Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR; Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2021;116(5):878-898. doi:10.14309/ajg.0000000000001259 [PubMed 33929376]Chambers CD, Johnson DL, Xu R, et al; OTIS Collaborative Research Group. Birth outcomes in women who have taken adalimumab in pregnancy: a prospective cohort study. PLoS One. 2019;14(10):e0223603. doi:10.1371/journal.pone.0223603 [PubMed 31626646]Chen HK, Shao SC, Weng MY, et al. Risk of heart failure in rheumatoid arthritis patients treated with tumor necrosis factor-α inhibitors. Clin Pharmacol Ther. 2021;110(6):1595-1603. doi:10.1002/cpt.2415 [PubMed 34496051]Choi SJ, Ahn SM, Oh JS, et al. Anti-tumor necrosis factor-induced lupus in patients with inflammatory bowel disease: a hospital-based cohort study from Korea. Therap Adv Gastroenterol. 2021;14:1756284821997794. doi:10.1177/1756284821997794 [PubMed 33747126]Choi SJ, Oh JS, Hong S, Lee CK, Yoo B, Kim YG. Liver enzyme elevation in patients with ankylosing spondylitis treated with tumor necrosis factor inhibitors: a single-center historical cohort study. Korean J Intern Med. 2020;35(3):723-731. doi:10.3904/kjim.2018.407 [PubMed 31870134]Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut. 2009;58(7):940-948. doi: 10.1136/gut.2008.159251. [PubMed 19201775]Conti F, Atzeni F, Massaro L, et al. The influence of comorbidities on the efficacy of tumour necrosis factor inhibitors, and the effect of tumour necrosis factor inhibitors on comorbidities in rheumatoid arthritis: report from a National Consensus Conference. Rheumatology (Oxford). 2018;57(57 suppl 7):vii11-vii22. doi:10.1093/rheumatology/key209 [PubMed 30289537]Cossio ML, Genois A, Jantchou P, Hatami A, Deslandres C, McCuaig C. Skin manifestations in pediatric patients treated with a TNF-alpha inhibitor for inflammatory bowel disease: a retrospective study. J Cutan Med Surg. 2020;24(4):333-339. doi:10.1177/1203475420917387 [PubMed 32527153]Crommelin HA, van der Burg LM, Vorselaars AD, et al. Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab. Respir Med. 2016;115:72-77. doi:10.1016/j.rmed.2016.04.011 [PubMed 27215507]Crowson CS, Liao KP, Davis JM 3rd, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166(4):622-628.e1. doi:10.1016/j.ahj.2013.07.010 [PubMed 24093840]Cyrenne BM, Parpia AS, Sibbald C. Paradoxical psoriasis in pediatric patients: a systematic review. Pediatr Dermatol. 2021;38(5):1086-1093. doi:10.1111/pde.14712 [PubMed 34402108]Darrigade AS, Milpied B, Truchetet ME, et al. Pattern and severity of psoriasiform eruptions in patients with inflammatory bowel diseases, arthritis or skin inflammatory disorders treated with TNF-alpha inhibitors. Acta Derm Venereol. 2017;97(6):731-734. doi:10.2340/00015555-2636 [PubMed 28218339]Davies HD, Committee on Infectious Disease. Infectious complications with the use of biologic response modifiers in infants and children. Pediatrics. 2016;138(2):e20161209. [PubMed 27432853]Drent M, Cremers JP, Jansen TL, Baughman RP. Practical eminence and experience-based recommendations for use of TNF-α inhibitors in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(2):91-107. [PubMed 25078637]Dubinsky MC, Rosh J, Faubion WA Jr, et al. Efficacy and safety of escalation of adalimumab therapy to weekly dosing in pediatric patients with Crohn's disease. Inflamm Bowel Dis. 2016;22(4):886-893. [PubMed 26950307]Eickstaedt JB, Killpack L, Tung J, Davis D, Hand JL, Tollefson MM. Psoriasis and psoriasiform eruptions in pediatric patients with inflammatory bowel disease treated with anti-tumor necrosis factor alpha agents. Pediatr Dermatol. 2017;34(3):253-260. doi:10.1111/pde.13081 [PubMed 28211161]Eissner G, Kirchner S, Lindner H, et al. Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages. J Immunol. 2000;164(12):6193-6198. doi:10.4049/jimmunol.164.12.6193 [PubMed 10843670]Engel S, Luessi F, Mueller A, Schopf RE, Zipp F, Bittner S. PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders. Ther Adv Neurol Disord. 2020;13:1756286419895155. doi:10.1177/1756286419895155 [PubMed 31921355]Faivre C, Villani AP, Aubin F, et al. Hidradenitis suppurativa (HS): an unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases. J Am Acad Dermatol. 2016;74(6):1153-1159. doi:10.1016/j.jaad.2016.01.018 [PubMed 26965410]Fernández-Crehuet P, Ruiz-Villaverde R. Acneiform eruption as a probable paradoxical reaction to adalimumab. Int J Dermatol. 2015;54(8):e306-e308. doi:10.1111/ijd.12416 [PubMed 24697221]Feuerstein JD, Cheifetz AS. Miscellaneous adverse events with biologic agents (excludes infection and malignancy). Gastroenterol Clin North Am. 2014;43(3):543-563. doi:10.1016/j.gtc.2014.05.002 [PubMed 25110258]Feuerstein JD, Ho EY, Shmidt E, et al; American Gastroenterological Association Institute Clinical Guidelines Committee. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn's disease. Gastroenterology. 2021;160(7):2496-2508. doi:10.1053/j.gastro.2021.04.022 [PubMed 34051983]Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827-834. doi: 10.1053/j.gastro.2017.07.032. [PubMed 28780013]Flanagan E, Gibson PR, Wright EK, et al; PICCOLO Study Group. Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure. Aliment Pharmacol Ther. 2020;52(10):1551-1562. doi:10.1111/apt.16102 [PubMed 32981127]Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-939. doi:10.1002/acr.24596 [PubMed 34101387]French JB, Bonacini M, Ghabril M, Foureau D, Bonkovsky HL. Hepatotoxicity associated with the use of anti-TNF-α agents. Drug Saf. 2016;39(3):199-208. doi:10.1007/s40264-015-0366-9 [PubMed 26692395]Frider B, Bruno A, Ponte M, Amante M. Drug-induced liver injury caused by adalimumab: a case report and review of the bibliography. Case Reports Hepatol. 2013;2013:406901. doi:10.1155/2013/406901 [PubMed 25431703]Fritzsche J, Pilch A, Mury D, Schaefer C, Weber-Schoendorfer C. Infliximab and adalimumab use during breastfeeding. J Clin Gastroenterol. 2012;46(8):718-719. [PubMed 22858514]Furst DE, Keystone EC, Braun J, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis. 2011;70(suppl 1):s2-s36. doi:10.1136/ard.2010.146852 [PubMed 21339216]Gallagher M, Quinones K, Cervantes-Castañeda RA, Yilmaz T, Foster CS. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol. 2007;91(10):1341-1344. [PubMed 17556427]Ghabril M, Bonkovsky HL, Kum C, et al. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013;11(5):558-564.e3. doi:10.1016/j.cgh.2012.12.025 [PubMed 23333219]Gilotra NA, Wand AL, Pillarisetty A, et al. Clinical and imaging response to tumor necrosis factor alpha inhibitors in treatment of cardiac sarcoidosis: a multicenter experience. J Card Fail. 2021;27(1):83-91. doi:10.1016/j.cardfail.2020.08.013 [PubMed 32889044]Godfrey MS, Friedman LN. Tuberculosis and biologic therapies: anti-tumor necrosis factor-α and beyond. Clin Chest Med. 2019;40(4):721-739. doi:10.1016/j.ccm.2019.07.003 [PubMed 31731980]González-Cuevas R, Peruilh-Bagolini L, Valenzuela F, Vargas-Mora P. Cutaneous lupus erythematosus induced by adalimumab: a case report. Dermatol Ther. 2020;33(6):e14339. doi:10.1111/dth.14339 [PubMed 32975341]Grace E, Goldblum O, Renda L, et al. Injection site reactions in the Federal Adverse Event Reporting System (FAERS) post-marketing database vary among biologics approved to treat moderate-to-severe psoriasis. Dermatol Ther (Heidelb). 2020;10(1):99-106. doi:10.1007/s13555-019-00341-2 [PubMed 31734937]Grasland A, Sterpu R, Boussoukaya S, Mahe I. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. Eur J Clin Pharmacol. 2012;68(5):895-898. doi:10.1007/s00228-011-1191-4 [PubMed 22205272]Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011;306(21):2331-2339. doi:10.1001/jama.2011.1692 [PubMed 22056398]Gulsen A, Wedi B, Jappe U. Hypersensitivity reactions to biologics (part II): classifications and current diagnostic and treatment approaches. Allergo J Int. 2020;29:139-154. doi:10.1007/s40629-020-00127-5Hammam N, Evans M, Morgan E, et al. Treatment of sarcoidosis in US rheumatology practices: data from the American College of Rheumatology's Rheumatology Informatics System for Effectiveness (RISE) Registry. Arthritis Care Res (Hoboken). 2022;74(3):371-376. doi:10.1002/acr.24496 [PubMed 33105057]Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33(11):2167-2172. [PubMed 16981296]Hansel K, Bianchi L, Tramontana M, et al. Immediate local and systemic hypersensitivity due to etanercept and adalimumab. J Allergy Clin Immunol Pract. 2019;7(2):726-727. doi:10.1016/j.jaip.2018.06.020 [PubMed 30006049]Hawryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. J Cutan Pathol. 2012;39(5):481-492. doi:10.1111/j.1600-0560.2012.01894.x [PubMed 22515220]Her M, Kavanaugh A. Alterations in immune function with biologic therapies for autoimmune disease. J Allergy Clin Immunol. 2016;137(1):19-27. doi:10.1016/j.jaci.2015.10.023 [PubMed 26768759]Hohlfeld R. Inhibitors of tumor necrosis factor-alpha: promising agents for the treatment of multiple sclerosis? Mult Scler. 1996;1(6):376-378. doi:10.1177/135245859600100619 [PubMed 9345421]Hulio (adalimumab) [product monograph]. Etobico*ke, Ontario, Canada: BGP Pharma ULC; August 2022.Hutto SK, Rice DR, Mateen FJ. CNS demyelination with TNFα inhibitor exposure: a retrospective cohort study. J Neuroimmunol. 2021;356:577587. doi:10.1016/j.jneuroim.2021.577587 [PubMed 33945946]Humira (adalimumab) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2021.Humira (adalimumab) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; March 2018.Humira (adalimumab) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; April 2021.Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology. 2012;143(2):365-374. [PubMed 22562021]Hyrimoz (adalimumab) [product monograph]. Boucherville, Québec, Canada: Sandoz Canada Inc; September 2021.Idacio (adalimumab) [product monograph]. Toronto, Ontario, Canada: Fresenius Kabi Canada Ltd; October 2020.Ingram JR. Hidradenitis suppurativa: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 14, 2021.Inoue A, Sawada Y, Yamaguchi T, et al. Lichenoid drug eruption caused by adalimumab: a case report and literature review. Eur J Dermatol. 2017;27(1):69-70. doi:10.1684/ejd.2016.2898 [PubMed 27777187]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-313. [PubMed 12534540]Juhász K, Buzás K, Duda E. Importance of reverse signaling of the TNF superfamily in immune regulation. Expert Rev Clin Immunol. 2013;9(4):335-348. doi:10.1586/eci.13.14 [PubMed 23557269]Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology. 2016;151(1):110-119. [PubMed 27063728]Kalinowska-Lyszczarz A, Fereidan-Esfahani M, Guo Y, Lucchinetti CF, Tobin WO. Pathological findings in central nervous system demyelination associated with infliximab. Mult Scler. 2020;26(9):1124-1129. doi:10.1177/1352458519894710 [PubMed 31845616]Kelly D, O'Connell O, Henry M. Adalimumab-induced lupus serositis. BMJ Case Rep. 2015;2015:bcr2014207323. Published 2015 Mar 4. doi:10.1136/bcr-2014-207323 [PubMed 25739794]Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers. Curr Neurol Neurosci Rep. 2017;17(4):36. doi:10.1007/s11910-017-0742-1 [PubMed 28337644]Kim E, Bressler B, Schaeffer DF, Yoshida EM. Severe cholestasis due to adalimumab in a Crohn's disease patient. World J Hepatol. 2013;5(10):592-595. doi:10.4254/wjh.v5.i10.592 [PubMed 24179620]Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016;375(5):422-434. doi:10.1056/NEJMoa1504370 [PubMed 27518661]Kingsbury DJ, Bader-Meunier B, Patel G, et al. Safety, effectiveness, and pharmaco*kinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years. Clin Rheumatol. 2014;33(10):1433–1441. [PubMed 24487484]Klarenbeek NB, van der Kooij SM, Huizinga TJ, et al. Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial. Ann Rheum Dis. 2010;69(7):1342-1345. doi:10.1136/ard.2009.124180 [PubMed 20472597]Kok B, Lester ELW, Lee WM, et al. Acute liver failure from tumor necrosis factor-α antagonists: report of four cases and literature review. Dig Dis Sci. 2018;63(6):1654-1666. doi:10.1007/s10620-018-5023-6 [PubMed 29564668]Koller T, Galambosova M, Filakovska S, et al. Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study. World J Gastroenterol. 2017;23(22):4102-4111. doi:10.3748/wjg.v23.i22.4102 [PubMed 28652663]Kotyla PJ. Bimodal function of anti-TNF treatment: shall we be concerned about anti-TNF treatment in patients with rheumatoid arthritis and heart failure? Int J Mol Sci. 2018;19(6):1739. doi:10.3390/ijms19061739 [PubMed 29895751]Kumar N, Abboud H. Iatrogenic CNS demyelination in the era of modern biologics. Mult Scler. 2019;25(8):1079-1085. doi:10.1177/1352458519828601 [PubMed 30767720]Kunchok A, Aksamit AJ Jr, Davis JM 3rd, et al. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77(8):937-946. doi:10.1001/jamaneurol.2020.1162 [PubMed 32421186]Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138(10):807-811. doi:10.7326/0003-4819-138-10-200305200-00008 [PubMed 12755552]Labetoulle R, Roblin X, Paul S. Prolonged persistence of adalimumab transferred from mother to infant during pregnancy. Ann Intern Med. 2018;169(1):60-61. [PubMed 29507939]Lan JL, Chen YM, Hsieh TY, et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2011;70(10):1719-1725. doi:10.1136/ard.2010.148783 [PubMed 21719446]Latus J, Klein R, Koetter I, et al. Cholestatic liver disease after rituximab and adalimumab and the possible role of cross-reacting antibodies to Fab 2 fragments. PLoS One. 2013;8(11):e78856. doi:10.1371/journal.pone.0078856 [PubMed 24244376]Lau G, Yu ML, Wong G, et al. APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021;15(5):1031-1048. doi:10.1007/s12072-021-10239-x [PubMed 34427860]Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis. 2009;68(7):1136-1145. doi:10.1136/ard.2008.091025 [PubMed 18753157]Li PH, Watts TJ, Lui MS, Lau CS, Chung HY. Recall urticaria in adalimumab hypersensitivity. J Allergy Clin Immunol Pract. 2018;6(3):1032-1033. doi:10.1016/j.jaip.2017.10.031 [PubMed 29175008]Li SJ, Perez-Chada LM, Merola JF. TNF Inhibitor-induced psoriasis: proposed algorithm for treatment and management. J Psoriasis Psoriatic Arthritis. 2019;4(2):70-80. doi:10.1177/2475530318810851 [PubMed 31093599]Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG clinical guideline: management of Crohn's disease in adults. Am J Gastroenterol. 2018;113(4):481-517. doi: 10.1038/ajg.2018.27. [PubMed 29610508]Lieberman MR, Liebman TN, Alapati U, Khachemoune A. TNF-inhibitor induced lupus in a patient treated with adalimumab for rheumatoid arthritis. Dermatol Online J. 2014;21(2):13030/qt18r2916d. [PubMed 25756476]Lok ASF, Bonis PAL. Hepatitis B virus reactivation associated with immunosuppressive therapy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed September 31, 2021.Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017;152(6):1297-1309. doi:10.1053/j.gastro.2017.02.009 [PubMed 28219691]Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810-820. [PubMed 18716298]Lower EE, Sturdivant M, Grate L, Baughman RP. Use of third-line therapies in advanced sarcoidosis. Clin Exp Rheumatol. 2020;38(5):834-840. [PubMed 31820728]Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Mahadevan U, Martin CF, Sandler RS et al. PIANO: A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142 (Suppl 1):S149.Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group. Am J Obstet Gynecol. 2019;220(4):308-323. doi:10.1016/j.ajog.2019.02.027 [PubMed 30948039]Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-92; quiz e24. doi:10.1016/j.cgh.2012.11.011 [PubMed 23200982]Mansitó López C, Torres Laboy P, Ortiz Bou M, Quintero Noriega A, Cintron Rivera V. Fatal new-onset congestive heart failure related to adalimumab use in a patient with relapsing hidradenitis suppurativa: a case report. Am J Case Rep. 2021;22:e929148. doi:10.12659/AJCR.929148 [PubMed 33563886]Marzano AV, Tavecchio S, Berti E, Gelmetti C, Cugno M. Pustular skin reaction to tumor necrosis factor alpha antagonists in patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2015;21(11):E26-E27. doi:10.1097/MIB.0000000000000600 [PubMed 26422518]Massarotti M, Marasini B. Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity. Int J Immunopathol Pharmacol. 2009;22(2):547-549. doi:10.1177/039463200902200234 [PubMed 19505409]Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure concentrations of infants breastfed by women receiving biologic therapies for inflammatory bowel diseases and effects of breastfeeding on infections and development. Gastroenterology. 2018;155(3):696-704. [PubMed 29857090]Matsui T, Umetsu R, Kato Y, et al. Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015. Int J Med Sci. 2017;14(2):102-109. doi:10.7150/ijms.17025 [PubMed 28260984]Mease P, Sieper J, Van den Bosch F, Rahman P, Karunaratne PM, Pangan AL. Randomized controlled trial of adalimumab in patients with nonpsoriatic peripheral spondyloarthritis. Arthritis Rheumatol. 2015;67(4):914-923. doi:10.1002/art.39008 [PubMed 25545240]Melani AS, Bigliazzi C, Cimmino FA, Bergantini L, Bargagli E. A comprehensive review of sarcoidosis treatment for pulmonologists. Pulm Ther. 2021;7(2):325-344. doi:10.1007/s41030-021-00160-x [PubMed 34143362]Melo FJ, Magina S. Clinical management of Anti-TNF-alpha-induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review. Int J Dermatol. 2018;57(12):1521-1532. doi:10.1111/ijd.14072 [PubMed 30028008]Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029-1072. doi:10.1016/j.jaad.2018.11.057 [PubMed 30772098]Mercer LK, Lunt M, Low AL, et al. Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2015;74(6):1087-1093. doi:10.1136/annrheumdis-2013-204851 [PubMed 24685910]Mocci G, Marzo M, Papa A, Armuzzi A, Guidi L. Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease. J Crohns Colitis. 2013;7(10):769-779. doi:10.1016/j.crohns.2013.01.009 [PubMed 23453887]Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862-2869. doi:10.1002/1529-0131(200112)44:12<2862::aid-art474>3.0.co;2-w [PubMed 11762947]Montolio Chiva L, Martínez Ferrer À, Mateu Puchades A, Campos Fernández C, Narváez Garcia J, Alegre Sancho JJ. Psoriasis induced by biological therapy. Reumatol Clin (Engl Ed). 2021;17(8):437-439. doi:10.1016/j.reumae.2020.06.003 [PubMed 34625145]Mounach A, Rezqi A, Nouijai A, et al. Stevens-Johnson syndrome complicating adalimumab therapy in rheumatoid arthritis disease. Rheumatol Int. 2013;33(5):1351-1353. doi:10.1007/s00296-011-2212-4 [PubMed 22187054]Moustou AE, Matekovits A, Dessinioti C, Antoniou C, Sfikakis PP, Stratigos AJ. Cutaneous side effects of anti-tumor necrosis factor biologic therapy: a clinical review. J Am Acad Dermatol. 2009;61(3):486-504. doi:10.1016/j.jaad.2008.10.060 [PubMed 19628303]Murdaca G, Spanò F, Contatore M, et al. Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety? Expert Opin Drug Saf. 2016;15(1):43-52. doi:10.1517/14740338.2016.1112375 [PubMed 26559805]Murdaca G, Spanò F, Puppo F. Selective TNF-α inhibitor-induced injection site reactions. Expert Opin Drug Saf. 2013;12(2):187-193. doi:10.1517/14740338.2013.755957 [PubMed 23330811]Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011;70(3):482-487. doi:10.1136/ard.2010.135871 [PubMed 21216812]Nakamizo S, Miyachi Y, Kabashima K. Addition of cyclosporine to adalimumab improved psoriasis and adalimumab-induced injection site reaction. Indian J Dermatol. 2014;59(5):522-523. doi:10.4103/0019-5154.139924 [PubMed 25284873]Navarro-Millán I, Yang S, DuVall SL, et al. Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration. Ann Rheum Dis. 2016;75(2):341-347. doi:10.1136/annrheumdis-2013-204987 [PubMed 25609412]Neves JM, Cunha N, Lencastre A, Cabete J. Paradoxical hidradenitis suppurativa to biologic agents: a case series and literature review. Int J Dermatol. 2019;58(11):e226-e228. doi:10.1111/ijd.14585 [PubMed 31290151]Nguyen GC, Loftus EV Jr, Hirano I, Falck-Ytter Y, Singh S, Sultan S; AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on the management of Crohn's disease after surgical resection. Gastroenterology. 2017;152(1):271-275. doi:10.1053/j.gastro.2016.10.038 [PubMed 27840074]Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52(2):412-420. doi:10.1002/art.20855 [PubMed 15692992]Nielsen OH, Gubatan JM, Juhl CB, Streett SE, Maxwell C. Biologics for inflammatory bowel disease and their safety in pregnancy: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2020:S1542-3565(20)31281-31287. doi:10.1016/j.cgh.2020.09.021 [PubMed 32931960]Page RL 2nd, O'Bryant CL, Cheng D, et al; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association [published correction appears in Circulation. 2016;134(12):e261]. Circulation. 2016;134(6):e32-e69. [PubMed 27400984]Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646. [PubMed 22235228]Paltiel M, Gober LM, Deng A, et al. Immediate type I hypersensitivity response implicated in worsening injection site reactions to adalimumab. Arch Dermatol. 2008;144(9):1190-1194. doi:10.1001/archderm.144.9.1190 [PubMed 18794465]Paramarta JE, De Rycke L, Heijda TF, et al. Efficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritis. Ann Rheum Dis. 2013;72(11):1793-1799. doi:10.1136/annrheumdis-2012-202245 [PubMed 23139265]Parekh R, Kaur N. Liver injury secondary to anti-TNF-alpha therapy in inflammatory bowel disease: a case series and review of the literature. Case Rep Gastrointest Med. 2014;2014:956463. doi:10.1155/2014/956463 [PubMed 24707412]Pariser RJ, Paul J, Hirano S, Torosky C, Smith M. A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis. J Am Acad Dermatol. 2013;68(5):765-773. doi:10.1016/j.jaad.2012.10.056 [PubMed 23276549]Pasadyn SR, Knabel D, Fernandez AP, Warren CB. Cutaneous adverse effects of biologic medications. Cleve Clin J Med. 2020;87(5):288-299. doi:10.3949/ccjm.87a.19119 [PubMed 32357984]Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res B Dev Reprod Toxicol. 2009;86(4):328-344. [PubMed 19626656]Picard M, Galvão VR. Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract. 2017;5(3):600-609. doi:10.1016/j.jaip.2016.12.001 [PubMed 28110056]Pugliese D, Guidi L, Ferraro PM, et al. Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study. Aliment Pharmacol Ther. 2015;42(7):880-888. doi:10.1111/apt.13352 [PubMed 26235565]Puxeddu I, Giori L, Rocchi V, et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol. 2012;108(2):123-124. doi:10.1016/j.anai.2011.11.004 [PubMed 22289732]Raaschou P, Frisell T, Askling J; ARTIS Study Group. TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis. 2015;74(12):2137-2143. doi:10.1136/annrheumdis-2014-205745 [PubMed 25107559]Rademaker M, Agnew K, Andrews M, et al. Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration. Australas J Dermatol. 2018;59(2):86-100. [PubMed 28543445]Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore). 2007;86(4):242-251. doi:10.1097/MD.0b013e3181441a68 [PubMed 17632266]Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, Cuadrado MJ, Khamashta MA; BIOGEAS Study Group. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010;9(3):188-193. doi:10.1016/j.autrev.2009.10.003 [PubMed 19854301]Refer to manufacturer's labeling.Rodrigues S, Lopes S, Magro F, et al. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol. 2015;21(24):7584-7588. doi:10.3748/wjg.v21.i24.7584 [PubMed 26140007]Rubin RL. Drug-induced lupus. Toxicology. 2005;209(2):135-147. doi:10.1016/j.tox.2004.12.025 [PubMed 15767026]Salomon BL, Leclerc M, Tosello J, Ronin E, Piaggio E, Cohen JL. Tumor necrosis factor α and regulatory T cells in oncoimmunology. Front Immunol. 2018;9:444. doi:10.3389/fimmu.2018.00444 [PubMed 29593717]Salvador-Rodriguez L, Montero-Vílchez T, Arias-Santiago S, Molina-Leyva A. Paradoxical hidradenitis suppurativa in patients receiving TNF-α inhibitors: case series, systematic review, and case meta-analysis. Dermatology. 2020;236(4):307-313. doi:10.1159/000506074 [PubMed 32135533]Schiff MH, Burmester GR, Kent JD, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(7):889-894. doi:10.1136/ard.2005.043166 [PubMed 16439435]Sedger LM, McDermott MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453-472. doi:10.1016/j.cytogfr.2014.07.016 [PubMed 25169849]Seow CH, Leung Y, Vande Casteele N, et al. The effects of pregnancy on the pharmaco*kinetics of infliximab and adalimumab in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45(10):1329-1338. [PubMed 28318043]Seror R, Richez C, Sordet C, et al. Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatology (Oxford). 2013;52(5):868-874. doi:10.1093/rheumatology/kes375 [PubMed 23287362]Shah P, Sundaram V, Björnsson E. Biologic and checkpoint inhibitor-induced liver injury: a systematic literature review. Hepatol Commun. 2020;4(2):172-184. doi:10.1002/hep4.1465 [PubMed 32025603]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. [PubMed 7746084]Shelton E, Chaudrey K, Sauk J, et al. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2015;41(10):972-979. doi:10.1111/apt.13159 [PubMed 25756190]Sieper J, van der Heijde D, Dougados M, et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis. 2013;72(6):815-822. doi:10.1136/annrheumdis-2012-201766 [PubMed 22772328]Simlandi (adalimumab) [product monograph]. Boucherville, Quebec, Canada: Pfizer Canada ULC; January 2022.Simonini G, Taddio A, Cattalini M, et al. Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab. Arthritis Care Res (Hoboken). 2011;63(4):612-618. doi:10.1002/acr.20404 [PubMed 21452272]Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625-639. doi:10.1002/acr.21641 [PubMed 22473917]Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2011(2):CD008794. doi:10.1002/14651858.CD008794.pub2 [PubMed 21328309]Singh S, Facciorusso A, Dulai PS, Jairath V, Sandborn WJ. Comparative risk of serious infections with biologic and/or immunosuppressive therapy in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2020;18(1):69-81.e3. doi:10.1016/j.cgh.2019.02.044 [PubMed 30876964]Solomon DH, Reed GW, Kremer JM, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol. 2015;67(6):1449-1455. doi:10.1002/art.39098 [PubMed 25776112]Sridhar S, Maltz RM, Boyle B, Kim SC. Dermatological manifestations in pediatric patients with inflammatory bowel diseases on anti-TNF therapy. Inflamm Bowel Dis. 2018;24(9):2086-2092. doi:10.1093/ibd/izy112 [PubMed 29718343]Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Acute and delayed hypersensitivity reactions to infliximab and adalimumab in a patient with Crohn's disease. J Crohns Colitis. 2012;6(1):108-111. doi:10.1016/j.crohns.2011.08.001 [PubMed 22261535]Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34(1):51-58. doi:10.1111/j.1365-2036.2011.04682.x [PubMed 21535447]Strangfeld A, Eveslage M, Schneider M, et al. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis. 2011;70(11):1914-1920. doi:10.1136/ard.2011.151043 [PubMed 21791449]Strangfeld A, Hierse F, Rau R, et al. Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res Ther. 2010;12(1):R5. doi:10.1186/ar2904 [PubMed 20064207]Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(1):46-54. [PubMed 24751453]Taylor TRP, Galloway J, Davies R, Hyrich K, Dobson R. Demyelinating events following initiation of anti-TNFα therapy in the British Society for Rheumatology Biologics Registry in Rheumatoid Arthritis. Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e992. doi:10.1212/NXI.0000000000000992 [PubMed 33863839]Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599. doi:10.1002/hep.29800 [PubMed 29405329]Thorne JE. Uveitis: treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 24, 2021.Titos Arcos JC, Hallal H, Robles M, Andrade RJ. Recurrent hepatotoxicity associated with etanercept and adalimumab but not with infliximab in a patient with rheumatoid arthritis. Rev Esp Enferm Dig. 2012;104(5):282-284. doi:10.4321/s1130-01082012000500014 [PubMed 22662786]Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;67(2):257-291. [PubMed 30044357]van Rheenen PF, Aloi M, Assa A, et al. The medical management of paediatric Crohn's disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis. Published online October 7, 2020. [PubMed 33026087]Vermeire S, Noman M, Van Assche G, et al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study. Gastroenterology. 2003;125(1):32-39. doi:10.1016/s0016-5085(03)00701-7 [PubMed 12851868]Wagner UG, Koetz K, Weyand CM, Goronzy JJ. Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1998;95(24):14447-14452. doi:10.1073/pnas.95.24.14447 [PubMed 9826720]Ward MM, Deodhar A, Gensler LS, et al. 2019 update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Care Res (Hoboken). 2019;71(10):1285-1299. doi:10.1002/acr.24025 [PubMed 31436026]Weizman AV, Nguyen GC, Seow CH, et al. Appropriateness of biologics in the management of Crohn's disease using RAND/UCLA appropriateness methodology. Inflamm Bowel Dis. 2019;25(2):328-335. doi: 10.1093/ibd/izy333. [PubMed 30346529]Williams EL, Gadola S, Edwards CJ. Anti-TNF-induced lupus. Rheumatology (Oxford). 2009;48(7):716-720. doi:10.1093/rheumatology/kep080 [PubMed 19416947]Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum. 2006;54(2):628-634. doi:10.1002/art.21568 [PubMed 16447241]Yanai H, Shuster D, Calabrese E, Mlynarsky L, Tumuluri S, Cohen RD. The incidence and predictors of lupus-like reaction in patients with IBD treated with anti-TNF therapies. Inflamm Bowel Dis. 2013;19(13):2778-2786. doi:10.1097/01.MIB.0000435435.91988.b6 [PubMed 24185311]Yuflyma (adalimumab) [product monograph]. Toronto, Ontario, Canada: Celltrion Healthcare Canada Limited; December 2021.Topic 13077 Version 338.0

CloseNaltrexone: Drug informationNaltrexone: Drug information(For additional information see "Naltrexone: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USVivitrolBrand Names: CanadaAPO-Naltrexone;ReViaPharmacologic CategoryAntidote;Opioid AntagonistDosing: AdultNote: Do not initiate therapy until patient has passed a naloxone challenge test or is opioid-free (including tramadol) for at least 7 to 10 days after last opioid use; up to 14 days may be necessary for patients on long-acting opioids (eg, methadone, buprenorphine) (Ref). If need for opioid pain management is anticipated during treatment (eg, for elective surgery), discontinue oral naltrexone ≥3 days prior to surgery or IM naltrexone ≥30 days prior to surgery (Ref).Alcohol use disorder, moderate to severeAlcohol use disorder, moderate to severe:Note: Not recommended for patients currently taking opioids or with acute hepatitis, liver enzymes ≥3 to 5 times normal, or liver failure (Ref). May be initiated while the patient is actively drinking (Ref). Some experts consider alternative therapy if goals are not met within 6 months of treatment (Ref).Oral: 50 mg once daily; may increase to 100 mg once daily after 1 week based on response and tolerability. Some experts initiate with 25 mg once daily for several days before increasing to 50 mg once daily (Ref).IM: 380 mg once every 4 weeks.Opioid use disorder, mild to severeOpioid use disorder, mild to severe (alternative agent for moderate to severe):Note: Treatment initiation should be medically supervised due to risk for precipitated withdrawal. Some experts consider switching to alternative therapy if goals are not met within 3 to 6 months of treatment (Ref).Oral (alternative route): Initial: 25 mg once daily for 1 to 3 days; if no withdrawal signs occur, administer 50 mg once daily thereafter. Note: Use only for patients who are highly motivated or able to comply with techniques such as observed dosing to enhance adherence; efficacy is limited when patient adherence is poor (Ref).IM: 380 mg once every 4 weeks. Note: Patients who experience a reduction in efficacy prior to 4 weeks (eg, breakthrough cravings, ability to overcome opioid receptor blockade), may benefit from dosing every 3 weeks; however, no clinical trials have evaluated dosing frequencies <4 weeks (Ref).Switching from buprenorphine to naltrexone: Taper the buprenorphine dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone. A naloxone challenge may be used to demonstrate an absence of physical dependence (Ref).Switching from methadone to naltrexone: Taper the methadone dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone. A naloxone challenge may be used to demonstrate an absence of physical dependence (Ref).Switching from naltrexone to methadone or buprenorphine: Begin methadone or buprenorphine ~1 day following last dose of oral naltrexone and ~28 days following last dose of IM naltrexone (Ref).PruritusPruritus (off-label use):Opioid-induced, associated with neuraxial opioid administration:Oral: 6 mg once; generally, doses >6 mg may reverse analgesia (Ref).Nonopioid-induced (eg, from cholestasis) (alternative agent): Note: Studies of naltrexone for uremic pruritus have mixed results (Ref).Oral: 12.5 mg to 50 mg once daily (Ref).Dosing: Kidney Impairment: AdultMild impairment: No dosage adjustment necessary.Moderate-to-severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); use with caution since naltrexone and its primary metabolite are primarily excreted in urine.Dosing: Hepatic Impairment: AdultMild to moderate impairment: No dosage adjustment necessary.Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); naltrexone AUC increased ~5- and 10-fold in patients with compensated or decompensated hepatic cirrhosis respectively. Use is not recommended in acute hepatitis or hepatic failure (Ref).Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension Reconstituted, Intramuscular: Vivitrol: 380 mg (1 ea)Tablet, Oral, as hydrochloride: Generic: 50 mgGeneric Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral, as hydrochloride: ReVia: 50 mgGeneric: 50 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Vivitrol: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021897s052lbl.pdf#page=33Administration: AdultOral: May be administered with or without food. Administration with food or after meals may minimize adverse gastrointestinal effects. Advise patient not to self-administer opioids while receiving naltrexone therapy.IM: Vivitrol: Administer deep IM into the gluteal muscle; must inject dose using one of the provided needles for administration. Use either the 1.5-inch needle (for very lean patients) or the 2-inch needle (for patients with a larger amount of subcutaneous tissue overlying the gluteal muscle). Either needle may be used for patients with average body habitus. Avoid inadvertent injection into a blood vessel; do not administer IV, SUBQ, or into fatty tissue (the risk of serious injection site reaction is increased if given incorrectly as a SUBQ injection or into fatty tissue instead of the gluteal muscle). Injection should alternate between the 2 buttocks. Do not substitute any components of the dose-pack.Use: Labeled IndicationsAlcohol use disorder: Treatment of alcohol use disorder.Opioid use disorder, mild to severe: For the blockade of the effects of exogenously administered opioids.Limitation of use: Oral naltrexone tablets have not been shown to be more effective than placebo for opioid use disorder due to poor patient adherence (SAMHSA 2021).Use: Off-Label: AdultPruritusMedication Safety IssuesSound-alike/look-alike issues:Naltrexone may be confused with methylnaltrexone, naloxoneReVia may be confused with RevatioAdministration issues:Vivitrol: For deep intramuscular (IM) gluteal injection onlyAdverse Reactions (Significant): ConsiderationsAccidental opioid overdoseNaltrexone may result in accidental opioid overdose in patients with opioid dependence or opioid use disorder. Risk of opioid overdose with naltrexone use may be higher than other opioid agonist treatments (Ref). Opioid overdose related to naltrexone use may result in life-threatening and fatal events (Ref).Mechanism: Related to the pharmacologic action; naltrexone is an opioid receptor-antagonist, reducing or blocking the effects of opioids and potentially leading to secondary up-regulation of opioid receptors. Patients may be hypersensitive to opioid effects and susceptible to overdose at lower opioid doses than previously tolerated (Ref). In addition, the opioid competitive receptor blockade produced by naltrexone is potentially surmountable in the presence of large amounts of opioids.Onset: Varied; overdose occurred within 2 weeks after discontinuation in one study (Ref). In another study, overdose occurred within a 12-month period (Ref).Risk factors:• Naltrexone discontinuation• Missed doses of naltrexone• Near the end of the naltrexone dosing interval• Opioid dose (Ref)• Time since opioid administration (Ref)• Patient metabolism (Ref)HepatotoxicityNaltrexone may cause transient, mildly increased serum transaminases (Ref). Most increases in serum transaminases resolve (some with continued therapy) (Ref). Naltrexone has not been associated with clinically significant cases of liver injury (Ref).Mechanism: Dose-related; unknown. May be direct toxicity (Ref).Onset: Varied; most increased serum alanine aminotransferase and increased serum aspartate aminotransferase occur in the first 30 days of therapy, but may occur later (Ref).Risk factors:• Higher oral doses (Ref)• Concurrent NSAIDs (Ref)• Older patients (> 50 years) (Ref)Injection site reactionsNaltrexone IM administration may cause injection site reaction, pain at injection site, tenderness at injection site, bruising at injection site, swelling at injection site, injection site nodule, and itching at injection site. Serious reactions, including abscess at injection site, cellulitis at injection site, hematoma at injection site, induration at injection site, sterile abscess at injection site, and tissue necrosis at injection site have been reported; some requiring surgical intervention (Ref). Nicolau syndrome or embolia cutis medicamentosa has been reported, characterized by blanching and pain around the injection site, followed by erythema and tissue necrosis (Ref).Mechanism: Most injection site reactions may be related to improper administration. Nicolau syndrome may occur due to direct damage to the end artery or cytotoxic effects of naltrexone and/or additives in the preparation (Ref).Onset: Varied; most injection site reactions occur within 1 to 3 days but may occur more than 10 days after injection (Ref). Nicolau syndrome may occur after 1 week (Ref).Risk factors:• Improper administration (eg, inadvertent SUBQ administration) (Ref)• Patients with HIV (Ref)Naltrexone-precipitated opioid withdrawalNaltrexone may precipitate opioid withdrawal syndrome in patients with opioid dependence or opioid use disorder. Symptoms may be severe and include abdominal pain, agitation, altered level of consciousness, confusion, diaphoresis, diarrhea, dilated pupils, dizziness, irritability, nausea, pain, tachycardia, and vomiting (Ref). Naltrexone-precipitated opioid withdrawal symptoms may last 48 to 72 hours (Ref). Withdrawal symptoms may require hospitalization but are rarely life-threatening (Ref).Mechanism: Related to the pharmacologic action; naltrexone displaces opioids from opioid receptors, precipitating withdrawal (Ref).Onset: Rapid; within 5 minutes, peaking between 1 to 3 hours (Ref).Risk Factors:• Dose and timing of opioid use (Ref)• Naltrexone administration prior to adequate opioid-free period• Accidental or deliberate naltrexone administration (Ref)• Transitioning from methadone or buprenorphine to naltrexone• Peri-operative pain management (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are as reported with the IM formulation.>10%:Cardiovascular: Syncope (≤13%)Gastrointestinal: Abdominal pain (11%), anorexia (≤14%), change in appetite (≤14%), decreased appetite (≤14%), diarrhea (13%), nausea (33%), vomiting (14%)Hepatic: Increased serum aspartate aminotransferase (2% to 14%) (table 1)Increased Serum Aspartate Aminotransferase, increased serum transaminases (20%) (table 2)NaltrexonIncreased Serum TransaminasesNaltrexone: Adverse Reaction: Increased Serum Aspartate AminotransferaseDrug (Naltrexone)Placebo Dosage FormIndication14%11%IMOpioid dependence2%0.9%IMAlcohol dependenceNaltrexone: Adverse Reaction: Increased Serum TransaminasesDrug (Naltrexone)Placebo Dosage FormIndication20%13%IMOpioid dependenceLocal: Induration at injection site (35%) (table 3)Induration at Injection Site, injection site reaction (69%, including injection site nodule and swelling at injection site) (table 4)Injection Site Reaction, pain at injection site (17%) (table 5)Pain at Injection Site, tenderness at injection site (45%) (table 6)Tenderness at Injection SiteNaltrexone: Adverse Reaction: Induration at Injection SiteDrug (Naltrexone)Placebo DoseDosage FormIndicationNumber of Patients (Naltrexone)Number of Patients (Placebo)35%8%380 mg every 4 weeksIMAlcohol dependence205214Naltrexone: Adverse Reaction: Injection Site ReactionDrug (Naltrexone)Placebo DoseDosage FormIndicationNumber of Patients (Naltrexone)Number of Patients (Placebo)69%50%380 mg every 4 weeksIMAlcohol dependence205214Naltrexone: Adverse Reaction: Pain at Injection SiteDrug (Naltrexone)Placebo DoseDosage FormIndicationNumber of Patients (Naltrexone)Number of Patients (Placebo)17%7%380 mg every 4 weeksIMAlcohol dependence205214Naltrexone: Adverse Reaction: Tenderness at Injection SiteDrug (Naltrexone)Placebo DoseDosage FormIndicationNumber of Patients (Naltrexone)Number of Patients (Placebo)45%39%380 mg every 4 weeksIMAlcohol dependence205214Nervous system: Anxiety (12%), dizziness (≤13%), headache (25%), insomnia (≤14%), sleep disorder (≤14%)Neuromuscular & skeletal: Arthralgia (≤12%), arthritis (≤12%), asthenia (23%), increased creatine phosphokinase in blood specimen (11% to 39%), joint stiffness (≤12%)Respiratory: Pharyngitis (11%)1% to 10%:Dermatologic: Skin rash (6%)Gastrointestinal: Xerostomia (5%)Local: Bruising at injection site (7%) (table 7)Bruising at Injection Site, itching at injection site (10%) (table 8)Itching at Injection SiteNaltrexone: Adverse Reaction: Bruising at Injection SiteDrug (Naltrexone)Placebo DoseDosage FormIndicationNumber of Patients (Naltrexone)Number of Patients (Placebo)7%5%380 mg every 4 weeksIMAlcohol dependence205214Naltrexone: Adverse Reaction: Itching at Injection SiteDrug (Naltrexone)Placebo DoseDosage FormIndicationNumber of Patients (Naltrexone)Number of Patients (Placebo)10%0%380 mg every 4 weeksIMAlcohol dependence205214Nervous system: Depression (8% to 10%), drowsiness (≤4%), sedated state (≤4%), suicidal ideation (≤1%) (Molero 2018), suicidal tendencies (≤1%) (Molero 2018)Neuromuscular & skeletal: Back pain (≤6%), back stiffness (≤6%), muscle cramps (8%)Frequency not defined:Cardiovascular: Acute ischemic stroke, acute myocardial infarction (Gubitosa 2020), angina pectoris, atrial fibrillation, cardiac failure, cerebral aneurysm, chest pain, chest tightness, coronary artery disease, deep vein thrombosis, facial edema, palpitations, pulmonary embolismDermatologic: Diaphoresis, night sweats, pruritusEndocrine & metabolic: Decreased libido, dehydration, hot flash, hypercholesterolemia, weight gain, weight lossGastrointestinal: Abdominal distress, acute pancreatitis (Verma 2016), cholecystitis, cholelithiasis, colitis, constipation, dysgeusia, flatulence, gastroenteritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, hemorrhoids, increased appetite, paralytic ileusHematologic & oncologic: Decreased platelet count, eosinophilia, leukocytosis, lymphadenopathyHepatic: Increased serum alanine aminotransferaseNervous system: Abnormal dreams, agitation, alcohol withdrawal syndrome, chills, decreased mental acuity, delirium (Gowing 2017), disturbance in attention, euphoria, heat exhaustion, irritability, lethargy, migraine, paresthesia, rigors, seizureNeuromuscular & skeletal: Limb pain, muscle spasm, myalgiaOphthalmic: Blurred vision, conjunctivitisRespiratory: Bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, nasal congestion, pharyngolaryngeal pain, pneumonia (including interstitial pneumonia) (Gastfriend 2011), sinusitisMiscellaneous: FeverPostmarketing:Dermatologic: UrticariaHepatic: HepatitisHypersensitivity: Anaphylaxis, angioedemaLocal: Abscess at injection site, cellulitis at injection site, hematoma at injection site, sterile abscess at injection site, tissue necrosis at injection siteNervous system: Opioid withdrawal syndrome (Hassanian-Moghaddam 2014; Yeo 2003)Respiratory: Eosinophilic pneumonitis (Gastfriend 2011)ContraindicationsHypersensitivity to naltrexone or any component of the formulation; current physiological opioid dependence or current use of opioid analgesics (including partial opioid agonists); acute opioid withdrawal; failure to pass naloxone challenge or positive urine screen for opioidsCanadian labeling: Additional contraindications (not in the US labeling): Acute hepatitis; hepatic failureWarnings/PrecautionsConcerns related to adverse effects:• Suicidal thoughts/depression: Suicidal thoughts, attempted suicide, and depression have been reported postmarketing; monitor closely.Disease-related concerns:• Bleeding disorders: Use IM injection with caution in patients thrombocytopenia or any bleeding disorder (including hemophilia and severe hepatic failure), or patients on anticoagulant therapy; bleeding/hematoma may occur from IM administration.• Hepatic impairment: Use is not recommended in acute hepatitis or hepatic failure (APA [Reus 2018]).• Renal impairment: Use with caution in patients with moderate to severe renal impairment (has not been studied).Dosage form specific issues:• Injection: Vehicle used in the injectable naltrexone formulation (polylactide-co-glycolide microspheres) has rarely been associated with retinal artery occlusion in patients with abnormal arteriovenous anastomosis following injection of other drug products that also use the polylactide-co-glycolide microspheres vehicle.Other warnings/precautions:• Discontinuation of therapy: There is no maximum recommended duration for maintenance treatment of opioid use disorder; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid use disorder treatment (SAMHSA 2021).• Opioid use disorder: Patients should be opioid-free (including tramadol) for a minimum of 7 to 10 days; a naloxone challenge test may be helpful to confirm patient is opioid-free prior to therapy if there is any suspicion since urinary opioid screen may not be sufficient proof. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Use of naltrexone does not eliminate or diminish withdrawal symptoms. Oral naltrexone tablets have not been shown to be more effective than placebo for opioid use disorder due to poor patient adherence (SAMHSA 2021).• Emergency pain management: In naltrexone-treated patients requiring emergency pain management, consider alternatives to opioid therapy (eg, regional analgesia, nonopioid analgesics, general anesthesia). If opioid therapy is required for pain therapy, patients should be under the direct care of a trained anesthesia provider.• Naloxone access: Discuss the availability of naloxone with all patients, as well as their caregivers, at initial treatment and regularly during therapy (eg, with each subsequent naltrexone injection). Patients being treated for an opioid use disorder have the potential for relapse and are at risk for opioid overdose; this risk may be increased in patients treated with naltrexone near the end of the naltrexone dosing interval (particularly if using naltrexone injection), if a dose of naltrexone is missed, or when naltrexone treatment is discontinued. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.• Surgery: In patients treated with naltrexone for opioid use disorder who are requiring surgery, discontinue oral naltrexone at least 72 hours before scheduled elective surgery if opioid use is anticipated; extended-release IM naltrexone should be discontinued at least 30 days prior to scheduled surgery (oral naltrexone may be used temporarily) (ASAM 2020).Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Bremelanotide: May decrease the serum concentration of Naltrexone. Risk X: Avoid combinationLofexidine: May decrease the serum concentration of Naltrexone. Risk C: Monitor therapyMethylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combinationNaldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased.Risk X: Avoid combinationNaloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased.Risk X: Avoid combinationOpioid Agonists: Naltrexone may diminish the therapeutic effect of Opioid Agonists.Management: Seek therapeutic alternatives to opioids.See full drug interaction monograph for detailed recommendations. Risk X: Avoid combinationSibutramine: May enhance the adverse/toxic effect of Centrally Acting Weight Loss Agents. Risk X: Avoid combinationReproductive ConsiderationsNaltrexone is not the preferred treatment for opioid use disorder during pregnancy; pregnancy testing is recommended prior to initiating naltrexone therapy (SAMHSA 2021).Pregnancy ConsiderationsNaltrexone and the 6-beta-naltrexol metabolite cross the placenta (Towers 2020).Alcohol use and opioid use disorder are associated with adverse fetal and obstetrical outcomes. Information related to the use of naltrexone during pregnancy is limited (ACOG 711 2017; Farid 2008; Towers 2020; Tran 2017).Information related to the use of naltrexone for the treatment of opioid use disorder during pregnancy is limited. Consider transitioning to a preferred agent or discontinue treatment if the patient and health care provider agree the risk of relapse is low. If treatment with naltrexone continues, the risks and benefits should be discussed (ASAM 2020; SAMHSA 2021). Pregnant patients are not appropriate candidates for the ER injection (SAMHSA 2021).Pharmacological agents should not be used for the treatment of alcohol use disorder in pregnant patients unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder; agents other than naltrexone are recommended for acute alcohol withdrawal (APA [Reus 2018]).Breastfeeding ConsiderationsNaltrexone and the 6-beta-naltrexol metabolite are present in breast milk (Chan 2004).According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Pharmacological agents should not be used for the treatment of alcohol use disorder in breastfeeding patients unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder; agents other than naltrexone are recommended for acute alcohol withdrawal (APA [Reus 2018]).Monitoring ParametersLiver function tests (baseline and periodic); signs or symptoms of opioid withdrawal, injection-site reactions with IM administration; pregnancy test (baseline); hepatitis and HIV testing, particularly for patients with opioid use disorder (prior to initiation) (SAMHSA 2021); and depression and/or suicidal thinkingMechanism of ActionNaltrexone (a pure opioid antagonist) is a cyclopropyl derivative of oxymorphone similar in structure to naloxone and nalorphine (a morphine derivative); it acts as a competitive antagonist at opioid receptor sites, showing the highest affinity for mu receptors. Endogenous opioids are involved in modulating the expression of alcohol's reinforcing effects (Hemby 1997; Lee 2005). Naltrexone also modifies the hypothalamic-pituitary-adrenal axis to suppress alcohol consumption (Williams 2004).Pharmaco*kineticsDuration: Oral: 50 mg: 24 hours; 100 mg: 48 hours; 150 mg: 72 hours; IM: 4 weeksAbsorption: Oral: Almost completeDistribution: Vd: ~1350 L; widely throughout the body but considerable interindividual variation existsMetabolism: Extensively metabolized via noncytochrome-mediated dehydrogenase conversion to 6-beta-naltrexol (primary metabolite) and related minor metabolites; glucuronide conjugates are also formed from naltrexone and its metabolitesOral: Extensive first-pass effectProtein binding: 21%Bioavailability: Oral: Variable range (5% to 40%)Half-life elimination: Oral: 4 hours; 6-beta-naltrexol: 13 hours; IM: Naltrexone and 6-beta-naltrexol: 5 to 10 days (dependent upon erosion of polymer)Time to peak, serum: Oral: ~60 minutes; IM: Biphasic: ~2 hours (first peak), ~2 to 3 days (second peak)Excretion: Primarily urine (as metabolites and small amounts of unchanged drug)Pharmaco*kinetics: Additional ConsiderationsHepatic function impairment: An increase in naltrexone AUC of approximately 5- and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with healthy liver function has been reported.Pricing: USSuspension (reconstituted) (Vivitrol Intramuscular)380 mg (per each): $1,800.25Tablets (Naltrexone HCl Oral)50 mg (per each): $2.14 - $4.28Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAbernil (VN);Adepend (BG, GB, HU, SK);Adinot (BD);Anarcol (EG);Antaxon (HU);Antaxone (IT, RU);Arrop (CR, DO, GT, HN, MX, NI, PA, SV);Basinal (PT);Dependex (AT);Destoxican (PT);Ethylex (AT);Ethytex (TR);Morfblock (EG);Nalcotrex (AR);Nalerona (CL, PE, PY);Nalorex (GB, HK, IT, PT);Naltima (IN, ZA);Naltox (LK);Naltraccord (NZ);Naltrax (BD);Naltrexin (CH, KR);Narpan (MY);Nemexin (AT, CH);Nodict (BD, IN);Nuo Xin Shejg (CN);Nutrexon (ID);Opizone (GB);Phaltrexia (ID);Re-Via (MX);Regental (UY);Revez (AR);Revia (AT, BR, DK, EG, FI, FR, KR, NO, RO, SE, TH, TW);ReVia (AU);Trexan (PK);Uninaltrex (BR)For country code abbreviations (show table)Abboud TK, Afrasiabi A, Davidson J, et al. Prophylactic oral naltrexone with epidural morphine: effect on adverse reactions and ventilatory responses to carbon dioxide. Anesthesiology. 1990a;72(2):233-237 [PubMed 2105673]Abboud TK, Lee K, Zhu J, et al. Prophylactic oral naltrexone with intrathecal morphine for cesarean section: effects on adverse reactions and analgesia. Anesth Analg. 1990b;71(4):367-370. doi:10.1213/00000539-199010000-00008 [PubMed 2205128]Ahamad K, Korthuis PT, Lum PJ, Johnson C, Wood E. A delayed injection-site reaction in a patient receiving extended-release naltrexone. Subst Abus. 2016;37(2):278-280. doi:10.1080/08897077.2016.1138919 [PubMed 26820699]American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice. Committee opinion No. 711: opioid use and opioid use disorder in pregnancy. Obstet Gynecol. 2017;130(2):e81-e94. doi: 10.1097/AOG.0000000000002235. [PubMed 28742676]American Society of Addiction Medicine (ASAM). The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020;14(2S)(suppl 1):1‐91. doi:10.1097/ADM.0000000000000633 [PubMed 32511106]Anton RF, O'Malley SS, Ciraulo DA, et al; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017. doi:10.1001/jama.295.17.2003 [PubMed 16670409]Carson KL, Tran TT, Cotton P, Sharara AI, Hunt CM. Pilot study of the use of naltrexone to treat the severe pruritus of cholestatic liver disease. Am J Gastroenterol. 1996;91(5):1022-1023. [PubMed 8633543]Chan CF, Page-Sharp M, Kristensen JH, O'Neil G, Ilett KF. Transfer of naltrexone and its metabolite 6,beta-naltrexol into human milk. J Hum Lact. 2004;20(3):322-326. doi: 10.1177/0890334404266881. [PubMed 15296587]Croop RS, Faulkner EB, Labriola DF. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. The Naltrexone Usage Study Group. Arch Gen Psychiatry. 1997;54(12):1130-1135. doi:10.1001/archpsyc.1997.01830240090013 [PubMed 9400350]Curatolo C, Trinh M. Challenges in the perioperative management of the patient receiving extended-release naltrexone. A A Case Rep. 2014;3(11):142-144. doi:10.1213/XAA.0000000000000069 [PubMed 25612099]Digiusto E, Shakeshaft A, Ritter A, O'Brien S, Mattick RP; NEPOD Research Group. Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD) [published correction appears in Addiction. 2005;100(1):139]. Addiction. 2004;99(4):450-460. doi:10.1111/j.1360-0443.2004.00654.x [PubMed 15049745]Farid WO, Dunlop SA, Tait RJ, Hulse GK. The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data. Curr Neuropharmacol. 2008;6(2):125-150. doi: 10.2174/157015908784533842. [PubMed 19305793]Fishman M. Precipitated withdrawal during maintenance opioid blockade with extended release naltrexone. Addiction. 2008;103(8):1399-1401. doi:10.1111/j.1360-0443.2008.02252.x [PubMed 18855831]Garbutt JC, Kranzler HR, O'Malley SS, et al; Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005;293(13):1617-1625. doi:10.1001/jama.293.13.1617 [PubMed 15811981]Gastfriend DR. Intramuscular extended-release naltrexone: current evidence. Ann N Y Acad Sci. 2011;1216:144-166. doi:10.1111/j.1749-6632.2010.05900.x [PubMed 21272018]Gibson AE, Degenhardt LJ. Mortality related to pharmacotherapies for opioid dependence: a comparative analysis of coronial records. Drug Alcohol Rev. 2007;26(4):405-410. doi:10.1080/09595230701373834 [PubMed 17564876]Gowing L, Ali R, White JM. Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev. 2017;5(5):CD002021. doi:10.1002/14651858.CD002021.pub4 [PubMed 28553701]Gubitosa JC, Terwillliger T, Ukazu A, Gordon E. Naltrexone-associated non-ST-elevated myocardial infarction. Cureus. 2020;12(10):e11198. doi:10.7759/cureus.11198 [PubMed 33269129]Hassanian-Moghaddam H, Afzali S, Pooya A. Withdrawal syndrome caused by naltrexone in opioid abusers. Hum Exp Toxicol. 2014;33(6):561-567. doi:10.1177/0960327112450901 [PubMed 23690227]Hemby SE, Johnson BA, Dworkin SI. Neurobiological basis of drug reinforcement. In: Drug Addiction and Its Treatment: Nexus of Neuroscience and Behavior. Johnson BA, Roache JD (Eds). Philadelphia, PA: Lippincott-Raven; 1997:137.Holt SR. Alcohol use disorder: pharmacologic management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 2, 2022.Kim SW, Grant JE, Yoon G, Williams KA, Remmel RP. Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients. Clin Neuropharmacol. 2006;29(2):77-79. doi:10.1097/00002826-200603000-00004 [PubMed 16614539]Lee YK, Park SW, Kim YK, et al. Effects of naltrexone on the ethanol-induced changes in the rat central dopaminergic system. Alcohol Alcohol. 2005;40(4):297-301. doi: 10.1093/alcalc/agh163. [PubMed 15897221]Legroux-Crespel E, Clèdes J, Misery L. A comparative study on the effects of naltrexone and loratadine on uremic pruritus. Dermatology. 2004;208(4):326-330. doi:10.1159/000077841 [PubMed 15178915]Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419. doi:10.1002/hep.30145 [PubMed 30070375]Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009;50(1):291-308. doi: 10.1002/hep.22906 [PubMed 19554543]Lucey MR, Silverman BL, Illeperuma A, O'Brien CP. Hepatic safety of once-monthly injectable extended-release naltrexone administered to actively drinking alcoholics. Alcohol Clin Exp Res. 2008;32(3):498-504. doi:10.1111/j.1530-0277.2007.00593.x [PubMed 18241321]Malik MH, Heaton H, Sloan B. Nicolau syndrome following intramuscular naltrexone injection. Dermatol Online J. 2020;26(7):13030/qt3gb5m0vr. [PubMed 32898411]Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Drug Alcohol Depend. 1997;45(1-2):131-134. doi:10.1016/s0376-8716(97)01348-3 [PubMed 9179515]Mitchell JE. Naltrexone and hepatotoxicity. Lancet. 1986;1(8491):1215. doi:10.1016/s0140-6736(86)91196-7 [PubMed 2871452]Molero Y, Zetterqvist J, Binswanger IA, Hellner C, Larsson H, Fazel S. Medications for alcohol and opioid use disorders and risk of suicidal behavior, accidental overdoses, and crime. Am J Psychiatry. 2018;175(10):970-978. doi:10.1176/appi.ajp.2018.17101112 [PubMed 30068260]Naltrexone hydrochloride tablets, USP [prescribing information]. Congers, NY: Chartwell Rx LLC; December 2021.Naltrexone. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Updated March 24, 2020. Accessed May 28, 2021. [PubMed 31643898]Pauli-Magnus C, Mikus G, Alscher DM, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study. J Am Soc Nephrol. 2000;11(3):514-519. [PubMed 10703675]Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet. 1996;348(9041):1552-1554. doi:10.1016/s0140-6736(96)04176-1 [PubMed 8950882]Perli D, Martone C, Rapose A. Naltrexone-induced Nicolau syndrome masquerading as cutaneous abscess. BMJ Case Rep. 2012;2012:bcr2012007785. doi:10.1136/bcr-2012-007785 [PubMed 23242099]Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry. 2018;175(1):86-90. doi: 10.1176/appi.ajp.2017.1750101. [PubMed 29301420]Revia (naltrexone) [product monograph]. Toronto, Ontario, Canada: Teva Canada Limited; April 2015.Sax DS, Kornetsky C, Kim A. Lack of hepatotoxicity with naltrexone treatment. J Clin Pharmacol. 1994;34(9):898-901. doi:10.1002/j.1552-4604.1994.tb04002.x [PubMed 7983232]Strain E. Pharmacotherapy for opioid use disorder. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 8, 2022.Substance Abuse and Mental Health Services Administration (SAMHSA). Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63. Publication No. PEP21-02-01-002. Substance Abuse and Mental Health Services Administration; 2021. https://store.samhsa.gov/product/TIP-63-Medications-for-Opioid-Use-Disorder-Full-Document/PEP21-02-01-002. Accessed February 7, 2022.Terg R, Coronel E, Sordá J, Muñoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol. 2002;37(6):717-722. doi:10.1016/s0168-8278(02)00318-5 [PubMed 12445410]Tetrault JM, Tate JP, McGinnis KA, et al. Hepatic safety and antiretroviral effectiveness in HIV-infected patients receiving naltrexone. Alcohol Clin Exp Res. 2012;36(2):318-324. doi:10.1111/j.1530-0277.2011.01601.x [PubMed 21797892]Towers CV, Katz E, Weitz B, Visconti K. Use of naltrexone in treating opioid use disorder in pregnancy. Am J Obstet Gynecol. 2020;222(1):83.e1-83.e8. doi: 10.1016/j.ajog.2019.07.037. [PubMed 31376396]Tran TH, Griffin BL, Stone RH, Vest KM, Todd TJ. Methadone, buprenorphine, and naltrexone for the treatment of opioid use disorder in pregnant women. Pharmacotherapy. 2017;37(7):824-839. doi: 10.1002/phar.1958. [PubMed 28543191]Verma R. Naltrexone-associated acute pancreatitis. Prim Care Companion CNS Disord. 2016;18(6):10.4088/PCC.16l01953. doi:10.4088/PCC.16l01953 [PubMed 27922226]Vivitrol (naltrexone) [prescribing information]. Waltham, MA: Alkermes Inc; September 2022.Williams KL, Broadbear JH, Woods JH. Noncontingent and response-contingent intravenous ethanol attenuates the effect of naltrexone on hypothalamic-pituitary-adrenal activity in rhesus monkeys. Alcohol Clin Exp Res. 2004;28(4):566-571. [PubMed 15100607]Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997;113(4):1264-1269. doi:10.1053/gast.1997.v113.pm9322521 [PubMed 9322521]Yeo M, Campbell V, Bonomo Y, Sawyer SM. Acute opioid withdrawal on accidental injection of naltrexone. J Paediatr Child Health. 2003;39(4):315-317. doi:10.1046/j.1440-1754.2003.00143.x [PubMed 12755943]Topic 9679 Version 261.0

CloseBaclofen: Drug informationBaclofen: Drug information(For additional information see "Baclofen: Patient drug information" and see "Baclofen: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningAbrupt withdrawal (injection): Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, which in rare cases has advanced to rhabdomyolysis, multiple organ-system failure, and death.Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Advise patients and caregivers of the importance of keeping scheduled refill visits and educate them on the early symptoms of baclofen withdrawal. Give special attention to patients at apparent risk (eg, spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information.Brand Names: USFleqsuvy;Gablofen;Lioresal;Lyvispah;OzobaxBrand Names: CanadaAPO-Baclofen;Baclofen-10;Baclofen-20;Lioresal DS [DSC];Lioresal Intrathecal;Lioresal [DSC];MYLAN-Baclofen;PMS-Baclofen;RATIO-Baclofen [DSC];RIVA-BaclofenPharmacologic CategorySkeletal Muscle RelaxantDosing: AdultNote: Gradual dose reduction is advised unless discontinuation is due to significant adverse effects or overdose-related emergencies; chronic oral baclofen therapy should be discontinued over at least 1 to 2 weeks or longer if withdrawal symptoms occur (Ref). Abrupt discontinuation of oral or intrathecal baclofen may result in severe adverse effects, including multiple organ-system failure and death.HiccupsHiccups (off-label use):Oral: Initial: 5 to 10 mg 3 times daily; may increase dose based on response and tolerability; usual maximum dose: 45 mg/day in divided doses (Ref).Muscle spasm and/or musculoskeletal painMuscle spasm and/or musculoskeletal pain (adjunctive therapy) (off-label use):Note: For skeletal muscle spasm and/or pain (eg, low back pain, neck pain) with muscle spasm, usually in combination with a nonsteroidal anti-inflammatory drug and/or acetaminophen (Ref). In general, muscle relaxants should be used temporarily (eg, for a few days or intermittently for a few days when needed) (Ref).Oral: Initial: 5 to 10 mg 3 times daily as needed (Ref).SpasticitySpasticity: Oral:Granules: Initial: 5 mg 3 times daily; may increase by 5 mg per dose every 3 days based on response and tolerability; maximum dose: 80 mg per day (20 mg 4 times per day).Solution, tablet: Initial: 5 mg 1 to 3 times daily; may increase by 5 mg per dose every 3 days based on response and tolerability; usual maximum dose: 80 mg/day in divided doses. Some patients may require doses up to 120 mg/day (Ref).Suspension: Initial: 5 mg (1 mL) 3 times daily; may increase by 5 mg (1 mL) per dose every 3 days based on response and tolerability; usual maximum dose: 80 mg (16 mL) per day (20 mg [4 mL] 4 times per day).Intrathecal:Note: Use extreme caution when filling the pump; follow manufacturer instructions.Screening dose: Initial bolus: 50 mcg over ≥1 minute then observe patient for 4 to 8 hours. A positive response consists of a significant decrease in muscle tone, frequency, and/or severity of spasms. If response is inadequate, may give 75 mcg as a second screening dose 24 hours after the first dose; observe patient for 4 to 8 hours. If response is still inadequate, may administer 100 mcg as a final screening dose 24 hours after the second dose. Patients not responding to screening dose of 100 mcg should not be considered for chronic infusion via implanted pump.Initial total daily continuous infusion dose via implanted pump:If screening dose provided positive response for >4 hours but <8 hours: Double the screening dose that gave a positive response and administer over 24 hours.If screening dose provided positive response for >8 hours: Infuse a dose equivalent to the screening dose over 24 hours.Initial titration after pump implantation: Do not increase dose in first 24 hours to allow steady state to be achieved; thereafter, initial dosage adjustments may be made by increasing daily dose by 10% to 30% (spasticity of spinal cord origin) or by 5% to 15% (spasticity of cerebral origin) once every 24 hours until satisfactory response.Maintenance dose and titration: Daily dose may be increased periodically (eg, during pump refills) by 10% to 40% (maximum increase: 40%) for spasticity of spinal cord origin or by 5% to 20% (maximum increase: 20%) for spasticity of cerebral origin. Dose may also be decreased 10% to 20% for adverse effects. Most patients have been adequately maintained on 300 to 800 mcg daily (spasticity of spinal cord origin) or 90 to 703 mcg daily (spasticity of cerebral origin). Experience with doses >1,000 mcg daily is limited.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function:Oral:The following dosage adjustments have been recommended (Ref): Note: Kidney function may be estimated using the co*ckcroft-Gault formula for dosage adjustment purposes.CrCl >80 mL/minute: No dosage adjustment necessary.CrCl 50 to 80 mL/minute: Initial: 5 mg every 12 hours; titrate cautiously to effect; do not exceed 50 mg/day or ~66% of the usual maximum daily dose, whichever is less.CrCl 30 to <50 mL/minute: Initial: 2.5 mg every 8 hours; titrate cautiously to effect; do not exceed 40 mg/day or ~50% of the usual maximum daily dose, whichever is less.CrCl <30 mL/minute: Avoid use; in some patients, even low initial doses for short duration have led to toxicity (Ref). If baclofen use cannot be avoided, initiate at a low dose (eg, 2.5 mg every 12 hours or less); titrate with extreme caution to effect; do not exceed 20 mg/day or ~33% of the usual maximum daily dose, whichever is less.Intrathecal: Mild to severe impairment: There are no specific dosage adjustments recommended. However, baclofen is primarily eliminated by the kidney; use with caution; dosage reduction may be necessary.Hemodialysis, intermittent (thrice weekly): Dialyzable (1 case report of 79% removal with a 4-hour session) (Ref):Oral, intrathecal: Avoid use. Numerous case reports and 1 population-based cohort study have demonstrated significant adverse events related to chronic maintenance dosing and unintentional overdoses (Ref). If baclofen use cannot be avoided, initiate at a low dose (eg, 2.5 mg orally every 12 hours or less); titrate with extreme caution to effect (Ref).Peritoneal dialysis:Oral, intrathecal: Avoid use. Baclofen clearance by peritoneal dialysis has not been characterized. Multiple case reports have reported hospitalization for encephalopathy (Ref). If baclofen use cannot be avoided, initiate at a low dose (eg, 2.5 mg orally every 12 hours or less); titrate with extreme caution to effect (Ref).CRRT:Oral, intrathecal: Avoid use. If baclofen use cannot be avoided, initiate at a low dose; titrate cautiously to effect (expert opinion). Note: CRRT data are primarily limited to the treatment of acute baclofen intoxication, which have demonstrated significant increases in baclofen clearance (Ref). However, because CRRT is often used short term and in acutely ill patients, dose increases in response to increased clearance are not recommended unless clinically indicated (eg, increased spasticity) (Ref).PIRRT (eg, sustained, low-efficiency diafiltration):Oral, intrathecal: Avoid use. Pharmaco*kinetics of baclofen in patients receiving PIRRT have not been well characterized (Ref).Dosing: Hepatic Impairment: AdultOral and intrathecal: There are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Pediatric(For additional information see "Baclofen: Pediatric drug information")Note: Gradual dose reduction is advised unless discontinuation is due to significant adverse effects or overdose-related emergencies; chronic oral baclofen therapy should be discontinued slowly (eg, over at least 1 to 2 weeks or longer if withdrawal symptoms occur) (Ref). Abrupt discontinuation of oral or intrathecal baclofen may result in severe adverse effects, including multiple organ system failure and death (Ref). Baclofen is available as both an oral solution and oral suspension; concentration varies by product; use extra caution during product selection and preparation and verify correct product/concentration is chosen.SpasticitySpasticity: Oral: Note: Dose-related side effects (eg, sedation) may be minimized by slow titration; lower initial doses than described below (2.5 to 10 mg administered daily) may be used with subsequent titration to 8 hourly doses (Ref).Infants ≥4 months and Children <2 years: Very limited data available: Oral: Usual dose: 10 to 20 mg/day in divided doses every 8 hours; begin at low end of range and titrate dose to patient response (Ref); titration intervals of every 7 days have been used in pediatric patients ≥2 years (Ref). Maximum daily dose: 40 mg/day (Ref). Dosing based on a retrospective study of 87 patients (age 9 ± 6 years; range: 0.4 to 23.5 years) with spasticity due to cerebral palsy or traumatic brain injury (Ref). Note: To minimize dose-related side effects (eg, sedation), lower initial doses (ie, 2.5 mg once to 3 times daily) may be considered and have been reported in pediatric patients >2 years (Ref).Children 2 to 7 years: Limited data available: Oral: Initial: 2.5 mg 3 times daily; titrate dose by 5 mg increments at weekly intervals to patient response; usual dose: 20 to 40 mg/day. Maximum daily dose: 60 mg/day (Ref). Note: Initial doses of 5 to 10 mg/day divided every 8 hours and more frequent titration intervals (ie, every 3 days) have also been described (Ref).Children ≥8 years and Adolescents: Limited data available in children <12 years: Oral: Initial: 5 mg 3 times daily; titrate dose to patient response every 3 to 7 days to usual dose of 30 to 40 mg/day; some patients ≥12 years may require every-6-hour dosing; maximum daily dose: 80 mg/day (Ref). Note: Lower initial doses (5 to 10 mg/day) have also been described (Ref). Higher maximum daily doses (up to 200 mg/day) have been described in some patients in a retrospective review; usually the higher doses were needed over time (Ref).Intrathecal: Note: Dosage adjustments may be required often during the first few months of therapy to adjust for lifestyle changes due to alleviation of spasticity. Maintain lowest dose that produces adequate response. Most patients require gradual increases over time to maintain optimal response. Sudden large requirements for a dose increase may indicate a catheter complication (eg, kink, dislodgement). Titrate dose to allow sufficient muscle tone and occasional spasms to optimize activities of daily living, support circulation, and possibly prevent deep vein thrombosis (DVT) formation. Use extreme caution when filling the pump; follow manufacturer instructions carefully. With chronic therapy, 5% to 10% of patients will become refractory to dose adjustments; may consider a drug holiday (hospitalized patients only) with a gradual withdrawal over 2 to 4 weeks and use of alternative spasticity management methods. Following the drug holiday, intrathecal baclofen may be resumed at the initial continuous infusion dose. Limited data available in children <4 years; dosing for this age group based on expert consensus recommendations (Ref).Screening dose: Children <4 years: Limited data available: Intrathecal: Initial: 25 mcg; if response is inadequate, double the initial dose and administer 24 hours after the first dose (Ref).Children ≥4 years and Adolescents: Intrathecal: Initial: 50 mcg (1 mL) for 1 dose; for patients considered very small for age, a 25 mcg initial screening dose may be considered; following administration of screening dose, observe patient for 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. If response is inadequate, may increase screening dose in 25 mcg increments every 24 hours until a 4- to 8-hour positive clinical response is demonstrated or 100 mcg/dose is given. Patients not responding to screening dose of 100 mcg should not be considered for chronic infusion/implanted pump (Ref).Initial dose titration following pump implant: Children and Adolescents: After positive response to screening dose, a maintenance intrathecal infusion can be administered via an implanted intrathecal pump.Initial total daily dose via pump: Children and Adolescents: Intrathecal: Double the screening dose that gave a positive response and administer over 24 hours, unless efficacy of the bolus dose was maintained for >8 hours or if negative reactions to the screening test dose (change in mental status, loss of function, or change in vital signs) occurred, then infuse a dose equivalent to the screening dose over 24 hours (Ref).Do not increase dose in first 24 hours (to allow steady state to be achieved); thereafter, increase daily dose slowly by 5% to 15% once every 24 hours until satisfactory response is achieved; usual range: 50 to 100 mcg daily (Ref).Maintenance dose titration (Ref):Children and Adolescents: Intrathecal:Inpatient titration: Daily dose may be increased periodically (eg, during pump refills) by 10% to 20% of dose; usual dose change is 50 mcg; maximum increment change: 100 mcg. Note: At lower doses, a 20% increase may be reasonable, but at higher doses a 20% increase may be excessive. Daily dose may be decreased by 10% to 20% for adverse effects.Outpatient titration: Daily dose may be increased periodically (eg, during pump refills) by 5% to 10% of daily dose (usual dose change is 25 mcg). Daily dose may be decreased by 10% to 20% for adverse effects.Usual maintenance dose: Children and Adolescents: Intrathecal: 100 to 2,000 mcg daily (Ref); the manufacturer provides the following:Children 4 to 12 years: Intrathecal: 24 to 1,199 mcg daily (average: 274 mcg/day).Children ≥12 years and Adolescents: Intrathecal: 90 to 703 mcg daily; daily doses have ranged from 22 to 1,400 mcg; experience with doses >1,000 mcg daily is limited.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricOral: There are no dosage adjustments provided in the manufacturer's labeling; however, baclofen is primarily renally eliminated; use with caution; dosage reduction may be necessary.Intrathecal: Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, baclofen is primarily renally eliminated; use with caution; dosage reduction may be necessary.Dosing: Hepatic Impairment: PediatricOral, Intrathecal: There are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultOral: Refer to adult dosing; use with caution. If benefits are not observed, withdraw the drug slowly.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Packet, Oral: Lyvispah: 5 mg (90 ea); 10 mg (90 ea); 20 mg (90 ea) [contains saccharin sodium]Solution, Intrathecal: Generic: 10 mg/20 mL (20 mL); 40 mg/20 mL (20 mL); 20,000 mcg/20 mL (20 mL)Solution, Intrathecal [preservative free]: Gablofen: 10,000 mcg/20 mL (20 mL); 20,000 mcg/20 mL (20 mL) [antioxidant free]Gablofen: 40,000 mcg/20 mL (20 mL)Lioresal: 0.05 mg/mL (1 mL); 40 mg/20 mL (20 mL) [antioxidant free]Lioresal: 10 mg/20 mL (20 mL); 10 mg/5 mL (5 mL) [antioxidant free, pyrogen free]Generic: 10 mg/20 mL (20 mL); 40 mg/20 mL (20 mL); 20,000 mcg/20 mL (20 mL)Solution, Oral: Ozobax: 5 mg/5 mL (473 mL) [contains methylparaben, propylparaben; grape flavor]Generic: 5 mg/5 mL (473 mL)Solution Prefilled Syringe, Intrathecal [preservative free]: Gablofen: 50 mcg/mL (1 mL) [antioxidant free, latex free]Gablofen: 20,000 mcg/20 mL (20 mL) [antioxidant free]Gablofen: 10,000 mcg/20 mL (20 mL); 40,000 mcg/20 mL (20 mL) [antioxidant free, pyrogen free]Generic: 50 mcg/mL (1 mL)Suspension, Oral: Fleqsuvy: 25 mg/5 mL (120 mL, 300 mL) [contains fd&c red #40 (allura red ac dye), propylene glycol, quinoline yellow (d&c yellow #10), sodium benzoate]Tablet, Oral: Generic: 5 mg, 10 mg, 20 mgGeneric Equivalent Available: USMay be product dependentDosage Forms ConsiderationsFirst-Baclofen suspension is a compounding kit. Refer to manufacturer’s labeling for compounding instructions.Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intrathecal: Lioresal Intrathecal: 500 mcg/mL (20 mL); 2000 mcg/mL (5 mL); 0.05 mg/mL (1 mL)Generic: 500 mcg/mL (20 mL); 0.05 mg/mL (1 mL); 2 mg/mL (5 mL, 20 mL)Tablet, Oral: Lioresal: 10 mg [DSC]Lioresal DS: 20 mg [DSC]Generic: 10 mg, 20 mgAdministration: AdultIntrathecal: For screening dosages, administer as a bolus injection (50 mcg/mL concentration) by barbotage into the subarachnoid space over at least 1 minute, followed by maintenance continuous infusion. Do not administer intrathecal formulation IV, IM, SUBQ, or epidurally.Oral:Granules: Contents of packet may be emptied into the mouth and swallowed or may be mixed with up to 15 mL of liquid or soft food (eg, applesauce, yogurt, pudding). If mixing with food, entire mixture should be consumed within 2 hours of mixing. If multiple packets are needed to complete dose, each packet must be mixed with separate volume of liquid or food.Solution, suspension: Administer without regards to meals. Shake suspension well; use a calibrated measuring device to administer; do not use a household teaspoon or tablespoon.Feeding tube: Oral granules may be administered by NG tube ≥8 French, gastrostomy tubes (G tube) ≥12 French, percutaneous endoscopic gastrostomy (PEG) tube ≥14 French, or gastrojejunostomy (GJ) tube ≥16 French. Prior to administration, flush feeding tube with up to 15 mL of water using a catheter tip syringe. Empty contents of 1 packet into 15 mL of liquid (eg, apple juice, milk) and mix until granules are wetted. Draw up suspension of granules/liquid into dosing syringe and administer via feeding tube. Using same syringe, flush the feeding tube with 15 mL of water after administration. Repeat process if multiple packets are needed to complete a dose. If dosing syringe is allowed to stand for ≥15 minutes prior to administration, invert syringe 3 times to ensure baclofen is mixed; administration must be completed within 2 hours of initial mixing.Administration: PediatricOral: Administer without regard to meals. If nausea occurs, may administer with food or milk (Ref).Oral liquid: Baclofen is available as both an oral solution and oral suspension; concentration varies by product; use extra caution during product selection and preparation and verify correct product/concentration is chosen. When using oral liquid product, administer with a calibrated measuring device; do not use a household teaspoon (overdosage may occur).Oral suspension: Shake well prior to administration.Oral granules: Contents of packet may be emptied into the mouth and swallowed or may be mixed with up to 15 mL of liquid or soft food (eg, applesauce, yogurt, pudding). If mixing with food, entire mixture should be consumed within 2 hours of mixing. If multiple packets are needed to complete dose, each packet must be mixed with separate volume of liquid or food.Administration via feeding tube: Oral granules may be administered by NG tube ≥8 French, gastrostomy tubes (G tube) ≥12 French, percutaneous endoscopic gastrostomy (PEG) tube ≥14 French, or gastrojejunostomy (GJ) tube ≥16 French. Prior to administration, flush feeding tube with up to 15 mL of water using a catheter tip syringe. Empty contents of 1 packet into 15 mL of liquid (eg apple juice or milk) and mix until granules wetted. Draw up suspension of granules/liquid into dosing syringe and administer via feeding tube. Using same syringe, flush the feeding tube with 15 mL of water after administration. Repeat process if multiple packets are needed to complete a dose. If dosing syringe is allowed to stand for ≥15 minutes prior to administration, invert syringe 3 times to ensure baclofen is mixed; administration must be completed within 2 hours of initial mixing.Parenteral: Intrathecal: Screening dosage: Administer as a bolus injection by barbotage into the subarachnoid space over at least 1 minute, followed by maintenance infusion via implantable infusion pump; do not abruptly discontinue intrathecal baclofen administration. Do not administer intrathecal formulation IV, IM, SUBQ, or epidurally.Use: Labeled IndicationsSpasticity:Oral:Solution (Ozobax), tablet: Management of reversible spasticity associated with multiple sclerosis or spinal cord lesions.Granules (Lyvispah), suspension (Fleqsuvy): Treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity; may also be of some value in patients with spinal cord injuries and other spinal cord diseases.Intrathecal: Management of severe spasticity of spinal cord origin (eg, spinal cord injury, multiple sclerosis) or cerebral origin (eg, cerebral palsy, traumatic brain injury) in patients ≥4 years of age; may be considered as an alternative to destructive neurosurgical procedures.Limitations of use: Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long-term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS adverse effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least 1 year after the injury before consideration of long-term intrathecal baclofen therapy.Use: Off-Label: AdultHiccups; Muscle spasm and/or musculoskeletal painMedication Safety IssuesSound-alike/look-alike issues:Baclofen may be confused with BactrobanLioresal may be confused with lisinopril, LotensinHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication (intrathecal administration) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.Administration issues:Different concentrations of the oral liquid are available; ensure appropriate strength and dose of oral liquid prior to administering, dispensing, and prescribing.Adverse Reactions (Significant): ConsiderationsCNS effectsCNS effects may include confusion, dizziness, drowsiness, sedation, asthenia, nausea, and vomiting (Ref). CNS effects may impair physical or mental abilities and be additive to alcohol and other CNS depressants (eg, opioids, benzodiazepines). Multiple cases describing neurotoxicity due to oral baclofen accumulation in adult patients with varying levels of renal impairment have been reported in the literature. In one study of 6,469 older adults on dialysis (360 receiving baclofen), 7.2% of patients started on baclofen were hospitalized for encephalopathy (median time to hospitalization of 3 days) compared to <0.1% of patients not receiving baclofen (Ref).Mechanism: Dose-related; related to the pharmacologic action. Reduces the release of excitatory neurotransmitters by binding to the GABA-B presynaptic receptors within the brain stem, dorsal horn of the spinal cord, and other CNS sites (Ref).Risk factors:• Oral doses >60 mg/day (Ref)• Oral (vs intrathecal) administration (Ref)• Severe kidney dysfunction (eGFR <30 mL/minute/1.73m2) (Ref)Withdrawal effectsIntrathecal baclofen: Abrupt withdrawal of intrathecal baclofen has been associated with altered mental status, exaggerated rebound spasticity, high fever, and muscle rigidity (which in rare cases has advanced to rhabdomyolysis, multiple organ-system failure, and death) (Ref).Oral baclofen: Abrupt withdrawal of oral baclofen has been associated with altered mental status, exaggerated rebound spasticity, hallucination, high fever, hypertension, hyperthermia, muscle rigidity, tachycardia, and seizure. Other symptoms include agitation, confusion, delusions, insomnia, and paranoid ideation (Ref). Neonatal withdrawal has also been reported in neonates whose mothers were treated with oral baclofen throughout pregnancy (Ratnayaka 2001).Mechanism: Withdrawal; related to the release of excitatory neurotransmitters (Ref).Onset: Rapid; symptoms appear within hours to a few days following interruption of intrathecal therapy (Ref) and within 12 to 72 hours after discontinuation of oral therapy (Ref). Neonatal withdrawal has been reported within hours to days after delivery.Risk factors:• Pump malfunction or removal (eg, battery failure, catheter displacement, infection, intrathecal mass) (Ref)• Preventable human errors (eg, programming or pump refill errors, oral baclofen administration or refill errors) (Ref)• Patients with spinal cord injuries at T-6 or above, communication difficulties, or history of withdrawal symptoms from intrathecal or oral baclofenAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Gastrointestinal: Nausea (≤12%), vomiting (≤11%)Nervous system: Asthenia (≤15%), confusion (≤11%), dizziness (2% to 15%), drowsiness (≤63%), headache (2% to 11%), hypotonia (2% to 35%)1% to 10%:Cardiovascular: Hypotension (≤9%), peripheral edema (2% to 3%)Dermatologic: Pruritus (4%), urticaria (≤1%)Gastrointestinal: Constipation (≤6%), diarrhea (≤2%), sialorrhea (3%), xerostomia (≤3%)Genitourinary: Difficulty in micturition (2%), impotence (≤2%), urinary frequency (≤6%), urinary incontinence (≤2%), urinary retention (≤8%)Nervous system: Abnormality in thinking (≤1%), agitation (≤1%), chills (≤1%), coma (≤2%), depression (2%), fatigue (2% to 4%), insomnia (≤7%), pain (≤4%), paresthesia (≤7%), seizure (≤10%), speech disturbance (≤4%), tremor (≤1%)Neuromuscular & skeletal: Back pain (≤2%)Ophthalmic: Amblyopia (≤2%)Respiratory: Dyspnea (≤1%), hypoventilation (≤4%), pneumonia (≤2%)Miscellaneous: Accidental injury (≤4%)<1%:Cardiovascular: Ankle edema (Bence 2014), bradycardia (Rifici 2011; Sechrist 2015), chest pain, hypertension, palpitations, syncope, vasodilationDermatologic: Alopecia, contact dermatitis, dermal ulcer, hyperhidrosis, skin rash (Pathak 2019; Saddichha 2011)Endocrine & metabolic: Weight gain (Hemingway 2001; Yang 2013)Gastrointestinal: Abdominal pain (Chen 1997), anorexia, dysgeusia, dysphagia, fecal incontinence, gastrointestinal hemorrhage, occult blood in stools, tongue irritationGenitourinary: Dysuria, hematuria, inhibited ejacul*tion (Saval 2008), nocturia, oliguria, vaginitisHematologic & oncologic: Carcinoma, leukocytosis (Gee 2016), petechial rashNervous system: Akathisia (Karol 2011), amnesia (Grande 2008; Zeman 2016), anxiety, ataxia (Porter 2017), dysarthria, dysautonomia, dystonia, euphoria (Das 2016; Ghosh 2017), excitement, hallucination, hyporeflexia, hypothermia (Singh 2009), hysteria, malaise, opisthotonus, personality disorder, slurred speechNeuromuscular & skeletal: Muscle rigidity, myalgiaOphthalmic: Accommodation disturbance, blurred vision, diplopia, miosis, mydriasis, nystagmus disorder, strabismusOtic: Tinnitus (Auffret 2014)Renal: NephrolithiasisRespiratory: Apnea (Locatelli 2019; Olivier 2016), hyperventilation, nasal congestionMiscellaneous: Fever (can be high fever with drug withdrawal)Frequency not defined:Endocrine & metabolic: Increased serum glucoseHepatic: Increased serum alkaline phosphatase, increased serum aspartate aminotransferaseNervous system: Withdrawal syndromePostmarketing:Cardiovascular: Deep vein thrombophlebitis (Carda 2008), pulmonary embolism (Carda 2008)Endocrine & metabolic: Decreased libido (Hornyak 2005), weight loss (Arima 2010)Gastrointestinal: Intestinal obstruction (Karthikeyan 2015), paralytic ileus (Morant 2006)Genitourinary: Erectile dysfunction (Denys 1998), org*sm disturbance (Hornyak 2005; Saval 2008), priapism, sexual disorder (McGehee 2006; Saval 2008)Nervous system: Delirium (Chauvin 2020), disorientation (Chauvin 2020), neonatal withdrawal (Ratnayaka 2001), suicidal ideation (Pelissier 2017; WeiBhaar 2012), transient ischemic attacks (Chauvin 2020)Neuromuscular & skeletal: Scoliosis (Panagopoulos 2020), scoliosis progression (Ginsburg 2007; Walker 2017)ContraindicationsHypersensitivity to baclofen or any component of the formulationIntrathecal formulation: IV, IM, SubQ, or epidural administrationWarnings/PrecautionsConcerns related to adverse effects:• Intrathecal mass: Cases (most from pharmacy compounded preparations) of intrathecal mass formation at the implanted catheter tip have been reported; patients may experience worsening or return of spasticity, pain, inadequate response to dose adjustments, and/or neurological deficit/dysfunction. Neurosurgical evaluation and/or an appropriate imaging study should be considered if a mass is suspected.• Urinary retention: May cause acute urinary retention (may be related to underlying disease); use with caution in patients with urinary obstruction.Disease-related concerns:• Autonomic dysreflexia: Use with caution in patients with a history of autonomic dysreflexia; presence of nociceptive stimuli or abrupt baclofen withdrawal may cause an autonomic dysreflexic episode.• Gastrointestinal disorders: Use with caution in patients with peptic ulcer disease, decreased GI motility, and/or GI obstructive disorders.• Psychiatric disease: Use with caution in patients with psychotic disorders, schizophrenia, or confusional states; may cause exacerbation of condition.• Renal impairment: Use with caution in patients with renal impairment; baclofen is eliminated primarily unchanged via the kidneys.• Respiratory disease: Use with caution in patients with respiratory disease.• Seizure disorder: Loss of seizure control has been reported in patients treated with baclofen; use with caution and monitor patients with a history of seizure disorder.Special populations:• Older adult: Use with caution in elderly patients; may be more sensitive to adverse CNS effects, especially at higher doses.• Neonates: Neonatal withdrawal symptoms (eg, increased muscle tone, jitteriness, tremor, seizure), beginning hours to days after delivery, have been reported in neonates born to mothers treated with baclofen throughout pregnancy.• Pediatric: Intrathecal: Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion.Dosage form specific issues:• Oral products: Multiple products available; ensure appropriate strength and dose of the oral formulation prior to administering, dispensing, and prescribing; oral suspension is a concentrated formulation.Other warnings/precautions:• Appropriate use: Intrathecal: For use only in an FDA-approved implantable pump for intrathecal baclofen administration; health care providers should be experienced with chronic intrathecal infusion therapy and resuscitative equipment should be readily available. Ensure patient is infection-free and then evaluate patient's response to bolus intrathecal injection (screening phase) prior to implanting pump. Monitor closely during the initial phase of pump use and when adjusting the dosing rate and/or the concentration in the reservoir. Educate patients and caregivers on proper home care of the pump and insertion site. Use extreme caution when filling an implantable pump; pumps should only be refilled through the reservoir refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Some pumps are equipped with a catheter access port that allows direct access to the intrathecal catheter; direct injection into this catheter access port or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose. Except in overdose related emergencies, intrathecal baclofen should be reduced slowly if discontinuation is necessary.• Appropriate use: Oral: Efficacy of oral baclofen has not been established in patients with Parkinson disease or cerebral palsy; therefore, use is not recommended. Use caution in patients with a history of stroke; poor tolerability to baclofen without significant benefit has been observed. Not indicated for spasticity associated with rheumatic disorders. Use with caution when spasticity is utilized to sustain upright posture and balance in locomotion, or when spasticity is necessary to obtain increased function.• Overdose: Intrathecal use: Monitor closely for signs and symptoms of overdose, which may appear suddenly or insidiously, especially during the initial screening and dose-titration phase of treatment, and during reintroduction of therapy after a period of interruption. Signs/symptoms of overdose may include drowsiness, dizziness, somnolence, hypothermia, respiratory depression, seizures, rostral progression of hypotonia, and loss of consciousness progressing to coma. If overdose is suspected, patient should be evaluated immediately in a hospital setting and the pump reservoir emptied.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).Risk C: Monitor therapyAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBotulinum Toxin-Containing Products: Muscle Relaxants (Centrally Acting) may enhance the adverse/toxic effect of Botulinum Toxin-Containing Products. Specifically, the risk for increased muscle weakness may be enhanced.Risk C: Monitor therapyBrexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyCNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapyDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDoxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants isnot recommended. Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationEsketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLacidipine: Baclofen may enhance the hypotensive effect of Lacidipine.Risk C: Monitor therapyLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMetoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPerampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPiribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil.Risk C: Monitor therapyPramipexole: CNS Depressants may enhance the sedative effect of Pramipexole.Risk C: Monitor therapyProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole.Risk C: Monitor therapyRotigotine: CNS Depressants may enhance the sedative effect of Rotigotine.Risk C: Monitor therapyRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationTolperisone: May enhance the adverse/toxic effect of Muscle Relaxants (Centrally Acting). Management: Monitor for increased sedation or CNS effects if tolperisone is combined with other centrally acting muscle relaxants. Consider decreasing the tolperisone dose if these agents are combined. Risk D: Consider therapy modificationTrimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyUrapidil: Baclofen may enhance the hypotensive effect of Urapidil.Risk C: Monitor therapyValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationPregnancy ConsiderationsLate-onset neonatal withdrawal may occur following in utero exposure. Feeding difficulties, high-pitched cry, hyperthermia, hypertonicity, loose stools, tremors, and seizures have been reported in newborns following maternal use of oral baclofen throughout pregnancy (Duncan 2013; Freeman 2016; Ratnayaka 2001). Use of intrathecal baclofen in pregnant females has been described (Dalton 2008; Hara 2018; Méndez-Lucena 2016; Tandon 2010). Maternal plasma concentrations following administration of intrathecal baclofen are significantly less than those with oral doses; exposure to the fetus is expected to be limited and adverse neonatal events have not been noted in available reports (Morton 2009).Breastfeeding ConsiderationsBaclofen is present in breast milk.The relative infant dose (RID) of oral baclofen is 5% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 80 mg/day.In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).The RID of baclofen was calculated using a milk concentration of 0.38 mcg/mL, providing an estimated daily infant dose via breast milk of 0.057 mg/kg/day. This milk concentration was obtained following maternal administration of oral baclofen 20 mg four times a day, shortly after birth (Lin 2014). A case report notes breast milk concentrations following maternal use of intrathecal baclofen 330 mcg/day throughout pregnancy were 0.617 ng/mL (Hara 2018). Adverse events were not observed in a breastfed infant following maternal use of intrathecal baclofen 200 mcg/day throughout pregnancy and postpartum (breast milk concentrations not sampled) (Morton 2009).Information related to milk concentrations is limited (Eriksson 1981; Lin 2014). Withdrawal symptoms may occur in a breastfed infant when maternal baclofen is discontinued or breastfeeding is stopped. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.Monitoring ParametersRegular EEG in patients with epilepsy (loss of seizure control has been reported); monitor for signs and symptoms of baclofen withdrawal (oral or intrathecal; eg, altered mental status, exaggerated rebound spasticity, hallucination, high fever, hypertension, hyperthermia, muscle rigidity, tachycardia, seizure, agitation, confusion, delusions, insomnia, and paranoid ideation); prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms; monitor closely during the initial phase of pump use and when adjusting the dosing rate and/or the concentration in the reservoir. monitor closely for signs and symptoms of overdose (eg, drowsiness, dizziness, somnolence, hypothermia, respiratory depression, seizures, rostral progression of hypotonia, and loss of consciousness progressing to coma), which may appear suddenly or insidiously, especially during the initial screening and dose-titration phase of treatment, and during reintroduction of therapy after a period of interruption.Mechanism of ActionInhibits the transmission of both monosynaptic and polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals, with resultant relief of muscle spasticityPharmaco*kineticsOnset of action: Intrathecal bolus: 30 minutes to 1 hour; Continuous infusion: 6 to 8 hours after infusion initiation.Peak effect: Intrathecal bolus: 4 hours (effects may last 4 to 8 hours); Continuous infusion: 24 to 48 hours.Absorption (dose dependent): Oral: Rapid; absorption from the GI tract is thought to be dose dependent; in pediatric patients (age range: 2 to 17 years) with cerebral palsy, absorption from GI tract highly variable and delayed (reported time lag: 0.59 ± 0.28 hours) (He 2014).Bioavailability: Oral: 74% (Agarwal 2015).Protein binding: 30%.Distribution: Volume of distribution: Pediatric patients (age range: 2 to 17 years: Oral: Highly variable: 1.16 L/kg with 43.5% interindividual variability (He 2014).Metabolism: Hepatic (15% of dose) (He 2014).Half-life elimination:Oral:Pediatric patients with cerebral palsy (age range: 2 to 17 years): 4.5 hours (He 2014).Adults: Granules: 5.5 hours; Solution: 5.7 hours; Suspension: ~5.6 hours; Tablets: 3.75 ± 0.96 hours (Brunton 2011).Intrathecal: CSF elimination half-life: 1.51 hours over the first 4 hours.Time to peak, serum: Oral: 1 hour (0.5 to 4 hours) (Brunton 2011); Suspension: 1 hour.Excretion: Urine (>70% as unchanged drug) and feces (Brunton 2011).Pricing: USPack (Lyvispah Oral)5 mg (per each): $11.0010 mg (per each): $11.0020 mg (per each): $22.00Solution (Baclofen Intrathecal)10 mg/20 mL (per mL): $7.08 - $11.6040 mg/20 mL (per mL): $28.38 - $46.39Solution (Baclofen Oral)5 mg/5 mL (per mL): $1.31Solution (Gablofen Intrathecal)10000 mcg/20 mL (per mL): $14.1820000 mcg/20 mL (per mL): $28.3540000 mcg/20 mL (per mL): $56.71Solution (Lioresal Intrathecal)0.05 mg/mL (per mL): $39.5610 mg/20 mL (per mL): $14.1810 mg/5 mL (per mL): $56.7140 mg/20 mL (per mL): $56.71Solution (Ozobax Oral)5 mg/5 mL (per mL): $2.07Solution Prefilled Syringe (Baclofen Intrathecal)50 mcg/mL (per mL): $52.80Solution Prefilled Syringe (Gablofen Intrathecal)50 mcg/mL (per mL): $105.5010000 mcg/20 mL (per mL): $15.2320000 mcg/20 mL (per mL): $30.4640000 mcg/20 mL (per mL): $61.00Suspension (Fleqsuvy Oral)25 mg/5 mL (per mL): $6.60Tablets (Baclofen Oral)5 mg (per each): $0.34 - $1.2410 mg (per each): $0.14 - $2.4720 mg (per each): $0.16 - $5.13Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalBaclan (IN, KR);Baclofen-ratiopharm (LU);Baclofene (FR);Baclon (FI, LK, TW);Baclopar (IE);Baclosal (IL, LV);Baclosan (RU);Baclosol (VN);Bacmax (IN);Bacofen (KR);Bacron (KR);Bamifen (VN);Barapa (KR);Bathecal (AU);Clofen (AU);Colmifen (MT, SG);Curofen (KR);Diafen (PY, UY);Espast (PE);Flexibac (LK);Gabalon (JP);Gablofen (NL);Liobac (TH);Liofen (IN);Lionova (DK, NO, SE);Liorel (BD);Lioresal (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CN, CO, CY, CZ, DE, DK, EE, ES, ET, FI, FR, GB, GH, GM, GN, GR, GY, HK, HR, HU, ID, IE, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KW, LB, LK, LR, LU, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, NZ, OM, PH, PK, PL, PT, PY, QA, RO, RU, SA, SC, SD, SE, SG, SI, SL, SN, SR, SY, TH, TN, TR, TT, TZ, UG, VE, YE, ZA, ZM, ZW);Lioresyl (CL);Liosal (BD);Lyflex (GB, IE);Miorel (GR);Mulax (TW);Mylinax (CR, DO, GT, HN, NI, PA, SV);Mylobac (EG);Myorel (LK);Onelaxant-R (PH);Pacifen (NZ, TW);Prex (KR);Skelofen (BD);Slaken (BD);Solofen (TW);Spinax (CN, TW);Stelax (AU, HK);Trilaxant (PH);Yylofen (VN);Zufen (CN)For country code abbreviations (show table)Agarwal SK, Kriel RL, Cloyd JC, et al. A pilot study assessing pharmaco*kinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers. J Child Neurol. 2015;30(1):37-41. doi:10.1177/0883073814535504 [PubMed 25028414]Aisen ML, Dietz M, McDowell F, Kutt H. Baclofen toxicity in a patient with subclinical renal insufficiency. Arch Phys Med Rehabil. 1994;75(1):109-111. [PubMed 8291951]Alden TD, Lytle RA, Park TS, Noetzel MJ, Ojemann JG. Intrathecal baclofen withdrawal: a case report and review of the literature. Childs Nerv Syst. 2002;18(9-10):522-525. doi:10.1007/s00381-002-0634-8 [PubMed 12382179]Al-Khodairy AT, Vuagnat H, Uebelhart D. Symptoms of recurrent intrathecal baclofen withdrawal resulting from drug delivery failure: a case report. Am J Phys Med Rehabil. 1999;78(3):272-277. doi:10.1097/00002060-199905000-00018 [PubMed 10340425]Alstermark C, Amin K, Dinn SR, et al. Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors. J Med Chem. 2008;51(14):4315-4320. doi:10.1021/jm701425k [PubMed 18578471]Alvis BD, Sobey CM. Oral baclofen withdrawal resulting in progressive weakness and sedation requiring intensive care admission. Neurohospitalist. 2017;7(1):39-40. doi:10.1177/1941874416637404 [PubMed 28042369]American Pain Society (APS). Principles of Analgesic Use. 7th ed. American Pain Society; 2016.Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]Arima H, Oiso Y. Positive effect of baclofen on body weight reduction in obese subjects: a pilot study. Intern Med. 2010;49(19):2043-2047. doi:10.2169/internalmedicine.49.3918 [PubMed 20930428]ASHP. Standardize 4 Safety Initiative Compounded Oral Liquid Version 1.01. July 2017. https://www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/s4s-ashp-oral-compound-liquids.ashx?la=en&hash=4C2E4F370B665C028981B61F6210335AD5D0D1D6.Auffret M, Rolland B, Deheul S, et al; CAMTEA Team. Severe tinnitus induced by off-label baclofen. Ann Pharmacother. 2014;48(5):656-659. doi:10.1177/1060028014525594 [PubMed 24577148]Baclofen tablet [prescribing information]. Memphis, TN: Northstar Rx LLC; October 2020.Baclofen tablets [prescribing information]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; April 2021.Baclofen tablets [prescribing information]. Amityville, NJ: Innogenix LLC; June 2021.Based on expert opinion.Bence C, Cottencin O, Deheul S, Gautier S, Bordet R, Rolland B. Baclofen-induced edema in alcohol use disorders. J Clin Pharmacol. 2014 ;54(4):478-481. doi:10.1002/jcph.233 [PubMed 24293402]Berweck S, Lütjen S, Voss W, et al. Use of intrathecal baclofen in children and adolescents: interdisciplinary consensus table 2013. Neuropediatrics. 2014;45(5):294-308. [PubMed 25188830]Boster AL, Adair RL, Gooch JL, et al. Best practices for intrathecal baclofen therapy: dosing and long-term management. Neuromodulation. 2016;19(6):623-631. doi:10.1111/ner.12388 [PubMed 27433993]Boz C, Velioglu S, Bulbul I, Ozmenoglu M. Baclofen is effective in intractable hiccups induced by brainstem lesions. Neurol Sci. 2001;22(5):409. [PubMed 11917982]Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill Medical; 2011.Carda S, Cazzaniga M, Taiana C, Pozzi R. Intrathecal baclofen bolus complicated by deep vein thrombosis and pulmonary embolism. A case report. Eur J Phys Rehabil Med. 2008;44(1):87-88. [PubMed 18385632]Chauvin KJ, Blake PG, Garg AX, et al. Baclofen has a risk of encephalopathy in older adults receiving dialysis. Kidney Int. 2020;S0085-2538(20)30552-4. doi:10.1016/j.kint.2020.04.047 [PubMed 32450156]Chen KS, Bullard MJ, Chien YY, Lee SY. Baclofen toxicity in patients with severely impaired renal function. Ann Pharmacother. 1997;31(11):1315-1320. doi:10.1177/106002809703101108 [PubMed 9391686]Chen YC, Chang CT, Fang JT, Huang CC. Baclofen neurotoxicity in uremic patients: is continuous ambulatory peritoneal dialysis less effective than intermittent hemodialysis? Ren Fail. 2009;25(2):297-305. doi:10.1081/jdi-120018730 [PubMed 12739836]Choo YM, Kim GB, Choi JY, et al. Severe respiratory depression by low-dose baclofen in the treatment of chronic hiccups in a patient undergoing CAPD. Nephron. 2000;86(4):546-547. doi:10.1159/000045866 [PubMed 11124626]Chou CL, Chen CA, Lin SH, Huang HH. Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hiccups. South Med J. 2006;99(11):1308-1309. doi:10.1097/01.smj.0000247632.84949.27 [PubMed 17195438]Chou R, Deyo R, Friedly J, et al. Systemic pharmacologic therapies for low back pain: a systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med. 2017;166(7):480-492. doi:10.7326/M16-2458 [PubMed 28192790]Committee on Safety of Medicines (CSM), Medicines Control Agency. Reminder: severe withdrawal reactions with baclofen. Curr Probl Pharmacovigilance. 1997;23:1-4. https://webarchive.nationalarchives.gov.uk/20090218060434/http://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con2023229.pdfDalton CM, Keenan E, Jarrett L, Buckley L, Stevenson VL. The safety of baclofen in pregnancy: intrathecal therapy in multiple sclerosis. Mult Scler. 2008;14(4):571-572. doi: 10.1177/1352458507085552 [PubMed 18562512]Dapas F, Hartman SF, Martinez L, et al. Baclofen for the treatment of acute low-back syndrome. A double-blind comparison with placebo. Spine (Phila Pa 1976). 1985;10(4):345-349. doi:10.1097/00007632-198505000-00010 [PubMed 2931831]Dario A, Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity. Drug Saf. 2004;27(11):799-818. doi:10.2165/00002018-200427110-00004 [PubMed 15350152]Das S, Palappalllil DS, Purushothaman ST, Rajan V. An unusual case of baclofen abuse. Indian J Psychol Med. 2016;38(5):475-476. doi:10.4103/0253-7176.191383 [PubMed 27833235]Denys P, Mane M, Azouvi P, Chartier-Kastler E, Thiebaut JB, Bussel B. Side effects of chronic intrathecal baclofen on erection and ejacul*tion in patients with spinal cord lesions. Arch Phys Med Rehabil. 1998;79(5):494-496. doi:10.1016/s0003-9993(98)90061-2 [PubMed 9596387]Duncan SD, Devlin LA. Use of baclofen for withdrawal in a preterm infant. J Perinatol. 2013;33(4):327-328. doi:10.1038/jp.2012.107 [PubMed 23536044]El-Husseini A, Sabucedo A, Lamarche J, Courville C, Peguero A. Baclofen toxicity in patients with advanced nephropathy: proposal for new labeling. Am J Nephrol. 2011;34(6):491-495. doi:10.1159/000333247 [PubMed 22041434]Eriksson G, Swahn CG. Concentrations of baclofen in serum and breast milk from a lactating woman. Scand J Clin Lab Invest. 1981;41(2):185-187. doi:10.3109/00365518109092032 [PubMed 7313501]Fleqsuvy (baclofen) [prescribing information]. Wilmington, MA: Azurity Pharmaceuticals Inc; February 2022.Freeman EH, Delaney RM. Neonatal baclofen withdrawal: A case report of an infant presenting with severe feeding difficulties. J Pediatr Nurs. 2016;31(3):346-349. doi:10.1016/j.pedn.2015.12.004. [PubMed 26810267]Gablofen (baclofen) [prescribing information]. Bethlehem, PA: Primal Critical Care Inc; October 2020.Galvez-Jimenez N. Symptom-based management of amyotrophic lateral sclerosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 6, 2022.Gee SW, Outsen S, Becknell B, Schwaderer AL. Baclofen toxicity responsive to hemodialysis in a pediatric patient with acute kidney injury. J Pediatr Intensive Care. 2016;5(1):37-40. doi:10.1055/s-0035-1568151. [PubMed 31110881]Ghosh S, Bhuyan D. Baclofen abuse due to its hypomanic effect in patients with alcohol dependence and comorbid major depressive disorder. Clin Psychopharmacol Neurosci. 2017;15(2):187-189. doi:10.9758/cpn.2017.15.2.187 [PubMed 28449569]Ginsburg GM, Lauder AJ. Progression of scoliosis in patients with spastic quadriplegia after the insertion of an intrathecal baclofen pump. Spine (Phila Pa 1976). 2007;32(24):2745-2750. doi:10.1097/BRS.0b013e31815a5219 [PubMed 18007255]Goyal V, Laisram N, Wadhwa RK, Kothari SY. Prospective randomized study of oral diazepam and baclofen on spasticity in cerebral palsy. J Clin Diagn Res. 2016;10(6):RC01-RC5. doi:10.7860/JCDR/2016/17067.7975 [PubMed 27504360]Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg. 2008;106(4):1284-1287, table of contents. doi:10.1213/ane.0b013e318165e1c6 [PubMed 18349207]Grant JA, Steiner EM, Johnson RH. Treatment of persistent hiccups. J Neurol Neurosurg Psychiatry. 1991;54(5):468. doi:10.1136/jnnp.54.5.468 [PubMed 1865216]Greenberg MI, Hendrickson RG. Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. J Toxicol Clin Toxicol. 2003;41(1):83-85. doi:10.1081/clt-120018277 [PubMed 12645974]Guelaud C, Similowski T, Bizec JL, Cabane J, Whitelaw WA, Derenne JP. Baclofen therapy for chronic hiccup. Eur Respir J. 1995;8(2):235-237. doi:10.1183/09031936.95.08020235 [PubMed 7758557]Hadjiyannacos D, Vlassopoulos D, Hadjiconstantinou V. Treatment of intractable hiccup in haemodialysis patients with baclofen. Am J Nephrol. 2001;21(5):427-8. doi:10.1159/000046290 [PubMed 11684810]Hara T, Nakajima M, Sugano H, et al. Pregnancy and breastfeeding during intrathecal baclofen therapy - a case study and review. NMC Case Rep J. 2018;5(3):65-68. doi:10.2176/nmccrj.cr.2017-0191 [PubMed 30023142]He Y, Brunstrom-Hernandez JE, Thio LL, et al. Population pharmaco*kinetics of oral baclofen in pediatric patients with cerebral palsy. J Pediatr. 2014;164(5):1181-1188.Hemingway C, McGrogan J, Freeman JM. Energy requirements of spasticity. Dev Med Child Neurol. 2001;43(4):277-278. doi:10.1017/s0012162201000524 [PubMed 11305407]Hornyak JE, McGehee MJ, Kelly B, Lin C. Oral baclofen as a cause of sexual dysfunction: A report of 2 cases. Archives of Physical Medicine and Rehabilitation. 2005;86(9):E39, Poster 197. https://www.archives-pmr.org/action/showPdf?pii=S0003-9993%2805%2900809-9Isaac Z. Management of non-radicular neck pain in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. doi:10.1056/NEJM200007133430208 [PubMed 10891521]Karol DE, Muzyk AJ, Preud'homme XA. A case of delirium, motor disturbances, and autonomic dysfunction due to baclofen and tizanidine withdrawal: a review of the literature. Gen Hosp Psychiatry. 2011;33(1):84.e1-e2. doi:10.1016/j.genhosppsych.2010.10.003 [PubMed 21353141]Karthikeyan VS, Senthilkumaran K, Easwaran B, Rajbhaskar R. Intestinal pseudo-obstruction following oral baclofen: An unusual complication. J Pharmacol Pharmacother. 2015;6(3):169-171. doi:10.4103/0976-500X.162010 [PubMed 26312004]Katsinelos P, Pilpilidis J, Xiarchos P, et al. Baclofen therapy for intractable hiccups induced by ultraflex esophageal endoprosthesis. Am J Gastroenterol. 2000;95(10):2986-2987. doi:10.1111/j.1572-0241.2000.03216.x [PubMed 11051387]Khazneh E, Shamlawi A, Jebrin K, Hamdan Z, Sawalmeh O. Single-dose baclofen-induced neurotoxicity in a patient with end stage renal disease: case report. BMC Nephrol. 2018;19(1):352. doi:10.1186/s12882-018-1167-z [PubMed 30537935]Lee J, Shin HS, Jung YS, Rim H. Two cases of baclofen-induced encephalopathy in hemodialysis and peritoneal dialysis patients. Ren Fail. 2013;35(6):860-862. doi:10.3109/0886022X.2013.794679 [PubMed 23682655]Lin HH, Barton N, Wiegand TJ. Baclofen distribution into breast milk - a potential for toxicity? J Med Toxicol. 2014;10:86.Lioresal Intrathecal (baclofen) [prescribing information]. Roswell, GA: Saol Therapeutics Inc; January 2019.Lioresal Intrathecal (baclofen) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; May 2020.Lioresal tablets (baclofen) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; May 2020.Locatelli F, Formica F, Galbiati S, et al. Polysomnographic analysis of a pediatric case of baclofen-induced central sleep apnea. J Clin Sleep Med. 2019;15(2):351-354. doi:10.5664/jcsm.7644 [PubMed 30736882]Lois F, Wallemacq P, de Tourtchaninoff M, et al. Prolonged unconsciousness in a patient on automated peritoneal dialysis. Eur J Emerg Med. 2006;13(6):361-363. doi:10.1097/01.mej.0000217992.32235.ff [PubMed 17091060]Lubsch L, Habersang R, Haase M, Luedtke S. Oral baclofen and clonidine for treatment of spasticity in children. J Child Neurol. 2006;21(12):1090-1092. doi:10.1177/7010.2006.00134 [PubMed 17156708]Lyvispah (baclofen) [prescribing information]. Roswell, GA: Saol Therapeutics Inc; November 2021.Marino RA. Baclofen therapy for intractable hiccups in pancreatic carcinoma. Am J Gastroenterol. 1998;93(10):2000. doi: 10.1111/j.1572-0241.1998.02000.x [PubMed 9772082]McGehee M, Hornyak JE, Lin C, Kelly BM. Baclofen-induced sexual dysfunction. Neurology. 2006;67(6):1097-1098. doi:10.1212/01.wnl.0000237332.25528.ac [PubMed 17000991]Medical Advisory Secretariat. Intrathecal baclofen pump for spasticity: an evidence-based analysis. Ont Health Technol Assess Ser. 2005;5(7):1-93. [PubMed 23074476]Méndez-Lucena C, Chacón Peña J, García-Moreno JM. Intrathecal baclofen for dystonia treatment during pregnancy: a case report. Neurologia. 2016;31(2):131-132. doi:10.1016/j.nrl.2014.04.008 [PubMed 24851698]Meulendijks D, Khan S, Koks CH, Huitema AD, Schellens JH, Beijnen JH. Baclofen overdose treated with continuous venovenous hemofiltration. Eur J Clin Pharmacol. 2015;71(3):357-361. doi:10.1007/s00228-014-1802-y [PubMed 25567218]Milla PJ, Jackson AD. A controlled trial of baclofen in children with cerebral palsy. J Int Med Res. 1977;5(6):398-404. doi:10.1177/030006057300100203 [PubMed 338390]Mirijello A, Addolorato G, D'Angelo C, et al. Baclofen in the treatment of persistent hiccup: a case series. Int J Clin Pract. 2013;67(9):918-921. doi:10.1111/ijcp.12184 [PubMed 23834241]Mohammed I, Hussain A. Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: a case report. BMC Clin Pharmacol. 2004;4:6. doi:10.1186/1472-6904-4-6 [PubMed 15301690]Morant A, Noé E, Boyer J, et al. Paralytic ileus: a complication after intrathecal baclofen therapy. Brain Inj. 2006;20(13-14):1451-1454. doi:10.1080/02699050601082016 [PubMed 17378237]Morton CM, Rosenow J, Wong C, Kirschner KL. Intrathecal baclofen administration during pregnancy: a case series and focused clinical review. PM R. 2009;1(11):1025-1029. doi:10.1016/j.pmrj.2009.07.010 [PubMed 19942189]Olek MJ, Narayan RM, Frohman EM, Frohman TC. Symptom management of multiple sclerosis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 6, 2022.Olivier PY, Joyeux-Faure M, Gentina T, et al. Severe central sleep apnea associated with chronic baclofen therapy: A case series. Chest. 2016;149(5):e127-e131. doi:10.1016/j.chest.2015.10.001 [PubMed 27157226]O'Rourke F, Steinberg R, Ghosh P, Khan S. Withdrawal of baclofen may cause acute confusion in elderly patients. BMJ. 2001;323(7317):870. [PubMed 11597980]Ozobax (baclofen) [prescribing information]. Athens, GA: Metacel Pharmaceuticals LLC; May 2020.Panagopoulos D, Apostolopoulou K, Themistocleous M. Severe neuromuscular scoliosis implicated by dysfunction of intrathecal baclofen pump: Case report and review of the literature. World Neurosurg. 2020;134:390-395. doi:10.1016/j.wneu.2019.11.027 [PubMed 31733394]Pathak LK, Athavale A, Martinez I. Baclofen-induced toxicity in renal disease with neurotoxicity and skin rash. Proc (Bayl Univ Med Cent). 2019;32(3):425-426. doi:10.1080/08998280.2019.1618659 [PubMed 31384209]Peces R, Navascués RA, Baltar J, Laurés AS, Alvarez-Grande J. Baclofen neurotoxicity in chronic haemodialysis patients with hiccups. Nephrol Dial Transplant. 1998;13(7):1896-1897. [PubMed 9681766]Pelissier F, de Haro L, Cardona F, et al. Self-poisoning with baclofen in alcohol-dependent patients: national reports to French Poison Control Centers, 2008-2013. Clin Toxicol (Phila). 2017;55(4):275-284. doi:10.1080/15563650.2017.1284330 [PubMed 28152635]Porter LM, Merrick SS, Katz KD. Baclofen toxicity in a patient with hemodialysis-dependent end-stage renal disease. J Emerg Med. 2017;52(4):e99-e100. doi:10.1016/j.jemermed.2016.09.025 [PubMed 27789113]Quality Standards Subcommittee of the American Academy of Neurology (AAN) and the Practice Committee of the Child Neurology Society, Delgado MR, Hirtz D, Aisen M, et al. Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2010;74(4):336-343. doi: 10.1212/WNL.0b013e3181cbcd2f [PubMed 20101040]Ratnayaka BD, Dhaliwal H, Watkin S. Drug points: Neonatal convulsions after withdrawal of baclofen. BMJ. 2001;323(7304):85. doi:10.1136/bmj.323.7304.85 [PubMed 11451783]Refer to manufacturer's labeling.Reis PV, Vieira CR, Midões AC, Rebelo V, Barbosa P, Gomes A. Intrathecal baclofen infusion pumps in the treatment of spasticity: A retrospective cohort study in a Portuguese Centre. Acta Med Port. 2019;32(12):754-759. doi:10.20344/amp.10482 [PubMed 31851884]Rifici C, D'Aleo G, D'Aleo P, Bramanti P, Saltuari L, Kofler M. Cardiovascular alterations heralded by intrathecal baclofen bolus. NeuroRehabilitation. 2011;28(4):389-393. doi:10.3233/NRE-2011-0668 [PubMed 21725173]Riva-baclofen (baclofen) [product monograph]. Blainville, Canada: Laboratoire Riva Inc; July 2020.Roberts JK, Westphal S, Sparks MA. Iatrogenic Baclofen neurotoxicity in ESRD: recognition and management. Semin Dial. 2015;28(5):525-529. doi:10.1111/sdi.12400. [PubMed 26096760]Saddichha S, Jayaram N, Manjunatha N, Benegal V. Baclofen-induced morbiliform rashes: a case series. J Clin Pharmacol. 2011;51(12):1733-1734. doi:10.1177/0091270010385936 [PubMed 21119092]Salim SA, Thomas L, Achanti A, et al. Baclofen-induced neurotoxicity in patients with compromised renal function: Review. Int J Clin Pharmacol Ther. 2018;56(10):467-475. doi:10.5414/CP203243 [PubMed 12769509]Saulino M, Anderson DJ, Doble J, et al. Best practices for intrathecal baclofen therapy: Troubleshooting. Neuromodulation. 2016;19(6):632-641. doi:10.1111/ner.12467 [PubMed 27434299]Saval A, Chiodo AE. Sexual dysfunction associated with intrathecal baclofen use: a report of two cases. J Spinal Cord Med. 2008;31(1):103-105. doi:10.1080/10790268.2008.11753989 [PubMed 18533420]Scheinberg A, Hall K, Lam LT, O'Flaherty S. Oral baclofen in children with cerebral palsy: a double-blind cross-over pilot study. J Paediatr Child Health. 2006;42(11):715-20. doi:10.1111/j.1440-1754.2006.00957.x [PubMed 17044900]Sechrist C, Kinsman S, Cain N. Profound bradycardia after intrathecal baclofen injection in a patient with hydranencephaly. Pediatr Neurol. 2015;53(6):532-534. doi:10.1016/j.pediatrneurol.2015.08.010 [PubMed 26411756]Seker MM, Aksoy S, Ozdemir NY, et al. Successful treatment of chronic hiccup with baclofen in cancer patients. Med Oncol. 2012;29(2):1369-1370. doi:10.1007/s12032-011-9910-3 [PubMed 21442315]Siegfried RN, Jacobson L, Chabal C. Development of an acute withdrawal syndrome following the cessation of intrathecal baclofen in a patient with spasticity. Anesthesiology. 1992;77(5):1048-1050. doi:10.1097/00000542-199211000-00034 [PubMed 1443727]Singh NK, Agarwal A, Salazar L, Henkle JQ. Osborn waves in hypothermia induced by baclofen overdose. BMJ Case Rep. 2009;2009:bcr10.2008.1142. doi:10.1136/bcr.10.2008.1142 [PubMed 21686448]Su W, Yegappan C, Carlisle EJ, Clase CM. Reduced level of consciousness from baclofen in people with low kidney function. BMJ. 2009;339:b4559. doi:10.1136/bmj.b4559 [PubMed 20044395]Swigar ME, Bowers MB. Baclofen withdrawal and neuropsychiatric symptoms: a case report and review of other case literature. Compr Psychiatry. 1986;27(4):396-400. doi:10.1016/0010-440x(86)90016-7 [PubMed 3731773]Tandon SS, Hoskins I, Azhar S. Intrathecal baclofen pump - a viable therapeutic option in pregnancy. Obstet Med. 2010;3(3):119-120. doi:10.1258/om.2010.100016 [PubMed 27576877]Turkyilmaz A, Eroglu A. Use of baclofen in the treatment of esophageal stent-related hiccups. Ann Thorac Surg. 2008;85(1):328-330. doi:10.1016/j.athoracsur.2007.07.059 [PubMed 18154840]van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM; Cochrane Back Review Group. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane Collaboration. Spine (Phila Pa 1976). 2003;28(17):1978-1992. doi:10.1097/01.BRS.0000090503.38830.AD [PubMed 12973146]Vlavonou R, Perreault MM, Barrière O, et al. Pharmaco*kinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations. J Clin Pharmacol. 2014;54(5):584-592. doi:10.1002/jcph.247 [PubMed 24414993]Walker KR, Novotny SA, Krach LE. Does intrathecal baclofen therapy increase prevalence and/or progression of neuromuscular scoliosis? Spine Deform. 2017;5(6):424-429. doi:10.1016/j.jspd.2017.03.006 [PubMed 29050720]Weißhaar GF, Hoemberg M, Bender K, et al. Baclofen intoxication: a "fun drug" causing deep coma and nonconvulsive status epilepticus--a case report and review of the literature. Eur J Pediatr. 2012;171(10):1541-1547. doi:10.1007/s00431-012-1780-y [PubMed 22729246]Wolf E, Kothari NR, Roberts JK, Sparks MA. Baclofen toxicity in kidney disease. Am J Kidney Dis. 2018;71(2):275-280. doi:10.1053/j.ajkd.2017.07.005 [PubMed 28899601]Wu VC, Lin SL, Lin SM, Fang CC. Treatment of baclofen overdose by haemodialysis: a pharmaco*kinetic study. Nephrol Dial Transplant. 2005;20(2):441-443. doi:10.1093/ndt/gfh297 [PubMed 15615812]Yang TF, Wang JC, Chiu JW, Lai CJ, Chan RC, Lee SS. Ultrasound-guided refilling of an intrathecal baclofen pump--a case report. Childs Nerv Syst. 2013;29(2):347-349. doi: 10.1007/s00381-012-1953-z [PubMed 23129445]Zeman A, Hoefeijzers S, Milton F, Dewar M, Carr M, Streatfield C. The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report. Cortex. 2016;74:9-19. doi:10.1016/j.cortex.2015.10.005 [PubMed 26599496]Zhang C, Zhang R, Zhang S, Xu M, Zhang S. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial. Trials. 2014;15:295. doi:10.1186/1745-6215-15-295 [PubMed 25052238]Topic 9062 Version 636.0

Between 50 and 90 percent of women with normal pregnancies have some degree of nausea, with or without vomiting, in the first half of pregnancy. The duration and severity of symptoms varies among individuals.This topic discusses ways to prevent and relieve nausea and vomiting, with and without medic

CloseLeuprolide: Drug informationLeuprolide: Drug information(For additional information see "Leuprolide: Patient drug information" and see "Leuprolide: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USCamcevi;Eligard;Fensolvi (6 Month);Lupron Depot (1-Month);Lupron Depot (3-Month);Lupron Depot (4-Month);Lupron Depot (6-Month);Lupron Depot-Ped (1-Month);Lupron Depot-Ped (3-Month)Brand Names: CanadaEligard;Lupron Depot;Lupron Depot (1-Month);Lupron Depot (3-Month);Lupron Depot 3 Month Kit;Lupron [DSC];Zeulide DepotPharmacologic CategoryAntineoplastic Agent, Gonadotropin-Releasing Hormone Agonist;Gonadotropin Releasing Hormone AgonistDosing: AdultNote: Do not use a fractional dose of the 3-, 4-, or 6-month depot formulation, or a combination of doses of the monthly depot formulation or any depot formulation due to different release characteristics. Do not use a combination of syringes to achieve a particular dose.Breast cancer, premenopausal ovarian suppressionBreast cancer, premenopausal ovarian suppression (off-label use):Lupron Depot: IM: 3.75 mg every 28 days for up to 24 months (Boccardo 1999).Lupron Depot-3 month: IM: 11.25 mg every 3 months for up to 24 months (Boccardo 1999; Schmid 2007).EndometriosisEndometriosis: Note: Initial treatment (maximum 6 months) may be as monotherapy or combination therapy with norethindrone acetate (add-back therapy). A single retreatment course (maximum 6 months) of leuprolide in combination with norethindrone acetate may be considered if symptoms recur. Monotherapy is not recommended for retreatment. Total duration of therapy (initial plus re-treatment for symptom recurrence) should not exceed 12 months.Initial therapy: May be used as monotherapy or in combination with norethindrone acetate.Lupron Depot: IM: 3.75 mg every month for up to 6 months.Lupron Depot-3 month: IM: 11.25 mg every 3 months for 1 to 2 doses (maximum 6 months).Symptom recurrence: Administer in combination with norethindrone acetate.Lupron Depot: IM: 3.75 mg every month for up to 6 months.Lupron Depot-3 month: IM: 11.25 mg every 3 months for 1 to 2 doses (maximum 6 months).Hormone therapy for transgender females, assigned male at birthHormone therapy for transgender females, assigned male at birth (adjunctive agent) (off-label use): IM (depot) or SUBQ: 3.75 mg monthly or 11.25 mg every 3 months in combination with other appropriate agents (ES [Hembree 2017]; Gava 2016). Lupron Depot should be administered IM and Eligard should be administered SUBQ.Paraphilia, malesParaphilia, males (off-label use):Note: May cause an initial increase in androgen concentrations, which may be treated with an antiandrogen (eg, flutamide, cyproterone) for 1 to 2 months (Guay 2009). Avoid use in patients with osteoporosis or active pituitary pathology (Guay 2009; Reilly 2000).Initial test dose: SUBQ: 1 mg once; if no hypersensitivity to the test dose, may proceed to treatment dosing (Guay 2009; Reilly 2000).Treatment dosing: Depot IM: 3.75 to 7.5 mg monthly (Guay 2009; Reilly 2000) or 11.25 mg every 3 months (WFSBP [Thibaut 2020]).Prostate cancer, advancedProstate cancer, advanced: Note: Treatment is usually continued after development of metastatic (castration-resistant) disease.Leuprolide acetate:Lupron Depot 7.5 mg (monthly): IM: 7.5 mg every month.Lupron Depot 22.5 mg (3 month): IM: 22.5 mg every 12 weeks.Lupron Depot 30 mg (4 month): IM: 30 mg every 16 weeks.Lupron Depot 45 mg (6 month): IM: 45 mg every 24 weeks.Eligard: SUBQ: 7.5 mg monthly or 22.5 mg every 3 months or 30 mg every 4 months or 45 mg every 6 months.Leuprolide acetate 5 mg/mL solution: SUBQ: 1 mg daily.Zeulide Depot [Canadian product]: IM: 3.75 mg once every month or 22.5 mg once every 3 months.Leuprolide mesylate:Camcevi: SUBQ:42 mg leuprolide (equivalent to ~48 mg leuprolide mesylate) once every 6 months.Uterine leiomyomataUterine leiomyomata (fibroids):Note: Prior to combination therapy with iron, consider a 1-month trial period of iron alone; the addition of leuprolide may be considered when response to iron monotherapy is inadequate.Lupron Depot: IM: 3.75 mg every month for up to 3 months (in combination with iron).Lupron Depot-3 month: IM: 11.25 mg as a single injection (in combination with iron).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).Dosing: Pediatric(For additional information see "Leuprolide: Pediatric drug information")Note: Each formulation (including different strengths) has unique release characteristics; do not use partial syringes or a combination of syringes to achieve dose.Central precocious pubertyCentral precocious puberty (CPP):Note: Dosing regimens and route of administration of international product may vary from US dosage forms; refer to specific international product labeling. Prior to initiation of therapy, diagnostic confirmation is necessary and baseline measurements/levels of luteinizing hormone (LH) (basal or stimulated with a gonadotropin-releasing hormone [GnRH] analog), sex steroids, bone age assessment (versus chronological age), and growth parameters (height and weight measurements).Children ≥2 years:Note: Consider discontinuing leuprolide therapy at the appropriate time for the onset of puberty.IM:Depot formulations: Lupron Depot-Ped (monthly formulation):≤25 kg: Initial: IM: 7.5 mg every 4 weeks; titrate dose in 3.75 mg increments every 4 weeks until clinical or laboratory tests indicate adequate suppression.>25 to 37.5 kg: Initial: IM: 11.25 mg every 4 weeks; titrate dose in 3.75 mg increments every 4 weeks until clinical or laboratory tests indicate adequate suppression.>37.5 kg: Initial: IM: 15 mg every 4 weeks; titrate dose in 3.75 mg increments every 4 weeks until clinical or laboratory tests indicate adequate suppression.Lupron Depot-Ped (3-month formulation): IM: 11.25 mg or 30 mg every 12 weeks.SubQ:Long-acting formulation: Fensolvi: SubQ: 45 mg every 6 months.Short-acting formulation: Note: Use has been replaced by long-acting formulations which require less frequent dosing (ESPE/LWPES [Carel 2009]). Leuprolide acetate 5 mg/mL solution: SubQ: Initial: 50 mcg/kg/dose once daily; may titrate dose upward by 10 mcg/kg/day if suppression of ovarian or testicular steroidogenesis is not achieved.EndometriosisEndometriosis: Note: Due to ongoing growth and bone maturation in adolescents, leuprolide use in patients <18 years of age should be reserved for patients with pain refractory to conservative surgical therapy (ACOG 2018); empiric therapy should not be used (Laufer 2008). Although the manufacturer's labeling suggest monotherapy with leuprolide as an option for initial courses, experts suggest that in adolescents, initial leuprolide therapy be in combination with norethindrone with or without conjugated estrogen (add-back therapy). Adolescent patients should also be supplemented with calcium and vitamin D (ACOG 2018; Laufer 2008).Lupron Depot (monthly formulation): Adolescents ≥18 years: IM: 3.75 mg every month for up to 6 months.Lupron Depot (3-month formulation): Post-menarche adolescent females: IM: 11.25 mg every 3 months for up to 2 doses as initial therapy; for retreatment, may repeat course for up to 2 doses; total treatment duration should not exceed 12 months.Leuprolide Stimulation TestLeuprolide (GnRHa) Stimulation Test (Female): Limited data available: Children ≥2 years: Leuprolide acetate 5 mg/mL solution: SubQ: 20 mcg/kg once; measure LH and follicle stimulating hormone at baseline and after administration (usually 2 spaced measurements ≤120 minutes [eg, 30 and 60 minutes or 60 and 120 minutes]) (Houk 2008; Sathasivam 2010; Sathasivam 2011).Uterine leiomyomataUterine leiomyomata (fibroids): Note: Use in combination with iron supplementation. Due to ongoing growth and bone maturation in adolescents, consider calcium and vitamin D supplementation with therapy based on experience in adolescents with leuprolide use for endometriosis.Lupron Depot (monthly formulation): Adolescents ≥18 years: IM: 3.75 mg every month for up to 3 months.Lupron Depot (3-month formulation): Post-menarche adolescent females: IM: 11.25 mg as a single injection.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Injectable, Intramuscular, as acetate: Generic: 22.5 mg (1 ea)Kit, Injection, as acetate: Generic: 1 mg/0.2 mLKit, Intramuscular, as acetate: Lupron Depot (1-Month): 7.5 mg [latex free; contains polysorbate 80]Lupron Depot (6-Month): 45 mg [latex free; contains polysorbate 80]Kit, Intramuscular, as acetate [preservative free]: Lupron Depot (1-Month): 3.75 mg [latex free; contains polysorbate 80]Lupron Depot (3-Month): 11.25 mg, 22.5 mg [latex free; contains polysorbate 80]Lupron Depot (4-Month): 30 mg [latex free; contains polysorbate 80]Lupron Depot-Ped (1-Month): 7.5 mg, 11.25 mg, 15 mg [latex free; contains polysorbate 80]Lupron Depot-Ped (3-Month): 30 mg (Ped), 11.25 mg (Ped) [latex free; contains polysorbate 80]Kit, Subcutaneous, as acetate: Eligard: 7.5 mg, 22.5 mg, 30 mg, 45 mg [contains methylpyrrolidone, polylactide-coglycolide]Fensolvi (6 Month): 45 mg [contains methylpyrrolidone, polylactide-coglycolide]Prefilled Syringe, Subcutaneous, as mesylate [preservative free]: Camcevi: 42 mg (1 ea) [latex free]Generic Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productInjectable, Intramuscular: Lupron Depot: 30 mg (1 ea) [contains polysorbate 80]Kit, Intramuscular, as acetate: Lupron Depot (1-Month): 3.75 mg, 7.5 mg [contains polysorbate 80]Lupron Depot (3-Month): 11.25 mg [contains polysorbate 80]Lupron Depot 3 Month Kit: 22.5 mg [contains polysorbate 80]Zeulide Depot: 3.75 mg, 22.5 mg [contains polysorbate 80]Kit, Subcutaneous, as acetate: Eligard: 7.5 mg, 22.5 mg, 30 mg, 45 mgSolution, Subcutaneous: Lupron: 5 mg/mL ([DSC]) [contains benzyl alcohol]Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information, and as follows, must be dispensed with this medication:Fensolvi: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213150s002lbl.pdf#page=15Lupron Injection: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019010s038lbl.pdf#page=27Lupron Depot-Ped: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020263s050lbl.pdf#page=23Administration: AdultDo not use a fractional dose of the 3-, 4-, or 6-month depot formulation, or a combination of doses of the monthly depot formulation or any depot formulation due to different release characteristics. Do not use a combination of syringes to achieve a particular dose. Do not administer IV.IM:Lupron Depot: Administer as a single injection into the gluteal area, anterior thigh, or deltoid. Injection site should be alternated. Administer within 2 hours of preparation.Zeulide Depot [Canadian product]: Allow product to reach room temperature before administration. Inject into the upper outer quadrant of the gluteus.SUBQ:Camcevi: Select an injection site in the upper or mid abdominal area with sufficient soft or loose SUBQ tissue that has not been used recently; do not administer into areas with brawny or fibrous SUBQ tissue or locations that could be rubbed or compressed (eg, belt or waistband). Bunch skin around injection site, insert needle at a 90-degree angle to the skin surface, release skin, and slowly and steadily inject full contents; remove needle at the same 90-degree angle. Avoid applying heat directly to the injection site.Eligard: Vary/rotate injection site; choose site with adequate subcutaneous tissue (eg, upper or mid-abdomen, upper buttocks) that does not have excessive pigment, nodules, lesions, or hair. Avoid areas with brawny or fibrous tissues or areas that may be compressed or rubbed (eg, belt or waistband). Administer within 30 minutes of preparation.Leuprolide acetate 5 mg/mL solution (1 mg/0.2 mL): Vary injection site; if an alternate syringe from the syringe provided is required, insulin syringes should be used.Administration: PediatricParenteral: Note: Do not use a fractional dose of the 3-, 4-, or 6-month depot formulation, or a combination of doses of the monthly depot formulation or any depot formulation due to different release characteristics. Do not use a combination of syringes to achieve a particular dose. Do not administer IV.IM: Lupron Depot, Lupron Depot-Ped: Administer as a single injection into the gluteal area, anterior thigh, or deltoid; rotate administration site periodically. Reconstituted solution does not contain preservatives and should be used immediately.SubQ:Long-acting formulation: Fensolvi: Should be administered by a health care professional. Administer as a single subcutaneous injection into the abdomen, upper buttocks, or other location with adequate subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair. Avoid areas for injection with brawny or fibrous subcutaneous tissue or areas of skin that may be rubbed or compressed (belts or clothing waistband). Rotate injection sites.Short-acting formulation: Leuprolide acetate 5 mg/mL solution: Administer undiluted into areas on the arm, thigh, or abdomen; rotate injection site. If an alternate syringe from the manufacturer-provided syringe is required, insulin syringes should be used.Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 1]).Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).Use: Labeled IndicationsCentral precocious puberty: Treatment of pediatric patients with central precocious puberty.Endometriosis: For use in the management of endometriosis, either as monotherapy (for pain relief and reduction of endometriotic lesions) or as combination therapy with norethindrone acetate (for the initial management of the painful symptoms of endometriosis and management of symptom recurrence).Limitations of use: Not for use prior to menarche or post-menopause. Monotherapy is not recommended for retreatment.Prostate cancer, advanced: Treatment of advanced prostate cancer.Uterine leiomyomata (fibroids): For use in combination with iron for the preoperative hematologic improvement of patients with anemia caused by fibroids when 3 months of hormonal suppression is deemed necessary.Limitations of use: Not for use prior to menarche or post-menopause. Leuprolide acetate is not indicated for combination use with norethindrone acetate for the preoperative hematologic improvement of patients with anemia caused by heavy menstrual bleeding due to fibroids.Use: Off-Label: AdultBreast cancer, premenopausal ovarian suppression; Hormone therapy for transgender females (assigned male at birth); Paraphilia, malesMedication Safety IssuesSound-alike/look-alike issues:Lupron Depot (1-month or 3-month formulation) may be confused with Lupron Depot-Ped (1-month or 3-month formulation)Lupron Depot-Ped is available in two formulations, a 1-month formulation and a 3-month formulation. Both formulations offer an 11.25 mg strength which may further add confusion.High alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.Other safety concerns:Leuprolide is available as different salt formulations (leuprolide acetate and leuprolide mesylate). Use caution when selecting a leuprolide formulation, as indications and dosing vary between the products.Adverse Reactions (Significant): ConsiderationsDecreased bone densityLeuprolide may cause decreased bone mineral density (BMD). Data in pediatric patients with central precocious puberty are conflicting (Ref). Data from use of gonadotropin-releasing hormone (GnRH) agonist therapy in males with prostate cancer show a 2% to 3% decrease in BMD of the hip and spine per year during initial therapy (Ref). Postmarketing claim-based studies show a bone fracture rate of 19.4% in males with prostate cancer receiving androgen deprivation therapy compared to 12.6% to those not receiving therapy (Ref). Bone loss with GnRH agonist therapy in females is less quantified but described as significant and may exceed 1% per month (Ref). In adult females, discontinuation of therapy did not ensure complete recovery of the bone loss (Ref).Mechanism: Time-related; fundamentally, it is the increase in bone turnover and decrease in BMD that causes adverse skeletal effects (Ref). The imbalance of osteoclast and osteoblast activity is secondary to parathyroid hormone, estrogen, and other sex hormone level changes (Ref).Onset: Varied; remarkable bone loss may occur after 3 to 6 months of GnRH agonist therapy but is more commonly associated with long-term GnRH therapy (Ref).Risk factors:• Treatment duration (Ref)• Family history of osteoporosis• Concurrent administration of medications associated with bone loss (eg, antiseizure medications, long-term corticosteroids, aromatase inhibitors) (Ref)• Lifestyle factors (eg, chronic tobacco or alcohol use, sedentary nature) (Ref)• Low calcium intake (Ref)• Vitamin D deficiency (Ref)• Hypogonadism (Ref)Hypersensitivity reactions (immediate and delayed)Immediate hypersensitivity reactions (urticaria, angioedema, anaphylaxis) have been reported (Ref). Recurrent anaphylaxis in response to depot leuprolide has been reported (Ref); with recurrent anaphylaxis or a history of anaphylaxis to multiple unrelated drugs (eg, leuprolide acetate depot and triamcinolone), a reaction to the excipient carboxymethylcellulose should be considered. Delayed cutaneous hypersensitivity reactions have also been reported, including maculopapular skin rash, mycosis-fungoides-like eruption, serum sickness, and hypersensitivity angiitis (Ref). Injection site granuloma may occur (Ref).Mechanism:Immediate hypersensitivity reactions: Non–dose-related; likely immunologic (ie, IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure) or due to histamine-releasing activity (Ref). In addition, leuprolide appears to be a peptide ligand for MRGPRX2 receptor on mast cells and a cause for non-IgE–mediated mast cell activation (Ref).Delayed hypersensitivity reactions: Non–dose-related; immunologic (involving a T-cell–mediated drug-specific immune response or immune complex-mediated) (Ref).Granuloma: Non–dose-related; may be caused by a foreign-body reaction against polymers used as a vehicle for leuprolide injection or a reaction to leuprolide (Ref).Onset:Immediate hypersensitivity reactions: Rapid; generally occurs within 1 hour of administration but may occur up to 14 days after injection of the depot (Ref). Reactions have occurred with the first injection up to the 25th injection (Ref).Delayed hypersensitivity reactions: Varied; typically occur days to 6 weeks after drug exposure (Ref).Granulomas: Delayed; usually appear weeks to months after injection (Ref).Risk factors:• Cross-reactivity with other GnRH analogues, including triptorelin and goserelin, may occur (Ref)• Leuprolide acetate depot contains both carboxymethylcellulose (carmellose in Australia/Asia, E466 in Europe) and polysorbate 80, which are excipients that have independently been associated with anaphylaxis (Ref)Metabolic changes/cardiovascular effectsMetabolic changes with androgen deprivation therapy (ADT) are concerning due to increased risk of both arterial and venous thromboembolic events (Ref). Gonadotropin releasing hormone (GnRH) agonists, such as leuprolide, may increase risk of a major cardiovascular and cerebrovascular event (20%) versus GnRH antagonists (3%) (Ref). Additionally, ischemic heart disease was found to be the most common cardiac disorder in a phase 3 randomized clinical trial with an incidence of 10% (Ref).Mechanism: Dose-related; ADT decreases testosterone levels which elicits metabolic changes, such as decreased lean muscle mass, increased visceral fat, insulin resistance, and dyslipidemia, leading to a prothrombotic state which expedites atherosclerosis (Ref). Immunomodulatory changes, such as activation of atherosclerotic plaque T-cell GnRH receptors leading to plaque destabilization, are also being explored (Ref).Onset: Delayed; risk increases during the first 6 months of ADT (Ref).Risk factors:• Duration of therapy (Ref)• Prior cardiovascular disease/event or preexisting risk factors (Ref)• Age ≥65 years (Ref)Pituitary apoplexyGonadotropin-releasing hormone (GnRH) analogues have rarely been associated with pituitary apoplexy (Ref). Presentation is generally a sudden severe headache associated with visual impairment (photophobia, diplopia, or blurry vision), headache, vomiting, hyponatremia, and ophthalmoplegia (Ref). Immediate care ranging from medical management to surgical invention may be required (Ref).Mechanism: Dose related; pituitary stimulation to underlying adenoma causes ischemic necrosis and subsequent hemorrhage, or compression of vessels may lead to infarction in the nonadenomatous gland (Ref).Onset: Varied; most commonly occurs within hours (<4 hours) of first administration; has also been observed up to 14 days after administration (Ref).Risk factors:• Elderly males with underlying gonadotropin-secreting adenoma (Ref)• Presence of pituitary macroadenoma (Ref)Psychiatric eventsLeuprolide has rarely been associated with acute mania and psychiatric symptoms (Ref). There are very few case reports in the literature; however, the development of such events can require hospitalization and initiation of antidepressants and/or neuroleptic medications (Ref). Presentation is more common in those without prior history of psychiatric events, but exacerbations of existing pathology have been reported (Ref). In 23% of women taking a gonadotropin-releasing hormone agonist, depression was reported (Ref).Mechanism: Unknown; however, estrogen withdrawal or deficit in central serotonin transmission is postulated (Ref).Onset: Dose- and time-related; symptoms appear after several injections have been received (Ref).QT prolongationCardiac arrhythmias associated with leuprolide therapy are very rare with incidence limited to clinical trials until a recent case report of prolonged QT interval on ECG and torsades de pointes (TdP) (Ref). In a phase 3 randomized clinical trial, supraventricular arrhythmias occurred in 4% of patients and prolonged QT interval occurred in 1% of patients (Ref).Risk factors: Drug-induced QTc prolongation/TdP (in general):• Females (Ref)• Age >65 years (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)• Genetic defects of cardiac ion channels (Ref)• History of drug-induced TdP (Ref)• Congenital long QT syndrome (Ref)• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Loop diuretic use (Ref)• Sepsis (Ref)• Concurrent administration of multiple medications (≥2) that prolong the QT interval or medications with drug interactions that increase serum concentrations of QT-prolonging medications (Ref)SeizuresThere are postmarketing reports of seizures with the use of long-acting leuprolide (Ref). While most seizures are classified as unspecified, cases of generalized, partial, and absence seizures are noted (Ref). Reports were mostly in females (average age 25 years) receiving therapy for endometriosis (Ref). There are 2 reports of seizure in pediatric patients with preexisting brain damage; resolution of seizure activity occurred with discontinuation of leuprolide therapy and initiation of treatment (Ref).Mechanism: Postulated to be dose-related; related to pharmacological action. Potentially same mechanism as catamenial seizures since leuprolide causes transient increase in hormones (Ref).Onset: Delayed; average onset is 41 days (Ref)Risk factors:• History of catamenial seizures (Ref)• Preexisting brain damage (Ref)Tumor flareA tumor flare or transient increase in prostate cancer symptoms, especially in patients with advanced disease, presents as an exacerbation of initial symptoms, such as ureteral obstruction, urinary retention, spinal cord compression, and/or lymphedema (Ref). Sudden death during tumor flare has been reported (Ref). At one time, the incidence was estimated to be as high as 11%; however, advances in screening, earlier treatment, and the concurrent use of antiandrogen therapy have decreased the rate of tumor flare (Ref).Mechanism: An initial increase in testosterone peaks ~3 days after administration, exacerbating symptoms (Ref)Onset: Intermediate; symptoms observed within the first 1 to 3 weeks of receiving leuprolide (Ref).Risk factors:• Advanced disease (Ref)• High prostate-specific antigen levels (Ref)• Impending cord compression (Ref)• Urethral obstruction (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults, unless otherwise indicated.>10%:Cardiovascular: ECG changes (≤19%), edema (5% to 21%), flushing (children: 5%; adults: ≤59%), hypertension (children, adults: ≤15%), ischemia (≤19%) (table 1)Ischemia, peripheral edema (children, adults: ≤12%)Leuprolide: Adverse Reaction: IschemiaDrug (Leuprolide)Comparator (Diethylstilbestrol)PopulationDoseDosage FormIndicationNumber of Patients (Leuprolide)Number of Patients (Diethylstilbestrol)Comments19%22%Adult males1 mg/daySUBQ injectionProstate cancer98101Described as "ECG changes/ischemia"Dermatologic: Diaphoresis (≤98%)Endocrine & metabolic: Decreased libido (3% to 11%), hot flash (≤98%), increased serum cholesterol (23%), increased serum triglycerides (12% to 32%), weight gain (children, adults: ≤13%), weight loss (≤13%)Gastrointestinal: Constipation (children: 6%; adults: ≤14%), diarrhea (≤14%), nausea (children: 8%; adults: ≤25%), vomiting (children: 6%; adults: ≤25%)Genitourinary: Testicular atrophy (4% to 20%), vaginitis (children: ≤3%; adults: 11% to 28%)Local: Bruising at injection site (3% to 12%), discomfort at injection site (≤19%), erythema at injection site (children: 9%; adults: 2% to 38%), injection site reaction (≤14%, including abscess at injection site), pain at injection site (children: 19% to 31%; adults: ≤19%)Nervous system: Depression (children: <2%; adults: ≤31%) (table 2)Depression, dizziness (children: <1%; adults: ≤16%), emotional lability (children: 5%; adults: ≤31%), fatigue (≤18%), headache (children: 2% to 16%; adults: ≤65%), insomnia (children, adults: ≤31%), lethargy (≤13%), malaise (≤18%), migraine (≤65%), pain (3% to 33%), sleep disorder (≤31%), vertigo (≤16%)Leuprolide: Adverse Reaction: DepressionDrug (Leuprolide)Comparator (Danazol)PlaceboDosage FormIndicationNumber of Patients (Leuprolide)Number of Patients (Danazol)Number of Patients (Placebo)Comments31%N/AN/A3.75 mg intramuscular injectionEndometriosis51N/AN/ADescribed as "depression/emotional lability"22%20%3%3.75 mg intramuscular injectionEndometriosis16613631Described as "depression/emotional lability"11%N/A4%3.75 mg intramuscular injectionUterine fibroids166N/A163Described as "depression/emotional lability"Neuromuscular & skeletal: Arthropathy (children: <2%; adults: 4% to 16%), asthenia (children: <1%; adults: 4% to 18%), musculoskeletal pain (children: <1%; adults: ≤11%)Respiratory: Cough (children, adults: 1% to 13%), flu-like symptoms (children: <2%; adults: ≤21%), nasopharyngitis (children, adults: ≤22%), upper respiratory tract infection (children: 6%; adults: ≤21%)Miscellaneous: Fever (children: 17%; adult: <5%)1% to 10%:Cardiovascular: Acute myocardial infarction (<5%), angina pectoris (<5%), atrial fibrillation (<5%), bradycardia (children, adults: <5%), cardiac arrhythmia (<5%), cardiac failure (1%), coronary artery disease (≤6%), deep vein thrombophlebitis (<5%), heart murmur (3%), hypotension (children; adults: <5%), palpitations (<5%), peripheral vascular disease (<2%), phlebitis (≤2%), syncope (children, adults: <5%), tachycardia (<5%), thrombosis (≤2%), varicose veins (<5%), vasodilation (children: 2%)Dermatologic: Acne vulgaris (children: ≤3%; adults: ≤10%), allergic skin reaction (≤10%), alopecia (children, adults: ≤4%), body odor (children, adults: <5%), cellulitis (<5%), cold and clammy skin (4%), dermatitis (5%), ecchymoses (<5%), erythema multiforme (children: ≤3%), hair disease (<5%), hyperpigmentation (including dyschromia: <5%), injection site pruritus (≤9%), leukoderma (children: <2%), nail disease (children, adults: <5%), night sweats (3%), pruritus (3%), seborrhea (children: ≤3%), skin hypertrophy (children: <2%), skin lesion (<5%), skin rash (adults: ≤6%), xeroderma (<5%)Endocrine & metabolic: Androgen-like effect (females: ≤4%), breast changes (≤6%), decreased HDL cholesterol (2% to 10%), decreased serum albumin (≥5%), decreased serum bicarbonate (≥5%), decreased serum total protein (≥5%), dehydration (8%), diabetes mellitus (children; adults: <5%), feminization (children: <2%), goiter (children, adults: <5%), growth retardation (children: <2%), gynecomastia (children, adults: ≤7%), hirsutism (children: <2%), hyperglycemia (≥5%), hyperphosphatemia (≥5%), hyperuricemia (≥5%), hypoglycemia (<5%), increased gamma-glutamyl transferase (≥5%), increased lactate dehydrogenase (≥5%), increased LDL cholesterol (8%), increased serum calcium (<5%), increased thirst (<5%), increased uric acid (≥5%), loss of libido (<2%), menstrual disease (children, adults: ≤2%), pitting edema (≤5%)Gastrointestinal: Abdominal distention (<5%), abdominal pain (children: 9%), anorexia (6%), change in appetite (4%), colitis (≤3%), duodenal ulcer (<5%), dysgeusia (<5%), dyspepsia (children, adults: <4%), dysphagia (children, adults: <5%), eructation (<5%), flatulence (≤4%), gastroenteritis (≤3%), gastrointestinal hemorrhage (<5%), gingival hemorrhage (<5%), gingivitis (children, adults: <5%), hernia of abdominal cavity (<5%), hiccups (<5%), increased appetite (children, adults: <5%), intestinal obstruction (<5%), melanosis (<5%), mucous membrane abnormality (reaction: ≤4%), peptic ulcer (<5%), periodontal abscess (<5%), rectal polyp (<5%), xerostomia (<5%)Genitourinary: Balanitis (<5%), bladder spasm (<5%), breast disease (children: <2%), breast hypertrophy (children; adults: <5%), breast tenderness (≤7%), cervical neoplasm (children: <2%), cervix disease (children: <2%), difficulty in micturition (<2%), dysmenorrhea (children: <2%), dysuria (≤6%), epididymitis (<5%), erectile dysfunction (<2%), hematuria (≤6%), hemorrhagic cystitis (including cystitis: ≤6%), impotence (males: 4% to 5%), lactation (<5%), mastalgia (≤7%), nocturia (1% to 6%), oliguria (<2%), penile disease (<5%), prostatic disease (<5%), reduction in penile size (<2%), sexual disorder (accelerated sexual maturity: children: <2%), testicular disease (<5%), testicular pain (2%), urinary frequency (≤6%), urinary incontinence (children, adults: <5%), urinary retention (<2%), urinary tract infection (≤6%), urinary tract obstruction (<5%), urinary urgency (≤6%), vagin*l discharge (children: ≤3%), vagin*l hemorrhage (children: ≤3%)Hematologic & oncologic: Anemia (≤6%), bladder carcinoma (<5%), carcinoma (<5%), eosinophilia (≥5%), increased erythrocyte sedimentation rate (children: <2%), leukopenia (≥5%), lymphadenopathy (<5%), lymphedema (<5%), malignant melanoma, neoplasm (<5%), non-Hodgkin’s lymphoma, prolonged partial thromboplastin time (≥5%), prolonged prothrombin time (≥5%), purpuric disease (children: <2%), second primary malignant neoplasm (including basal cell carcinoma, malignant melanoma, non-Hodgkin’s lymphoma, pulmonary neoplasm), skin carcinoma (including ear: <5%), squamous cell carcinoma (7%), thrombocythemia (≥5%), tumor flare (children: <2%)Hepatic: Abnormal hepatic function tests (≥5%), hepatomegaly (<5%), increased serum alanine aminotransferase (≥5%), increased serum aspartate aminotransferase (≥5%), increased serum transaminases (3%)Hypersensitivity: Hypersensitivity reaction (children, adults: <5%)Immunologic: Increased ANA titer (children: <2%)Infection: Abscess (<5%), herpes zoster infection (<5%), infection (children, adults: ≤5%)Local: Induration at injection site (children, adults:<3%), swelling at injection site (children: 2%)Nervous system: Abnormality in thinking (<5%), agitation (<5%), altered sense of smell (<2%), amnesia (<5%), anxiety (≤8%), chills (<5%), confusion (<5%), delusion (<5%), dementia (<5%), drowsiness (children: <2%), hypoesthesia (<5%), irritability (including impatience: 2%), loss of consciousness (<5%), memory impairment (6%), mood changes (≤5%), nervousness (children: <2%; adults: ≤8%), neuropathy (<5%), numbness (<5%), paralysis (children; adults: <5%), paresthesia (≤8%), peripheral neuropathy (children; adults: <5%), personality disorder (<5%), rigors (<2%), voice disorder (<5%)Neuromuscular & skeletal: Amyotrophy (<2%), arthralgia (children: <2%; adults: 1% to 9%), back pain (5%), bone disease (temporal bone swelling: <5%), hyperkinetic muscle activity (children: <2%), limb pain (children, adults: ≤10%), lower limb cramp (≤2%), myalgia (can be severe: children: <2%; adults: ≤8%), myopathy (children: <2%), neck pain (<5%), ostealgia (5%), pathological fracture (<5%), tremor (<2%)Ophthalmic: Amblyopia (<5%), blepharoptosis (<5%), blurred vision (<5%), conjunctivitis (<5%), visual disturbance (children, adults: <5%), xerophthalmia (<5%)Otic: Tinnitus (<5%)Renal: Decreased urine specific gravity (≥5%), increased blood urea nitrogen, increased serum creatinine, increased urine specific gravity (≥5%)Respiratory: Asthma (children, adults: <5%), bronchitis (<5%), bronchospasm (children: 6%), chronic obstructive pulmonary disease (5%), dyspnea (≤5%), dyspnea on exertion (1% to 5%), epistaxis (children, adults: <5%), hemoptysis (<5%), hypoxia (<5%), increased bronchial secretions (<5%), paranasal sinus congestion (5%), pharyngitis (children, adults: <5%), pleural effusion (<5%), pleural rub (<5%), pneumonia (<5%), productive cough (children: 6%), pulmonary edema (<5%), pulmonary emphysema (<5%), pulmonary fibrosis (<5%), rhinitis (children, adults: <5%), sinus headache (≤8%), sinusitis (children, adults: <5%)Miscellaneous: Abnormal healing (<5%), cyst (<5%), inflammation (<5%)<1%:Dermatologic: Hyperhidrosis (children), pallor (children)Endocrine & metabolic: Obesity (children)Gastrointestinal: Decreased appetite (children)Genitourinary: Exacerbation of hematuriaLocal: Hematoma at injection site (children), warm sensation at injection site (children)Nervous system: Abnormal gait (children)Frequency not defined (all populations):Cardiovascular: Aortic aneurysm (ruptured), carotid stenosis, cerebrovascular accident, chest tightness, extrasystoles, facial edema, retinal vascular disease (perivascular cuffing), transient ischemic attacksDermatologic: Facial swelling, hyperkeratosis, skin ulceration at injection site, spider telangiectasiaEndocrine & metabolic: Decreased serum potassium, galactorrhea not associated with childbirth (females), hyperkalemia, increased libido, increased testosterone level, pituitary insufficiency (suppression of pituitary-gonadal system), thyroid noduleGastrointestinal: Occult blood in stools, rectal fistula, rectal irritation (erythema)Genitourinary: Blisters on penis, increased post-void residual urine volume, penile swelling, pyuriaHematologic & oncologic: Bruise, hypoproteinemia, leukocytosis, thrombocytopeniaHepatic: HepatitisLocal: Burning sensation at injection site (including stinging)Nervous system: Anosmia, auditory hallucination, burning sensation of feet, euphoria, hyperreflexia, hyporeflexia, motor dysfunction, spinal cord compressionNeuromuscular & skeletal: Ankylosing spondylitis, arthritis, bone fracture (including spinal) (Shahinian 2005), knee effusion, muscle cramps, muscle rigidity, muscle tendernessOphthalmic: Eyelid edemaOtic: Auditory disturbance (including decreased hearing)Renal: Nephrolithiasis, pyelonephritisRespiratory: Abnormal breath sounds (decreased), dry throat, pleuritic chest pain, pulmonary infiltrates, rales, rhonchi, streptococcal pharyngitis, wheezingMiscellaneous: Fibrosis (pelvic), massPostmarketing (all populations):Cardiovascular: Chest pain, deep vein thrombosis, hypersensitivity angiitis (Gnanaraj 2010), prolonged QT interval on ECG (Abbasi 2020), pulmonary embolism, torsades de pointes (Abbasi 2020)Dermatologic: Hypertrichosis, skin photosensitivity, urticaria (Okdemir 2015)Endocrine & metabolic: Pituitary apoplexy (Fabiano 2016; Tanios 2017)Gastrointestinal: Gastrointestinal distressHematologic & oncologic: Adenoma (pituitary), decreased white blood cell countHepatic: Acute hepatotoxicity, hepatic insufficiency, severe hepatotoxicityHypersensitivity: Anaphylaxis (Fujisaki 2012), angioedema (Kirkgoz 2020), nonimmune anaphylaxis, serum sickness (Gnanaraj 2010)Local: Injection site granuloma (Yasukawa 2005)Nervous system: Aggressive behavior (Chavez 2010), fibromyalgia syndrome, intracranial hypertension (including idiopathic intracranial hypertension) (Tan 2019), mania (Pong 2014), outbursts of anger (Chavez 2010), seizure (Akaboshi 2000), suicidal ideation, suicidal tendenciesNeuromuscular & skeletal: Decreased bone mineral density (Dawood 1995; Kaya 2015; Smith 2006), muscle spasm, slipped capital femoral epiphysis, tenosynovitis (symptoms)Respiratory: Interstitial pulmonary diseaseMiscellaneous: Crying (children, including tearfulness), nodule (throat)ContraindicationsHypersensitivity to leuprolide, GnRH, GnRH-agonist analogs, or any component of the formulation.Fensolvi, Lupron-Depot-Ped: Additional contraindications: pregnancy.Lupron Depot 3.75 mg (monthly) and Lupron Depot 11.25 mg (3-month): Additional contraindications: patients with undiagnosed uterine bleeding; pregnancy.Canadian labeling: Additional contraindications (not in US labeling): Patients who are or who could become pregnant; breastfeeding. Zeulide Depot (Canadian product) is also contraindicated in females.Warnings/PrecautionsConcerns related to adverse effects:• Hyperglycemia: Hyperglycemia, diabetes, and/or worsening of glycemic control have been reported in men receiving GnRH agonists.• Pseudotumor cerebri: Pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients receiving GnRH agonists, including leuprolide acetate, but is very rare (Omar 2020).Disease-related concerns:• Asthma: Asthma exacerbations have been reported with therapy in patients with histories of asthma, sinusitis, or environmental or drug allergies.• Central precocious puberty: Children treated for precocious puberty may experience signs and symptoms of puberty, including vagin*l bleeding, during the first weeks of treatment or after subsequent doses due to the initial stimulatory effect of leuprolide before suppression occurs; health care provider should be notified if symptoms continue after the second month.• Depression: Monitor for new or worsening depression, especially in patients with a history of depression.• Endometriosis: Due to the physiologic effects of the drug, exacerbation of endometriosis symptoms may occur after the first dose of leuprolide.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.• Depot formulations: Vehicle used in injectable (polylactide-co-glycolide microspheres) has rarely been associated with retinal artery occlusion in patients with abnormal arteriovenous anastomosis (eg, patent foramen ovale) (Tang 2007). Do not use a fractional dose of the 3-, 4-, or 6-month depot formulation, or a combination of doses of the monthly depot formulation or any depot formulation due to different release characteristics. The Atrigel delivery system (used in Eligard/Fensolvi) is a nongelatin-based, biodegradable, polymer matrix.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions: • Appropriate use: For the treatment of endometriosis, leuprolide can be used in combination with norethindrone acetate (referred to as add-back therapy) to reduce bone mineral density loss and reduce vasomotor symptoms associated with use of leuprolide acetate. Leuprolide in combination with norethindrone acetate (add-back therapy) is not indicated for the preoperative hematologic improvement of patients with anemia caused by heavy menstrual bleeding due to uterine fibroids.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyCholine C 11: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Choline C 11.Risk C: Monitor therapyCorifollitropin Alfa: Luteinizing Hormone-Releasing Hormone Analogs may enhance the therapeutic effect of Corifollitropin Alfa.Risk X: Avoid combinationGallium Ga 68 PSMA-11: Androgen Deprivation Therapy Agents may diminish the therapeutic effect of Gallium Ga 68 PSMA-11.Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of gallium Ga 68 PSMA-11 (gozetotide) in prostate cancer. The impact of ADT on the performance of gallium Ga 68 PSMA-11 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modificationHaloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol.Risk C: Monitor therapyIndium 111 Capromab Pendetide: Luteinizing Hormone-Releasing Hormone Analogs may diminish the diagnostic effect of Indium 111 Capromab Pendetide.Risk X: Avoid combinationPiflufolastat F18: Androgen Deprivation Therapy Agents may diminish the diagnostic effect of Piflufolastat F18.Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of ADT on the performance of piflufolastat F18 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modificationQT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyReproductive ConsiderationsEvaluate pregnancy status prior to use and throughout treatment in patients who could become pregnant; pregnancy should be excluded prior to use.Treatment with leuprolide usually inhibits ovulation and stops menstruation; however, contraception is not ensured. When contraception is indicated, a nonhormonal contraceptive should be used during leuprolide therapy.Leuprolide suppresses ovarian and testicular steroidogenesis. Decreased libido, impotence, erectile dysfunction, and menstrual disorders may result and fertility may be impaired. Suppression of fertility is reversible following discontinuation of leuprolide. Pregnancy rates are not expected to be affected once leuprolide is discontinued. When used to treat pain associated with endometriosis in patients who are infertile, fertility is not improved by leuprolide treatment (ASRM 2012).Leuprolide is used off label to suppress menstruation and preserve ovarian function and fertility in patients undergoing chemotherapy; however, leuprolide is not considered to be an effective contraceptive; a nonhormonal contraceptive is recommended when leuprolide is used during chemotherapy (ACOG 2018; ACOG 2021).Pregnancy ConsiderationsBased on the mechanism of action and data from animal reproduction studies, in utero exposure to leuprolide may cause fetal harm. Use is contraindicated during pregnancy.Breastfeeding ConsiderationsIt is not known if leuprolide is present in breast milk.According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.Monitoring ParametersMonitor bone mineral density. Monitor for signs/symptoms of hypersensitivity and pseudotumor cerebri. Monitor for development or worsening of psychiatric symptoms. Evaluate pregnancy status in patients who could become pregnant (prior to use and during therapy).Endometriosis: Endometrial-related pain.Paraphilia: CBC (baseline, monthly for 4 months then every 6 months); serum testosterone (baseline, monthly for 4 months then every 6 months); serum luteinizing hormone (LH) (baseline and every 6 months), follicle-stimulating hormone (FSH) (baseline), serum BUN and creatinine (baseline and every 6 months); bone density (baseline and yearly); ECG (baseline) (Reilly 2000).Precocious puberty:Response to treatment (GnRH agonist stimulation test, basal serum luteinizing hormone levels or serum sex steroid levels), height, bone age.Prostate cancer: LH and FSH levels, serum testosterone (~4 weeks after initiation of therapy), prostate specific antigen. Screen for diabetes (monitor blood glucose and HbA1c; periodically and as clinically necessary) and cardiovascular risk prior to initiating and periodically during treatment. Consider periodic monitoring of electrocardiograms and electrolytes in patients at risk for QT prolongation. Monitor for signs/symptoms of emerging cardiovascular disease, tumor flare, urinary tract, and spinal cord compression (observe patients with metastatic vertebral lesions closely, particularly in the first few weeks of treatment).Transgender hormone therapy: Serum testosterone levels (goal <50 ng/dL) every 3 months during the first year and then annually or biannually; serum LH, FSH, and prolactin levels at baseline and annually; routine cancer and laboratory screening as in non-transgender individuals for all tissues present (ES [Hembree 2017]; Gava 2016).Reference RangeTestosterone, castrate levels: ≤50 ng/dL.Mechanism of ActionLeuprolide is an agonist of gonadotropin releasing hormone (GnRH) receptors. Acting as a potent inhibitor of gonadotropin secretion, leuprolide produces an initial increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH), which leads to a transient increase (5 to 12 days [Cook 2000]) in testosterone and dihydrotestosterone (in males) and estrone and estradione (in premenopausal females). Continuous leuprolide administration then results in suppression of ovarian and testicular steroidogenesis due to decreased levels of LH and FSH with subsequent decrease in testosterone (male) and estrogen (female) levels. In males, testosterone levels are reduced to below castrate levels. Leuprolide may also have a direct inhibitory effect on the testes, and act by a different mechanism not directly related to reduction in serum testosterone.Pharmaco*kineticsOnset of action: Following transient increase, testosterone suppression occurs in ~2 to 4 weeks of continued therapy.Onset of therapeutic suppression for precocious puberty: Leuprolide: 2 to 4 weeks; Leuprolide depot: 1 month.Distribution: Males: Vd: 27 L.Protein binding: 43% to 49%.Metabolism: Metabolized to smaller inactive peptides, then may be further catabolized; Major metabolite, pentapeptide (M-1).Bioavailability: SUBQ: 94%.Half-life elimination: ~3 hours.Time to peak: Camcevi: 3.2 hours (first dose) and 2.1 hours (second dose); Eligard: ~5 hours (7.5 mg), ~3.3 hours (30 mg), or ~4.5 hours (45 mg).Excretion: Urine (<5% as parent and major metabolite).Clearance: Camcevi: 7.6 L/hour; Eligard: 8.34 L/hour.Pricing: USKit (Eligard Subcutaneous)7.5 mg (per each): $542.0322.5 mg (per each): $1,626.0830 mg (per each): $2,168.1145 mg (per each): $3,252.16Kit (Fensolvi (6 Month) Subcutaneous)45 mg (per each): $28,583.75Kit (Lupron Depot (1-Month) Intramuscular)3.75 mg (per each): $1,867.047.5 mg (per each): $2,224.87Kit (Lupron Depot (3-Month) Intramuscular)11.25 mg (per each): $5,601.1722.5 mg (per each): $6,674.58Kit (Lupron Depot (4-Month) Intramuscular)30 mg (per each): $8,899.46Kit (Lupron Depot (6-Month) Intramuscular)45 mg (per each): $13,349.39Kit (Lupron Depot-Ped (1-Month) Intramuscular)7.5 mg (per each): $2,246.0511.25 mg (per each): $4,077.6715 mg (per each): $4,491.14Kit (Lupron Depot-Ped (3-Month) Intramuscular)11.25 mg (ped) (per each): $12,233.0530 mg (ped) (per each): $13,473.48Prefilled Syringe (Camcevi Subcutaneous)42 mg (per each): $4,680.00Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalDivalin (ID);Eligard (AR, AU, BG, BH, BR, CH, CR, CY, DE, DK, DO, EE, FR, GT, HK, HN, HR, HU, ID, IE, IL, IN, IS, LB, LT, LV, MT, MY, NI, NL, NZ, PA, PH, PL, PT, QA, RO, SG, SI, SK, SV, TH, TR, TW, UA, VN);Enanton Depot (DK, FI, NO, SE);Enantone (AT, DE, FR);Enantone Depot (IT);Enantone LP (TH);Enantone SR (CN, HK);Endrolin (ID);Leoprostin (EC);Lerin (AU);Leuplin (KR);Leuplin Depot (TW);Leuplin Pro (JP);Leuplin SR (JP);Leuprodex (PH);Lorelin (MX, PK);Lucrin (AU, HU, MY, NZ, PT, RU, SG, TR, VN);Lucrin Depot (AU, CH, CR, CZ, DK, GT, HN, IL, KR, MX, NI, NZ, PA, PL, RO, SG, SV, TR);Lucrin PDS (MY);Lucrine (EG);Luphere Depot (PH, VN);Lupride (IN, LK);Luprolex (PH);Luprolex Depot (PH);Lupron (AR, BM, BR, BS, CL, CO, EC, GY, JM, JO, NL, PR, PY, QA, SR, TT, UY, VE);Lupron Depot (AE, AR, BB, BR, CL, EC, EG, KW, PE, PY, SA, UY, VE);Lupron SC (CO, PE);Lutkate (GB);Lutrate Depot (AT, BE);Prelar Depot (MX);Procren Depot (DK, FI, NO, SE);Procrin (ES);Prostap (GB, IE);Tapros (ID);Tapros 3M (ID)For country code abbreviations (show table)<800> Hazardous Drugs–Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.Abbasi D, Faiek S, Shetty S, Khan E. Shock from twisting peaks: A rare case of recurrent torsades de pointes secondary to leuprolide-induced prolonged QT. Cureus. 2020;12(7):e9041. doi:10.7759/cureus.9041 [PubMed 32782861]Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst. 2007;99(7):516-525. doi:10.1093/jnci/djk109 [PubMed 17405996]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. doi:10.1067/mpd.2001.116281 [PubMed 11487763]Akaboshi S, Takesh*ta K. A case of atypical absence seizures induced by leuprolide acetate. Pediatr Neurol. 2000;23(3):266-268. doi:10.1016/s0887-8994(00)00181-8 [PubMed 11033292]Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]American College of Obstetricians and Gynecologists’ (ACOG) Committee on Adolescent Health Care. Options for prevention and management of menstrual bleeding in adolescent patients undergoing cancer treatment: ACOG committee opinion, no. 817. ObstetGynecol. 2021;137(1):e7-e15. doi:10.1097/AOG.0000000000004209 [PubMed 33399429]American College of Obstetricians and Gynecologists' (ACOG) committee opinion no. 760: dysmenorrhea and endometriosis in the adolescent. Obstet Gynecol. 2018 Dec;132(6):e249-e258. doi:10.1097/AOG.0000000000002978 [PubMed 30461694]Bhatia N, Santos M, Jones LW, et al. Cardiovascular effects of androgen deprivation therapy for the treatment of prostate cancer: ABCDE steps to reduce cardiovascular disease in patients with prostate cancer. Circulation. 2016;133(5):537-541. doi:10.1161/CIRCULATIONAHA.115.012519 [PubMed 26831435]Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 201420;32(30):3436-3448. doi:10.1200/JCO.2013.54.8404 [PubMed 25199761]Bellón T. Mechanisms of severe cutaneous adverse reactions: Recent advances. Drug Saf. 2019;42(8):973-992. doi:10.1007/s40264-019-00825-2 [PubMed 31020549]Bernad DM, Dal Pra A, Baule C, Frey BN, Faria S. New-onset psychosis following androgen deprivation therapy for prostate cancer. Can J Urol. 2013;20(4):6868-68670. [PubMed 23930615]Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9 [PubMed 30558872]Boccardo F, Rubagotti A, Amoroso D, et al. Endocrinological and clinical evaluation of two depot formulations of leuprolide acetate in pre- and perimenopausal breast cancer patients. Cancer Chemother Pharmacol. 1999;43(6):461-466. doi:10.1007/s002800050924 [PubMed 10321505]Burris K, Ding CY, Lim GF. Leuprolide acetate-induced generalized papular eruption. J Drugs Dermatol. 2014;13(6):755-757. [PubMed 24918569]Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol. 2016;34(14):1689-1701. doi:10.1200/JCO.2015.65.9573 [PubMed 26884586]Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2019;37(5):423-438. doi:10.1200/JCO.18.01160 [PubMed 30452337]Caballero ML, Krantz MS, Quirce S, Phillips EJ, Stone CA Jr. Hidden dangers: Recognizing excipients as potential causes of drug and vaccine hypersensitivity reactions. J Allergy Clin Immunol Pract. 2021;9(8):2968-2982. doi:10.1016/j.jaip.2021.03.002 [PubMed 33737254]Camcevi (leuprolide mesylate) [prescribing information]. Taipei City 115, Taiwan: Foresee Pharmaceuticals Co., Ltd; May 2021.Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123(4):752-762. doi:10.1542/peds.2008-1783 [PubMed 19332438]Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm. [PubMed 6423951]Chavez B, Reilly T. Manic and psychotic symptoms following subcutaneous leuprolide in a male patient with no prior psychiatric history. J Clin Psychiatry. 2010;71(12):1696-1698. doi:10.4088/JCP.10l06190yel [PubMed 21190641]Cook T, Sheridan WP. Development of GnRH antagonists for prostate cancer: new approaches to treatment. Oncologist. 2000;5(2):162-168. doi:10.1634/theoncologist.5-2-162 [PubMed 10794807]Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321(7):419-424. doi:10.1056/NEJM198908173210702. Erratum in: N Engl J Med 1989;321(20):1420. [PubMed 2503724]Dangle P, Palit V, Sundaram SK, Weston P. Noninfective cutaneous granuloma with leuprorelin acetate--reality or myth. Urology. 2007;69(4):779.e5-e6. doi:10.1016/j.urology.2007.02.013 [PubMed 17445679]Dawood MY, Ramos J, Khan-Dawood FS. Depot leuprolide acetate versus danazol for treatment of pelvic endometriosis: changes in vertebral bone mass and serum estradiol and calcitonin. Fertil Steril. 1995;63(6):1177-1183. doi:10.1016/s0015-0282(16)57593-1 [PubMed 7750585]Dittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes. 2005;113(10):586-592. doi: 10.1055/s-2005-865900. [PubMed 16320157]Eligard (leuprolide acetate) [prescribing information]. Fort Collins, CO: Tomar Therapeutics, Inc; April 2019.Eligard (leuprolide acetate) [product monograph]. Oakville, Ontario, Canada: Innomar Strategies Inc; December 2021.Fabiano AJ, George S. Pituitary Apoplexy After Initial Leuprolide Injection. World Neurosurg. 2016;95:616.e7-616.e9. doi:10.1016/j.wneu.2016.08.091 [PubMed 27586180]Fensolvi (leuprolide acetate) [prescribing information]. Fort Collins, CO: Tolmar Pharmaceuticals Inc; March 2022.Francis PA, Pagani O, Fleming GF, et al; SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137. doi:10.1056/NEJMoa1803164 [PubMed 29863451]Fujisaki A, Kondo Y, Goto K, Morita T. Life-threatening anaphylaxis to leuprorelin acetate depot: case report and review of the literature. Int J Urol. 2012;19(1):81-84. doi:10.1111/j.1442-2042.2011.02886.x [PubMed 22050405]Gatti J, Brinker A, Avigan M. Spontaneous reports of seizure in association with leuprolide (lupron depot), goserelin (zoladex implant), and naferelin (synarel nasal spray). Obstet Gynecol. 2013;121(5):1107. doi:10.1097/AOG.0b013e31828c9cb3 [PubMed 23635751]Gava G, Cerpolini S, Martelli V, Battista G, Seracchioli R, Meriggiola MC. Cyproterone acetate vs leuprolide acetate in combination with transdermal oestradiol in transwomen: a comparison of safety and effectiveness. Clin Endocrinol (Oxf). 2016;85(2):239-46. doi:10.1111/cen.13050 [PubMed 26932202]Gnanaraj J, Saif MW. Hypersensitivity vasculitis associated with leuprolide (Lupron). Cutan Ocul Toxicol. 2010;29(3):224-227. doi:10.3109/15569527.2010.487505 [PubMed 20470239]Guay DR. Drug treatment of paraphilic and nonparaphilic sexual disorders. Clin Ther. 2009;31(1):1-31. doi:10.1016/j.clinthera.2009.01.009 [PubMed 19243704]Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: Final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab. 1999;84(12):4583-4590.Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. Endocr Pract. 2017;23(12):1437. doi:10.4158/1934-2403-23.12.1437 [PubMed 29320642]Houk CP, Kunselman AR, Lee PA. The diagnostic value of a brief GnRH analogue stimulation test in girls with central precocious puberty: a single 30-minute post-stimulation LH sample is adequate. J Pediatr Endocrinol Metab. 2008;21(12):1113-1118. doi:10.1515/jpem.2008.21.12.1113 [PubMed 19189683]Hu JR, Duncan MS, Morgans AK, et al. Cardiovascular effects of androgen deprivation therapy in prostate cancer: Contemporary meta-analyses. Arterioscler Thromb Vasc Biol. 2020;40(3):e55-e64. doi:10.1161/ATVBAHA.119.313046 [PubMed 31969015]"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Pediatrics. 1997;99(2):268-278. doi:10.1542/peds.99.2.268 [PubMed 9024461]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-323. doi:10.1034/j.1600-0536.2002.4705104.x [PubMed 12534540]Jaggi S, Slone H, Strauss R, Zaeeter W, Pallie V. SUN-421 leuprolide injection induced pituitary apoplexy. J Endocrine Society. 2019;3(suppl 1);SUN-421. https://doi.org/10.1210/js.2019-SUN-421Kappy MS, Stuart T, Perelman A. Efficacy of leuprolide therapy in children with central precocious puberty. Am J Dis Child. 1988;142(10):1061-1064. doi:10.1001/archpedi.1988.02150100055025 [PubMed 3140654]Kaya A, Cayir A, Turan MI, Ozkan B. An examination of the effects of leuprolide acetate used in the treatment of central precocious puberty on bone mineral density and 25-hydroxy vitamin D. West Indian Med J. 2015;64(2):104-107. doi:10.7727/wimj.2014.346 [PubMed 26360682]Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448-4456. doi:10.1200/JCO.2006.06.2497 [PubMed 16983113]Kirkgoz T, Karakoc-Aydiner E, Bugrul F, et al. Management of systemic hypersensitivity reactions to gonadotropin-releasing hormone analogues during treatment of central precocious puberty. Horm Res Paediatr. 2020;93(1):66-72. doi:10.1159/000505329 [PubMed 31972562]Kluger N, Hahtola S, Lempinen T, Jeskanen L. Cutaneous granulomas caused by subcutaneous injections of leuprorelin acetate. Presse Med. 2017;46(10):966-968. doi:10.1016/j.lpm.2017.08.004 [PubMed 28919272]Krueger RB, Kaplan MS. Depot-leuprolide acetate for treatment of paraphilias: a report of twelve cases. Arch Sex Behav. 2001;30(4):409-422. doi:10.1023/a:1010213432606 [PubMed 11446201]Lam C, Tjon J, Hamilton J, Ahmet AH. Recurrent anaphylaxis associated with gonadotropin-releasing hormone analogs: case report and review of the literature. Pharmacotherapy. 2006;26(12):1811-1815. doi:10.1592/phco.26.12.1811 [PubMed 17125443]Laufer MR. Current approaches to optimizing the treatment of endometriosis in adolescents. Gynecol Obstet Invest. 2008;66(Suppl 1):19-27. doi:10.1159/000148027 [PubMed 18936548]Lee PA, Page JG. Effects of leuprolide in the treatment of central precocious puberty. J Pediatr. 1989;114(2):321-324. doi:10.1016/s0022-3476(89)80806-6 [PubMed 2492599]Letterie GS, Stevenson D, Shah A. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol. 1991;78(5 pt 2):943-946. [PubMed 1923237]Leuprolide acetate injection [prescribing information]. E. Windsor, NJ: AuroMedics Pharma LLC; March 2021.Levine GN, D'Amico AV, Berger P, et al; American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, the American Cancer Society, and the American Urological Association. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121(6):833-840. doi:10.1161/CIRCULATIONAHA.109.192695 [PubMed 20124128]Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500-2510. Accessed September 29, 2014. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.2678. [PubMed 23715580]Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Lüchinger AB, Mijatovic V, Rustemeyer T, Hompes PG. Anaphylactic reaction to different gonadotropin-releasing hormone agonists for the treatment of endometriosis. Am J Med Sci. 2011;341(3):240-242. doi:10.1097/MAJ.0b013e31820094da [PubMed 21233692]Lupron (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2019.Lupron Depot 1-month 7.5 mg, 3-month 22.5 mg, 4-month 30 mg, 6-month 45 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; April 2022.Lupron Depot 1-month 7.5 mg, 3-month 22.5 mg, 4-month 30 mg, 6-month 45 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2019.Lupron Depot 3.75 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2021.Lupron Depot 3-month 11.25 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2020.Lupron Depot-PED (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; April 2022.Lupron and Lupron Depot (leuprolide acetate) [product monograph]. St Laurent, Quebec, Canada: AbbVie Corp; November 2021.Magon N. Gonadotropin releasing hormone agonists: Expanding vistas. Indian J Endocrinol Metab. 2011;15(4):261-267. doi:10.4103/2230-8210.85575 [PubMed 22028996]Margel D, Peer A, Ber Y, et al. Cardiovascular morbidity in a randomized trial comparing GnRH agonist and GnRH antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. J Urol. 2019;202(6):1199-1208. doi:10.1097/JU.0000000000000384 [PubMed 31188734]McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237-241. doi:10.1038/nature14022 [PubMed 25517090]Melloni C, Roe MT. Androgen deprivation therapy and cardiovascular disease. Urol Oncol. 2020;38(2):45-52. doi:10.1016/j.urolonc.2019.02.010 [PubMed 30879969]Metzger ML, Meacham LR, Patterson B, et al.. Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol. 2013;31(9):1239-1247. doi:10.1200/JCO.2012.43.5511 [PubMed 23382474]Mitchell BG, Adams AL, Thandi PK. Psychotic exacerbation following subcutaneous leuprolide in a male patient with previous history of schizophrenia. Prim Care Companion CNS Disord. 2017;19(2). doi:10.4088/PCC.16l02038 [PubMed 28387484]National Institute for Health and Care Excellence (NICE). Drug allergy: Diagnosis and management. Clinical guideline; 2014. https://www.nice.org.uk/guidance/cg183/resources/drug-allergy-diagnosis-and-management-pdf-35109811022821Ökdemir D, Hatipoğlu N, Akar HH, et al. A patient developing anaphylaxis and sensitivity to two different GnRH analogues and a review of literature. J Pediatr Endocrinol Metab. 2015;28(7-8):923-925. doi:10.1515/jpem-2014-0402 [PubMed 25719301]Okwuosa TM, Morgans A, Rhee JW, et al; American Heart Association Cardio-Oncology Subcommittee of the Council on Clinical Cardiology and the Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular Radiology and Intervention. Impact of hormonal therapies for treatment of hormone-dependent cancers (breast and prostate) on the cardiovascular system: Effects and modifications: A scientific statement from the American Heart Association. Circ Genom Precis Med. 2021;14(3):e000082. doi:10.1161/HCG.0000000000000082 [PubMed 33896190]Omar AA, Nyaga G, Mungai LNW. Pseudotumor cerebri in patient on leuprolide acetate for central precocious puberty. Int J Pediatr Endocrinol. 2020;2020(1):22. doi:10.1186/s13633-020-00092-4 [PubMed 33292495]Oshima M, Murao K, Ishigami T, Kubo Y. Drug eruption induced by gonadotropin-releasing hormone analogs accompanying radiation-recall phenomenon. J Dermatol. 2012;39(12):1080-1081. doi:10.1111/j.1346-8138.2012.01576.x [PubMed 22568476]Palomba S, Affinito P, Tommaselli GA, Nappi C. A clinical trial of the effects of tibolone administered with gonadotropin-releasing hormone analogues for the treatment of uterine leiomyomata. Fertil Steril. 1998;70(1):111-118. doi:10.1016/s0015-0282(98)00128-9 [PubMed 9660431]Pong YH, Lu YC, Tsai VF, Huang PL, Hsieh JT, Chang HC. Acute manic and psychotic symptoms following subcutaneous leuprolide acetate in a male patient without prior psychiatric history: A case report and literature review. 2014;25(1):22-24. https://doi.org/10.1016/j.urols.2013.05.010Practice Committee of the American Society for Reproductive Medicine (ASRM). Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591-598. doi:10.1016/j.fertnstert.2012.05.031 [PubMed 22704630]Reilly DR, Delva NJ, Hudson RW. Protocols for the use of cyproterone, medroxyprogesterone, and leuprolide in the treatment of paraphilia. Can J Psychiatry. 2000;45(6):559-563. doi:10.1177/070674370004500608 [PubMed 10986575]Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013-1022. doi:10.1056/NEJMra032426 [PubMed 14999113]Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34(25):3069-3103. doi:10.1200/JCO.2016.67.1487 [PubMed 27217461]Sadler Gallagher J, Feldman HA, Stokes NA, et al. The effects of gonadotropin-releasing hormone agonist combined with add-back therapy on quality of life for adolescents with endometriosis: A randomized controlled trial. J Pediatr Adolesc Gynecol. 2017;30(2):215-222. doi:10.1016/j.jpag.2016.02.008 [PubMed 26927501]Sasagawa Y, Tachibana O, Nakagawa A, Koya D, Iizuka H. Pituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma. J Clin Neurosci. 2015;22(3):601-603. doi:10.1016/j.jocn.2014.08.015 [PubMed 25455737]Sathasivam A, Garibaldi L, Shapiro S, Godbold J, Rapaport R. Leuprolide stimulation testing for the evaluation of early female sexual maturation. Clin Endocrinol (Oxf). 2010;73(3):375-381. doi:10.1111/j.1365-2265.2010.03796.x [PubMed 20184599]Sathasivam A, Rosenberg HK, Shapiro S, Wang H, Rapaport R. Pelvic ultrasonography in the evaluation of central precocious puberty: comparison with leuprolide stimulation test. J Pediatr. 2011;159(3):490-495. doi:10.1016/j.jpeds.2011.02.032 [PubMed 21489559]Schmid P, Untch M, Kossé V, et al. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007;25(18):2509-2515. doi:10.1200/JCO.2006.08.8534 [PubMed 17577027]Schmid P, Untch M, Wallwiener D, et al; TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Anticancer Res. 2002;22(4):2325-2332. [PubMed 12174922]Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352(2):154-164. doi:10.1056/NEJMoa041943 [PubMed 15647578]Shalin SC, Brantley J, Diwan AH. Follicular mucinosis and mycosis-fungoides-like drug eruption due to leuprolide acetate: a case report and review. J Cutan Pathol. 2012;39(11):1022-1025. doi:10.1111/j.1600-0560.2012.01980.x [PubMed 22882386]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8960):1312-1313. doi:10.1016/s0140-6736(95)90963-x [PubMed 7746084]Shiota M, Tokuda N, Kanou T, Yamasaki H. Injection-site granulomas resulting from the administration of both leuprorelin acetate and goserelin acetate for the treatment of prostatic cancer. J Nippon Med Sch. 2007;74(4):306-308. doi:10.1272/jnms.74.306 [PubMed 17878701]Smith MR. Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res. 2006;12(20 Pt 2):6315s-6319s. doi:10.1158/1078-0432.CCR-06-0846 [PubMed 17062721]Smith MR, Klotz L, Persson BE, Olesen TK, Wilde AA. Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol. 2010;184(6):2313-2319. doi:10.1016/j.juro.2010.08.012 [PubMed 20952020]Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91(4):1305-1308. doi:10.1210/jc.2005-2507 [PubMed 16434464]Spry NA, Galvão DA, Davies R, et al. Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-month observational study. BJU Int. 2009;104(6):806-812. doi:10.1111/j.1464-410X.2009.08458.x [PubMed 19281463]Tanaka T, Niimi H, Matsuo N, et al. Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. J Clin Endocrinol Metab. 2005;90(3):1371-1376. doi:10.1210/jc.2004-1863 [PubMed 15598675]Tang J, Weiter JJ. Branch retinal artery occlusion after injection of a long-acting risperidone preparation. Ann Intern Med. 2007;147(4):283-284. doi:10.7326/0003-4819-147-4-200708210-00021 [PubMed 17709768]Tan MG, Worley B, Kim WB, Ten Hove M, Beecker J. Drug-induced intracranial hypertension: A systematic review and critical assessment of drug-induced causes. Am J Clin Dermatol. 2020;21(2):163-172. doi:10.1007/s40257-019-00485-z [PubMed 31741184]Tanios G, Mungo NA, Kapila A, Bajaj K. Pituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment. BMJ Case Rep. 2017;2017:bcr2016218514. doi:10.1136/bcr-2016-218514 [PubMed 28710301]Thibaut F, Cosyns P, Fedoroff JP, et al; WFSBP Task Force on Paraphilias. The World Federation of Societies of Biological Psychiatry (WFSBP) 2020 guidelines for the pharmacological treatment of paraphilic disorders. World J Biol Psychiatry. 2020;21(6):412-490. doi:10.1080/15622975.2020.1744723 [PubMed 32452729]Thompson IM. Flare associated with LHRH-agonist therapy. Rev Urol. 2001;3 suppl 3(suppl 3):S10-S104. [PubMed 16986003]Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol. 1990;144(6):1479-1480. doi:10.1016/s0022-5347(17)39774-4 [PubMed 2122011]Tisdale JE, Chung MK, Campbell KB, et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology and Council on Cardiovascular and Stroke Nursing. Drug-induced arrhythmias: A scientific statement from the American Heart Association. Circulation. 2020;142(15):e214-e233. doi:10.1161/CIR.0000000000000905 [PubMed 32929996]Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479-487. doi:10.1161/CIRCOUTCOMES.113.000152. Erratum in: Circ Cardiovasc Qual Outcomes. 2013;6(6):e57. [PubMed 23716032]Tung YC, Lee JS, Tsai WY, Hsiao PH. The effects of gonadotropin releasing hormone analogue therapy on girls with gonadotropin-dependent precocious puberty. J Formos Med Assoc. 2007;106(10):826-831. doi:10.1016/S0929-6646(08)60047-9 [PubMed 17964961]US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. Updated September 2016. Accessed October 5, 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf.Warrington R, Silviu-Dan F, Wong T. Drug allergy. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):60. doi:10.1186/s13223-018-0289-y [PubMed 30275849]Waxman J, Man A, Hendry WF, et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br Med J (Clin Res Ed). 1985;291(6506):1387-1388. doi:10.1136/bmj.291.6506.1387 [PubMed 2933122]Yasukawa K, Sawamura D, Sugawara H, Kato N. Leuprorelin acetate granulomas: case reports and review of the literature. Br J Dermatol. 2005;152(5):1045-1047. doi:10.1111/j.1365-2133.2005.06341.x [PubMed 15888168]Zeulide Depot (leuprolide acetate) [product monograph]. Mississauga, Ontario, Canada: Verity Pharmaceuticals Inc; August 2021.Topic 9549 Version 330.0

The sources of childhood lead exposure and strategies for primary and secondary prevention of exposure are reviewed here. The clinical manifestations, diagnosis, and treatment of lead poisoning are discussed separately. (See"Childhood lead poisoning: Clinical manifestations and diagnosis" and"Childh

ClosePatient education: Optic neuritis (The Basics)Patient education: Optic neuritis (The Basics) Please read the Disclaimer at the end of this page.What is optic neuritis? — Optic neuritis is a condition that causes vision problems, eye pain, and other symptoms. It happens when the nerve that goes from the eye to the brain gets inflamed (figure 1). This nerve is called the "optic nerve."Optic neuritis is common in people who have a disease called "multiple sclerosis" (called "MS" for short). It can also happen in people who have no other health conditions.Optic neuritis sometimes happens to people who have conditions other than MS. This is not common. The conditions include:●Infections – Children are more likely to get optic neuritis after an infection, such as chickenpox or the flu.●Diseases that affect the body's infection-fighting system (called the "immune system") – These include lupus and sarcoid.What are the symptoms of optic neuritis? — The main symptoms of optic neuritis are:●Vision loss – A person with optic neuritis usually has trouble seeing clearly from 1 or both eyes. Optic neuritis usually happens in 1 eye at a time. But it sometimes happens in both eyes. Vision usually gets worse for several hours or days. Most people do not lose all their vision. Vision usually starts to get better in a few weeks.●Eye pain – The eyes might hurt more when they move. Pain usually starts when vision starts to get worse. As vision gets better, the pain goes away.Less common symptoms include:●Seeing flashes or flickers of light●Having trouble seeing colors – You might think that bright colors look dark.Should I see a doctor or nurse? — See your doctor or nurse right away if you start to lose your vision.Will I need tests? — Yes. Doctors will do tests to see if optic neuritis is the cause of your symptoms. They will also check for signs of MS. This is because optic neuritis can be the first symptom of MS.You will have the following tests:●Eye exam – During this exam, the doctor will check your vision. They will do tests to measure your side or "peripheral" vision and how well you see colors. The doctor will also examine the back of your eye, where the optic nerve is, to check for signs of optic neuritis. For your eye exam, you might get special eye drops that make your pupils open up. (When your pupils are open, it is easier for the doctor to see the different parts of the inside of your eye.) ●MRI of the brain – This is an imaging test that creates pictures of the brain. It can show changes to the optic nerve and brain. It can help doctors find MS or another condition that is causing the optic neuritis.●Blood tests – Doctors sometimes do these to look for signs of MS or conditions that sometimes happen with MS.Some people also have a test called a "lumbar puncture." Another name for this test is a "spinal tap." In this procedure, a doctor puts a thin needle into your lower back and takes out a small amount of spinal fluid. Spinal fluid is the fluid around your brain and spinal cord. Lab tests of the fluid can tell the doctor more about what is causing the optic neuritis. Most people do not need this test, but some do.How is optic neuritis treated? — Optic neuritis usually gets better without treatment. This can take a few weeks or many months.Doctors can treat severe optic neuritis with steroid medicines given through a thin tube that goes into a vein, called an "IV." The medicines help the optic neuritis go away faster.If you have optic neuritis and your MRI shows you are at high risk of getting MS, your doctor might give you medicines. These medicines can slow down the MS or keep it from happening. They include interferon beta-1a (sample brand names: Avonex, Rebif), interferon beta-1b (sample brand names: Betaseron, Extavia), or glatiramer acetate (brand name: Copaxone).Will my vision get better? — Most people start to see better in a few weeks. Within a year, most people have vision that is almost as good as before the optic neuritis. But some people have lifelong vision loss or even blindness.About 1 of every 3 people who get optic neuritis gets it again later.Will I get MS? — About half the people who get optic neuritis get MS in the next 15 years. If the results of your MRI are normal, you have a lower chance of getting MS. If the MRI shows changes to the optic nerve and brain, you have a higher chance of MS. People with more changes have a higher risk than people with just a few.More on this topic Patient education: Multiple sclerosis in adults (The Basics) Patient education: Vasculitis (Beyond the Basics)This topic retrieved from UpToDate on: Jan 01, 2023.This generalized information is a limited summary of diagnosis, treatment, and/or medication information. It is not meant to be comprehensive and should be used as a tool to help the user understand and/or assess potential diagnostic and treatment options. It does NOT include all information about conditions, treatments, medications, side effects, or risks that may apply to a specific patient. It is not intended to be medical advice or a substitute for the medical advice, diagnosis, or treatment of a health care provider based on the health care provider's examination and assessment of a patient's specific and unique circ*mstances. Patients must speak with a health care provider for complete information about their health, medical questions, and treatment options, including any risks or benefits regarding use of medications. This information does not endorse any treatments or medications as safe, effective, or approved for treating a specific patient. UpToDate, Inc. and its affiliates disclaim any warranty or liability relating to this information or the use thereof.The use of this information is governed by the Terms of Use, available at https://www.wolterskluwer.com/en/know/clinical-effectiveness-terms ©2023 UpToDate, Inc. and its affiliates and/or licensors. All rights reserved.Topic 83437 Version 5.0

CloseCefazolin: Pediatric drug informationCefazolin: Pediatric drug information(For additional information see "Cefazolin: Drug information" and see "Cefazolin: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Therapeutic CategoryAntibiotic, Cephalosporin (First Generation)Dosing: NeonatalGeneral dosing: Limited data available:Weight-directed dosing (Ref):Preterm and term neonates: IM, IV:Body WeightPostnatal AgeDose≤2 kg≤7 days50 mg/kg/day divided every 12 hours8 to 28 days75 mg/kg/day divided every 8 hours29 to 60 days100 to 150 mg/kg/day divided every 6 to 8 hours>2 kg≤7 days100 mg/kg/day divided every 12 hours8 to 28 days150 mg/kg/day divided every 8 hours29 to 60 days100 to 150 mg/kg/day divided every 6 to 8 hoursGestational age-directed dosing (Ref):Preterm and term neonates: IM, IV:Gestational AgePostnatal AgeDose<32 weeks<7 days25 mg/kg/dose every 12 hours7 to 28 days25 mg/kg/dose every 8 hours≥32 weeks≤7 days50 mg/kg/dose every 12 hours8 to 28 days50 mg/kg/dose every 8 hoursSurgical prophylaxisSurgical prophylaxis: Limited data available:Perioperative: Preterm and term neonates: IV: 30 mg/kg as a single dose; administer within 30 to 60 minutes prior to surgical incision; consider redosing in 4 hours if procedure lasts >4 hours (Ref).Postoperative, cardiac surgery: Note: Continue for up to 48 hours after surgery; refer to institutional protocols (Ref).Term neonates:PNA ≤7 days: IV: 30 mg/kg/dose every 12 hours.PNA >7 days: IV: 30 mg/kg/dose every 8 hours.Dosing: PediatricGeneral dosing, susceptible infection (Ref): Infants, Children, and Adolescents: IM, IV:Mild to moderate infections: 25 to 100 mg/kg/day divided every 8 hours; maximum daily dose: 6 g/day Severe infections (eg, bone/joint infections): 100 to 150 mg/kg/day divided every 6 to 8 hours; maximum daily dose: 12 g/day Endocarditis, bacterialEndocarditis, bacterial:Prophylaxis for dental and upper respiratory procedures: Infants, Children, and Adolescents: IM, IV: 50 mg/kg 30 to 60 minutes before procedure; maximum dose: 1,000 mg/dose (Ref). Note: AHA guidelines (Ref) limit the use of prophylactic antibiotics to patients at the highest risk for infective endocarditis (IE) or adverse outcomes (eg, prosthetic heart valves, patients with previous IE, unrepaired cyanotic congenital heart disease, repaired congenital heart disease with prosthetic material or device during first 6 months after procedure, repaired congenital heart disease with residual defects at the site or adjacent to site of prosthetic patch or device, and heart transplant recipients with cardiac valvulopathy).Treatment: Children and Adolescents: IV: 100 mg/kg/day in divided doses every 8 hours; usual adult dose: 2,000 mg/dose; maximum daily dose: 12 g/day; treat for at least 4 weeks; longer durations may be necessary; may use with or without gentamicin (Ref).PeritonitisPeritonitis (peritoneal dialysis) (Ref): Limited data available: Infants, Children, and Adolescents:Prophylaxis:Touch contamination of PD line: Intraperitoneal: 125 mg per literInvasive dental procedures: IV: 25 mg/kg administered 30 to 60 minutes before procedure; maximum dose: 1,000 mg/doseGastrointestinal or genitourinary procedures: IV: 25 mg/kg administered 60 minutes before procedure; maximum dose: 2,000 mg/doseTreatment: Intraperitoneal:Intermittent: 20 mg/kg every 24 hours in the long dwellContinuous: Loading dose: 500 mg per liter of dialysate; maintenance: 125 mg per liter of dialysatePneumonia, community-acquired pneumonia, S. aureus, methicillin susceptiblePneumonia, community-acquired pneumonia (CAP), S. aureus, methicillin susceptible: Infants >3 months, Children, and Adolescents: IV: 50 mg/kg/dose every 8 hours (Ref); usual maximum dose for severe infections: 12 g/day (Ref)Skin and soft tissue infections, S. aureus, methicillin susceptibleSkin and soft tissue infections, S. aureus, methicillin susceptible (mild to moderate): (Ref): Infants, Children, and Adolescents:S. aureus, methicillin susceptible skin and soft tissue infections including pyomyositis: IV: 50 mg/kg/day divided every 8 hours; maximum dose: 1,000 mg/dose; higher doses may be required in severe cases; duration of therapy at least 5 days, but longer may be necessary in some cases, eg, febrile and neutropenic patients: 7 to 14 days; pyomyositis: 14 to 21 daysS. aureus, methicillin susceptible necrotizing infection of skin, fascia, or muscle: IV: 100 mg/kg/day divided every 8 hours; maximum dose: 1,000 mg/dose; continue therapy until surgical debridement no longer necessary, clinical improvement and afebrile for 48 to 72 hoursStreptococcal, nonpurulent skin infection (cellulitis): IV: 100 mg/kg/day divided every 8 hours; maximum dose: 1,000 mg/dose; duration of therapy at least 5 days, but longer may be necessary in some casesSurgical prophylaxisSurgical prophylaxis: Infants, Children, and Adolescents: IV: 30 mg/kg within 60 minutes prior to procedure, may repeat in 4 hours for prolonged procedure or excessive blood loss (eg, >1,500 mL in adults); maximum dose dependent upon patient weight: Weight <120 kg: 2,000 mg/dose; weight ≥120 kg: 3,000 mg/dose (Ref)Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricNote: Dosing is based on pharmaco*kinetic parameters, limited pediatric studies, adult studies, and expert opinion (Ref).The following dose adjustments assume a usual recommended dose of 25 to 50 mg/kg/dose every 8 hours.Altered kidney function:Infants, Children, and Adolescents (Ref): IV, IM:GFR ≥50 mL/minute/1.73 m2: No dosage adjustment necessary.GFR 30 to <50 mL/minute/1.73 m2: 25 to 30 mg/kg/dose every 12 hours; doses up to 50 mg/kg/dose may be needed for severe infections; maximum dose: 2,000 mg/dose.GFR 10 to 30 mL/minute/1.73 m2: 25 to 30 mg/kg/dose every 24 hours; doses up to 50 mg/kg/dose may be needed for severe infections; maximum dose: 2,000 mg/dose.GFR ≤10 mL/minute/1.73 m2: 25 to 30 mg/kg/dose every 48 hours; doses up to 50 mg/kg/dose may be needed for severe infections; maximum dose: 2,000 mg/dose.Hemodialysis, intermittent: Dialyzable: 35% to 65% (Ref).Note: Appropriate dosing requires consideration of drug penetration to site of infection, minimum inhibitory concentration (MIC) of bacteria, severity of illness, residual kidney function, and interval between dialysis sessions.Infants, Children, and Adolescents (Ref):Intermittent dosing (eg, 3 times weekly): IV: 25 to 50 mg/kg/dose after dialysis; maximum dose: 2,000 mg/dose. Note: Children with residual kidney function may require higher or more frequent dosing.Peritoneal dialysis:Infants, Children, Adolescents (Ref): IV, IM: 25 to 30 mg/kg/dose every 24 to 48 hours; maximum dose: 1,000 mg/dose.CRRT:Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of ≥1,500 mL/m2/hour) unless otherwise noted; flow rates vary widely in pediatric patients. Appropriate dosing requires consideration of drug penetration to site of infection, MIC of bacteria, and severity of illness. Close monitoring of response and adverse reactions due to drug accumulation (eg, neurotoxicity) is important. Due to minimal data in pediatric patients receiving CRRT, consider monitoring serum concentrations (eg, trough concentration) if available. Dosing based on limited adult information and expert opinion (Ref).CVVH/CVVHD/CVVHDF: Infants, Children, and Adolescents (Ref): IV: 25 to 50 mg/kg/dose IV every 8 to 12 hours. Maximum dose: 2,000 mg/dose.Augmented renal clearance (ARC): Note: ARC is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations that results in increased drug elimination. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Infants, Children, and Adolescents:GFR ≥200 mL/minute/1.73 m2:Continuous infusion: 150 mg/kg/day as a continuous infusion; maximum daily dose: 12 g/day. May give an initial loading dose of 30 mg/kg (maximum dose: 2,000 mg/dose) before starting the continuous infusion if rapid attainment of therapeutic drug concentrations is desired (eg, sepsis). Dosing is based on a pharmaco*kinetic modeling study; additional dosages (eg, lower daily doses, every-6-hour dosing) may be appropriate depending on the clinical situation (Ref).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Cefazolin: Drug information")Bloodstream infectionBloodstream infection:Pathogen-directed therapy for methicillin-susceptible staphylococci:IV: 2 g every 8 hours (Ref); treat uncomplicated Staphylococcus aureus bacteremia for ≥14 days starting from day of first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (Ref).Pathogen-directed therapy for susceptible Enterobacteriaceae:IV: 2 g every 8 hours (Ref). Usual duration is 7 to 14 days; individualize depending on source and extent of infection as well as clinical response. A 7-day duration is recommended for patients with uncomplicated Enterobacteriaceae infection who respond appropriately to antibiotic therapy (Ref).Antibiotic lock technique (catheter-salvage strategy): Note: For infections caused by susceptible organisms when the catheter cannot be removed; use in addition to systemic antibiotics. Catheter salvage is not recommended for S. aureus.Intracatheter: Prepare lock solution to final concentration of cefazolin 5 to 10 mg/mL (may be combined with heparin). Instill into each lumen of the catheter access port using a volume sufficient to fill the catheter (2 to 5 mL), with a dwell time of up to 72 hours depending on frequency of catheter use and solution stability. Withdraw lock solution prior to catheter use; replace with fresh cefazolin lock solution after catheter use. Antibiotic lock therapy is given for the same duration as systemic antibiotics (Ref).Endocarditis, prophylaxisEndocarditis, prophylaxis (dental or invasive respiratory tract procedures) (alternative agent for patients with nonsevere, non-IgE-mediated penicillin allergy who cannot take oral therapy) (off-label use): IM, IV: 1 g as a single dose 30 to 60 minutes before procedure; if inadvertently not given prior to the procedure, may be administered up to 2 hours after the procedure. Note: Reserve for select situations (cardiac condition with the highest risk of adverse endocarditis outcomes and procedure likely to result in bacteremia with an organism that can cause endocarditis) (Ref).Endocarditis, treatmentEndocarditis, treatment: Note: Cefazolin should not be used in patients with concomitant CNS infections (eg, brain abscess) (Ref).Pathogen-directed therapy for methicillin-susceptible staphylococci (alternative agent for patients with nonsevere, non-IgE-mediated penicillin allergy):Native valve: IV: 2 g every 8 hours for 6 weeks. Note: Duration intended for complicated right-sided infective endocarditis (IE) or left-sided IE. For uncomplicated right-sided IE, 2 weeks of therapy may be adequate (Ref).Prosthetic valve: IV: 2 g every 8 hours for ≥6 weeks (combine with rifampin for entire duration of therapy and gentamicin for the first 2 weeks) (Ref).Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failureIntra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure: Note: Reserve for patients with low risk for resistant pathogens (eg, local Enterobacteriaceae resistance rate to cefazolin <10% and no recent antibiotic exposure) (Ref).Cholecystitis, acute: IV: 1 to 2 g every 8 hours; continue for 1 day after gallbladder removal or until clinical resolution in patients managed nonoperatively (Ref). Note: The addition of anaerobic therapy (eg, metronidazole) is recommended if biliary-enteric anastomosis is present (Ref).Other intra-abdominal infections (eg, perforated appendix, appendiceal abscess, diverticulitis) (off-label use): IV: 1 to 2 g every 8 hours in combination with metronidazole. Total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control (Ref); for diverticulitis or uncomplicated appendicitis managed without intervention, duration is 10 to 14 days (Ref).Osteomyelitis and/or discitisOsteomyelitis and/or discitis:Treatment, pathogen-directed therapy for methicillin-susceptible S. aureus:IV: 2 g every 8 hours for ≥6 weeks depending on extent of infection, debridement, and clinical response (Ref).Prevention, following open fractures:IV: 2 g for patients <120 kg or 3 g for patients ≥120 kg every 8 hours; ideally administer within 6 hours of injury. For type I or II fractures (no more than moderate comminution or contamination, no or minimal periosteal stripping, adequate soft tissue coverage), discontinue 24 hours following wound closure. For type III fractures (severe contamination or comminution), use as part of an appropriate combination regimen and continue for 72 hours after injury or up to 24 hours after wound closure (Ref). Note: For patients with risk for methicillin-resistant S. aureus (MRSA), potential water exposure, or fecal or clostridial contamination, alternative or additional antibiotics are recommended (Ref).Peritonitis, treatmentPeritonitis, treatment (peritoneal dialysis patients) (off-label use):Note: As a component of empiric therapy in patients at low risk for MRSA or as pathogen-directed therapy. Intraperitoneal administration is preferred to IV administration. Duration of therapy is ≥2 to 3 weeks, depending on organism, for patients with adequate clinical response (Ref). Consider a 25% dose increase in patients with significant residual renal function (urine output >100 mL/day) (Ref).Intermittent: Intraperitoneal: 15 to 20 mg/kg added to one exchange of dialysis solution once daily (allow to dwell for ≥6 hours). For patients on continuous ambulatory peritoneal dialysis, add cefazolin to the overnight dwell. Note: Some experts recommend adding cefazolin to each exchange in patients on automated peritoneal dialysis as nighttime intraperitoneal levels of cefazolin may fall below the minimum inhibitory concentration of most organisms (Ref).Continuous (with every exchange) (dose is per liter of dialysate): Intraperitoneal: Loading dose: 500 mg/L of dialysate added to first exchange of dialysate; maintenance dose: 125 mg/L of dialysate with each subsequent exchange of dialysate (Ref).PneumoniaPneumonia: Pathogen-directed therapy for methicillin-susceptible S. aureus: IV: 2 g every 8 hours (Ref). Minimum duration is generally 5 days for community-acquired pneumonia and 7 days for hospital-acquired or ventilator-associated pneumonia; patients should be clinically stable with normal vital signs before therapy is discontinued (Ref).Prostatitis, acute bacterialProstatitis, acute bacterial: Pathogen-directed therapy for susceptible organisms: IV: 1 g every 8 hours; may switch to oral therapy 24 to 48 hours after improvement in fever and clinical symptoms. Total duration of therapy is 4 to 6 weeks (Ref).Prosthetic joint infectionProsthetic joint infection: Pathogen-directed therapy for methicillin-susceptible S. aureus: IV: 2 g every 8 hours. Duration ranges from 2 to 6 weeks depending on prosthesis management, use of rifampin, and other patient-specific factors. Note: In select cases (eg, debridement and retention of prosthesis or one-stage arthroplasty), combine with oral rifampin and give oral suppressive antibiotic therapy following completion of IV treatment (Ref).Septic arthritis, without prosthetic materialSeptic arthritis, without prosthetic material: Pathogen-directed therapy for methicillin-susceptible S. aureus: IV: 2 g every 8 hours. Duration is 3 to 4 weeks (in the absence of osteomyelitis), including oral step-down therapy (Ref). Some experts recommend 4 weeks of parenteral therapy for patients with concomitant bacteremia (Ref).Skin and soft tissue infectionSkin and soft tissue infection:Erysipelas or nonpurulent cellulitis in patients without risk for methicillin-resistant S. aureus: IV: 1 to 2 g every 8 hours. Total duration of therapy ≥5 days (including oral step-down therapy); may extend to 14 days depending on severity and clinical response (Ref).Pathogen-directed therapy for methicillin-susceptible S. aureus: IV: 1 to 2 g every 8 hours. Total duration of therapy is 5 to 14 days (including oral step-down therapy) depending on severity of infection, need for debridement, and clinical response (Ref). Note: For necrotizing infections, antibiotic therapy must be used in conjunction with early and aggressive surgical exploration and debridement of necrotic tissue; continue until further debridement is not necessary and the patient has clinically improved and is afebrile for 48 to 72 hours (Ref).Surgical site incisional infection (trunk or extremity surgery, not involving axilla or perineum): IV: 1 g every 8 hours; duration is dependent upon severity, need for debridement, and clinical response (Ref).Streptococcus, maternal prophylaxis for prevention of neonatal diseaseStreptococcus (group B), maternal prophylaxis for prevention of neonatal disease (alternative agent) (off-label use): IV: 2 g as a single dose at onset of labor or prelabor rupture of membranes, then 1 g every 8 hours until delivery. Reserve for patients with penicillin allergy who are at low risk for anaphylaxis (eg, rash without urticaria and no systemic symptoms) (Ref).Surgical prophylaxisSurgical prophylaxis: IV: 2 g for patients <120 kg or 3 g for patients ≥120 kg; administer within 60 minutes of surgical incision. Use in combination with metronidazole for procedures requiring anaerobic coverage (eg, colorectal and clean-contaminated head and neck procedures). May repeat dose intraoperatively in 4 hours if procedure is lengthy or if there is excessive blood loss (Ref); maximum dose: 12 g/day (manufacturer's labeling). In cases where an extension of prophylaxis is warranted postoperatively, total duration should be ≤24 hours (Ref). Postoperative prophylaxis is not recommended in clean and clean-contaminated surgeries (Ref).Toxic shock syndromeToxic shock syndrome (off-label use): Pathogen-directed therapy for group A streptococcus (alternative agent for patients with nonsevere, non–IgE-mediated penicillin allergy) or methicillin-susceptible S. aureus(off-label use): IV: 2 g every 8 hours in combination with clindamycin. In the absence of bacteremia, treat for a total of ≥10 days, including oral step-down therapy (Ref).Urinary tract infection, complicatedUrinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms): Pathogen-directed therapy for susceptible organisms: IV: 1 g every 8 hours (Ref). Switch to an appropriate oral regimen once symptoms improve, if culture and susceptibility results allow. Total duration of therapy ranges from 5 to 14 days and depends on clinical response and the antimicrobial chosen to complete the regimen (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: The following dose adjustments are for the usual recommended dosing of 1 to 2 g IV every 8 hours.Altered kidney function (Ref): IV:Note: Consider an initial unadjusted dose appropriate to the severity of the infection before reducing the dose.CrCl ≥50 mL/minute: 1 to 2 g every 8 hours.CrCl 30 to <50 mL/minute: 1 to 2 g every 8 to 12 hours.CrCl >10 to <30 mL/minute: 500 mg to 1 g every 12 hours (some experts give 2 g every 12 hours for severe infections in patients with CrCl 10 to <30 mL/minute (Ref)).CrCl ≤10 mL/minute: 500 mg to 1 g every 24 hours.Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).IV: 2 g every 6 hours (Ref).Hemodialysis, intermittent (thrice weekly): Dialyzable (45% to 60% (Ref)):IV:Daily dosing: 500 mg to 1 g every 24 hours (when scheduled dose falls on a dialysis day, administer after dialysis).orThrice weekly (post dialysis) dosing: 2 g after dialysis 3 times weekly (Ref) or 20 mg/kg (maximum dose: 2 g) after dialysis 3 times weekly (Ref) or 2 g after dialysis if next dialysis is expected in 48 hours or 3 g after dialysis if next dialysis is expected in 72 hours (Ref).Peritoneal dialysis: IV: 500 mg every 12 hours or 1 g every 24 hours (Ref).CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection), organism MIC, residual kidney function, and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity (Ref)) due to drug accumulation is important.CVVH/CVVHD/CVVHDF: IV: 2 g loading dose followed by either 1 g every 8 hours or 2 g every 12 hours (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection), organism MIC, residual kidney function, and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity (Ref)) due to drug accumulation is important.IV: 2 g loading dose followed by either 1 g every 8 hours or 2 g every 12 hours (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling. Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intravenous [preservative free]: Generic: 1 g/50 mL in Dextrose 4% (50 mL); 2 g/100 mL in Dextrose 4% (100 mL)Solution Reconstituted, Injection: Generic: 1 g (1 ea); 10 g (1 ea)Solution Reconstituted, Injection [preservative free]: Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 20 g (1 ea [DSC]); 100 g (1 ea); 300 g (1 ea)Solution Reconstituted, Intravenous [preservative free]: Generic: 1 g (1 ea); 1 g and Dextrose 4% (1 ea); 2 g and Dextrose 3% (1 ea)Solution Reconstituted, Injection, as sodium [preservative free]: Generic: 2 g (1 ea)Generic Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution Reconstituted, Injection: Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 100 g (1 ea)Solution Reconstituted, Intravenous: Generic: 1 g ([DSC])Solution Reconstituted, Injection, as sodium: Generic: 2 g (1 ea)Administration: PediatricParenteral:IM: Deep IM injection into a large muscle mass.IV: Infuse over 10 to 60 minutes; may be administered IVP over 3 to 5 minutes.Administration: AdultIM: Inject deep IM into large muscle mass.IV: Inject direct IV over 3 to 5 minutes or may infuse as an intermittent infusion over 30 to 60 minutes.Some penicillins (eg, carbenicillin, ticarcillin and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.Storage/StabilityStore intact vials at room temperature and protect from temperatures exceeding 40°C. Reconstituted solutions of cefazolin are light yellow to yellow. Protection from light is recommended for the powder and for the reconstituted solutions. Reconstituted solutions are stable for 24 hours at room temperature and for 10 days under refrigeration. Stability of parenteral admixture in D5W, D5LR, D51/4NS, D51/2NS, D5NS, D10W, LR, or NS at room temperature (25°C) is 48 hours. Stability of parenteral admixture at refrigeration temperature (4°C) is 14 days.DUPLEX: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) prior to activation; do not freeze. Following activation, stable for 24 hours at room temperature and for 7 days under refrigeration.GALAXY: Store at or below -20°C (-4°F). Thawed solution stable for 48 hours at room temperature and for 30 days under refrigeration. Do not refreeze.UseTreatment of susceptible infections involving the respiratory tract, skin and skin structure, urinary tract, biliary tract, bone and joint, genitals, and septicemia (FDA approved in ages ≥1 month and adults); perioperative prophylaxis (FDA approved in adults); treatment of bacterial endocarditis (FDA approved in adults); has also been used for bacterial endocarditis prophylaxis for dental and upper respiratory procedures; prophylaxis of peritonitis in patients with peritoneal dialysis (PD) catheters undergoing invasive dental procedures, gastrointestinal or genitourinary procedures, touch contamination prophylaxis of PD catheter, and treatment of peritonitis in patients with peritoneal cathetersMedication Safety IssuesSound-alike/look-alike issues:CeFAZolin may be confused with cefoTEtan, cefOXitin, cefprozil, cefTAZidime, cefTRIAXone, cephalexin.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Frequency not defined:Cardiovascular: Hypotension, syncopeDermatologic: Pruritus (including genital pruritus), skin rash, Stevens-Johnson syndrome, urticariaGastrointestinal: Abdominal cramps, anorexia, Clostridioides difficile colitis, diarrhea, epigastric pain, flatulence, heartburn, nausea, oral candidiasis, oral mucosal ulcer, pruritus ani, vomitingGenitourinary: Vaginitis, vulvovagin*l candidiasis, vulvovagin*l pruritusHematologic & oncologic: Eosinophilia, leukopenia, neutropenia, thrombocythemia, thrombocytopeniaHepatic: Hepatitis, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferaseHypersensitivity: AnaphylaxisLocal: Induration at injection site, injection site phlebitis, pain at injection siteNervous system: Confusion, dizziness, drowsiness, drug fever, fatigue, headacheNeuromuscular: AstheniaRenal: Increased blood urea nitrogen, increased serum creatinine, renal failure syndromePostmarketing:Dermatologic: Acute generalized exanthematous pustulosisGastrointestinal: Clostridioides difficile associated diarrheaHypersensitivity: Serum sicknessRenal: Acute interstitial nephritisContraindicationsHypersensitivity to cefazolin, other cephalosporin antibiotics, penicillins, other beta-lactams, or any component of the formulation.Warnings/PrecautionsConcerns related to adverse effects:• Elevated INR: May be associated with increased INR, especially in nutritionally-deficient patients, prolonged treatment, hepatic or renal disease.• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, may occur. If an allergic reaction occurs, discontinue treatment and institute appropriate supportive measures.• Penicillin allergy: Use with caution in patients with a history of penicillin allergy.• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including Clostridioides difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.Disease-related concerns:• Gastrointestinal disease: Use with caution in patients with a history of gastrointestinal disease, particularly colitis.• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required.• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.Metabolism/Transport EffectsSubstrate of OAT1/3Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAminoglycosides: Cephalosporins may enhance the nephrotoxic effect of Aminoglycosides. Cephalosporins may decrease the serum concentration of Aminoglycosides.Risk C: Monitor therapyBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationFosphenytoin: CeFAZolin may increase the serum concentration of Fosphenytoin. Specifically, the ratio of free phenytoin to total phenytoin may be increased.Risk C: Monitor therapyFurosemide: May enhance the nephrotoxic effect of Cephalosporins. Risk C: Monitor therapyImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyPhenytoin: CeFAZolin may increase the serum concentration of Phenytoin. Specifically, the ratio of free phenytoin to total phenytoin may be increased.Risk C: Monitor therapyProbenecid: May increase the serum concentration of Cephalosporins. Risk C: Monitor therapyRifAMPin: CeFAZolin may enhance the adverse/toxic effect of RifAMPin. Specifically, the risk for bleeding may be increased.Management: Avoid concomitant use of rifampin with cefazolin when possible. If combined, closely monitor prothrombin time or other coagulation tests and administer vitamin K as needed. Risk D: Consider therapy modificationSodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationVitamin K Antagonists (eg, warfarin): Cephalosporins may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyDietary ConsiderationsSome products may contain sodium.Pregnancy ConsiderationsCefazolin crosses the placenta.Based on available data, cephalosporin antibiotics are generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Czeizel 2001; Lamont 2014; Muanda 2017a; Muanda 2017b). Adverse events have not been reported in the fetus following administration of cefazolin prior to cesarean delivery.Due to pregnancy-induced physiologic changes, some pharmaco*kinetic parameters of cefazolin may be altered (Allegaert 2009; Elkomy 2014; Philipson 1987). In addition to pregnancy, obesity has been found to influence the pharmaco*kinetics of cefazolin (Ahmadzia 2015; Duff 2019; Eley 2020; Groff 2017; Kram 2017; Pevzner 2011; Stitely 2013; Young 2015). Higher doses are recommended in obese patients; however, additional studies are needed to determine the ideal dose, especially in pregnant patients with extreme obesity (ACOG 2018; Dallmann 2019; La Rosa 2020).A targeted antibiotic such as cefazolin is recommended prior to all cesarean deliveries unless the patient is already receiving an appropriate antibiotic. A single dose administered within 60 minutes prior to the delivery is recommended unless drug allergies are present. Dose adjustments of cefazolin may be considered based on maternal weight (ACOG 2018).Cefazolin is recommended as an alternative antibiotic for group B streptococcus (GBS) prophylaxis in pregnant patients who are penicillin allergic and at low risk for anaphylaxis. Treatment is intended to prevent early-onset disease in newborns. Prophylaxis is reserved for pregnant patients with a positive GBS vagin*l or rectal screening in late gestation; GBS bacteriuria during the current pregnancy; history of birth of an infant with early-onset GBS disease; and unknown GBS culture status with any of the following: birth <37 0/7 weeks gestation, intrapartum fever, prolonged rupture of membranes, known GBS positive in a previous pregnancy, or intrapartum nucleic acid amplification testing positive for GBS (ACOG 2020).Cefazolin is one of the recommended antibiotics that may be used prior to vagin*l delivery in patients at high risk for endocarditis. This includes patients with congenital heart disease, prosthetic valves, previous infective endocarditis, or cardiac transplant. Cefazolin is given 30 to 60 minutes prior to a vagin*l delivery; the endocarditis prophylactic dose is the same as nonpregnant patients (ACOG 2018).Monitoring ParametersRenal function periodically when used in combination with other nephrotoxic drugs, hepatic function tests, and CBC; prothrombin time in patients at risk; number and type of stools/day for diarrhea. Monitor closely for signs and symptoms of hypersensitivity including anaphylaxis.Mechanism of ActionInhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.Pharmaco*kinetics (Adult data unless noted)Distribution: Widely into most body tissues and fluids including gallbladder, liver, kidneys, bone, sputum, bile, pleural, and synovial; CSF penetration is poor.Vd:Preterm neonates (GA: 25 to <32 weeks; PNA: Median: 16 days [range: 3 to 91 days]): 0.39 L/kg (range: 0.31 to 0.52 L/kg) (Balevic 2019).Preterm and term neonates (GA: 30 to 40 weeks; PNA: 2 to 28 days): 0.212 to 0.373 L/kg (Deguchi 1988).Children 3 to 12 years of age: 0.133 ± 0.015 L/kg (Koshida 1987).Adults: 0.193 ± 0.064 L/kg (Scheld 1981).Bone:serum concentration ratio: Median: 0.25 (range: 0.06 to 0.41) (Zeller 2009).Protein binding:Neonates (GA: 30 to 40 weeks; PNA: 2 to 28 days): 49% (range: 17% to 78%) (Deguchi 1988); protein binding is decreased (with a resulting higher free fraction) with lower albumin concentrations, higher bilirubin concentration, higher total cefazolin concentration, and lower PMA (Smits 2012).Children 3 to 12 years: 78% ± 2.5% (range: 75% to 82.3%) (Koshida 1987).Adults: 80% (Marshall 1999).Half-life elimination:Preterm neonates (PNA: 2 to 12 days): IV: 4.05 ± 0.72 hours (range: 2.8 to 4.74 hours) (Sakata 1980).Infants ≥9 months of age and children ≤10 years of age: IV: 1.7 ± 0.6 hours (Nahata 1991).Children 10 to 12 years of age: IV: 1.95 hours (range 1.44 to 2.88 hours) (Schmitz 2015).Adults: IV: 1.8 hours; IM: ~2 hours (prolonged with renal impairment).Time to peak, serum: IM: 0.5 to 2 hours; IV: Within 5 minutes.Excretion: Urine (70% to 80% as unchanged drug).Pharmaco*kinetics: Additional ConsiderationsAnti-infective considerations:Parameters associated with efficacy: Time dependent, associated with time free drug concentration (fT) > minimum inhibitory concentration (MIC).Organism specific:S. aureus (methicillin-susceptible [MSSA]): Goal: ≥ ~24% to 55% fT > MIC (bacteriostatic) (Turnidge 1998; Zelenitsky 2018); ≥ ~55% to 100% fT > MIC (bacteriocidal) (Vogelman 1988; Zelenitsky 2018).E. coli: Goal: ≥60% fT > MIC (bacteriostatic); ≥100% fT > MIC (2-log kill) (Vogelman 1988).Population specific:Critically ill patients in the ICU: Minimum goal: ≥50% fT > MIC; preferred goal: ≥100% fT > MIC (Roberts 2015); some experts favor ≥100% fT ≥4 times the MIC (Guilhaumou 2019).Expected drug concentrations in patients with normal renal function:Infants ≥9 months of age and children ≤10 years of age: Cmax (peak), single dose: Mean dose: 22.7 mg/kg ± 4 mg/kg: 137 ± 87.9 mg/L (Nahata 1991).Adults: Cmax (peak), steady state: 1 g every 8 hours: 94 ± 30.33 mg/L (Bhalodi 2013).Postantibiotic effect: Generally little to no postantibiotic effect (<1 hour) for streptococci and gram-negative bacilli; for S. aureus: ~4 hours (Craig 1993; Craig 1998).Pricing: USSolution (ceFAZolin Sodium-Dextrose Intravenous)1GM/50ML 4% (per mL): $0.132GM/100ML 4% (per mL): $0.11Solution (reconstituted) (ceFAZolin Sodium Injection)1 g (per each): $1.10 - $7.502 g (per each): $7.3110 g (per each): $7.20 - $60.00100 g (per each): $126.00300 g (per each): $366.00500 mg (per each): $1.01 - $9.74Solution (reconstituted) (ceFAZolin Sodium Intravenous)1 g (per each): $3.28Solution (reconstituted) (ceFAZolin Sodium-Dextrose Intravenous)1GM 4%(50ML) (per each): $13.622GM 3%(50ML) (per each): $15.32Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAlfazole (VN);Altazolin (SI);Azepo (CZ);Azolin (IN);Basocef (DE);Biofazolin (PL);Cefa (TW);Cefacidal (EC, LU, PE, VE, ZA);Cefamezin (AE, AR, HR, JP, KR, RU, SA, TR);Cefarad (AE, BF, BH, BJ, CI, CY, ET, GH, GM, GN, IQ, IR, JO, KE, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW);Cefazillin (TH);Cefazol (ID, IL, TH);Cefazolina (LB);Cefazoline Panpharma (FR);Cefazovit (PH);Cefizol (TR);Cefzalin (AE);Celmetin (NO);Cizo (PH);Cloviz (PH);Evalin (ID);Fazlin (PH, TZ);Fazolin (TH);Fazolon (BR);Fonvicol (PH);Ilozef (PH);Intrazolina (ES);Izacef (ZA);Kefarin (GR);Kefzol (AT, AU, BE, BF, BJ, CH, CI, ET, GB, GH, GM, GN, HN, HR, HU, IS, KE, LR, LU, MA, ML, MR, MU, MW, NE, NG, NL, PK, SC, SD, SL, SN, TN, TZ, UG, VN, ZM, ZW);Kelin (TW);Kofatol (TW);Oricef (TW);Orizolin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Primacef (PE);Reflin (IN, JO, LT);Saifuning (CN);Stazolin (TW);Tasep (ES);Totacef (EE, HN, HU);Uzolin (TW);Venozol (ID);Volmizolin (SK);Vulmizolin (CZ);Zepilen (BG, HR, LT, NZ, SG, TR);Zinol (EG);Zofadep (PH);Zolecef (AE, BH, CY, IQ, IR, JO, LB, LY, OM, SA, SY, YE);Zolidina (PY);Zolinef (RO);Zolival (ES)For country code abbreviations (show table)Ahern JW, Possidente CJ, Hood V, Alston WK. Cefazolin dosing protocol for patients receiving long-term hemodialysis. Am J Health Syst Pharm. 2003;60(2):178-181. [PubMed 12561661]Ahmadzia HK, Patel EM, Joshi D, et al. Obstetric surgical site infections: 2 grams compared with 3 grams of cefazolin in morbidly obese women. ObstetGynecol. 2015;126(4):708-715. doi:10.1097/AOG.0000000000001064 [PubMed 26348186]Ailes EC, Gilboa SM, Gill SK, et al; and The National Birth Defects Prevention Study. Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011. Birth Defects Res A Clin Mol Teratol. 2016;106(11):940-949. doi:10.1002/bdra.23570 [PubMed 27891788]Allegaert K, van Mieghem T, Verbesselt R, et al, "Cefazolin Pharmaco*kinetics in Maternal Plasma and Amniotic Fluid During Pregnancy," Am J Obstet Gynecol, 2009, 200(2):170. [PubMed 19006783]American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.American Academy of Pediatrics (AAP). In: Kimberlin DW, Barnett E, Lynfield R, Sawyer MH, eds. Red Book: 2021 Report of the Committee on Infectious Diseases. 32nd ed. American Academy of Pediatrics; 2021.American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 199: Use of prophylactic antibiotics in labor and delivery. Obstet Gynecol. 2018;132(3):e103-e119. [PubMed 30134425]American College of Obstetricians and Gynecologists (ACOG). Prevention of group B streptococcal early-onset disease in newborns: ACOG committee opinion, number 797. Obstet Gynecol. 2020;135(2):e51-e72. doi:10.1097/AOG.0000000000003668 [PubMed 31977795]American Dental Association Council on Scientific Affairs, “Combating Antibiotic Resistance,” J Am Dent Assoc, 2004, 135(4):484-7. [PubMed 15127872]Anderson DJ, Podgorny K, Berríos-Torres SI, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect ControlHosp Epidemiol. 2014;35(6):605-627. doi: 10.1086/676022. [PubMed 24799638]Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. American College of Physicians; 2007.Baddour LM, Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association [published correction appears in Circulation. 2015;132(17):e215]. Circulation. 2015;132(15):1435-1486. doi:10.1161/CIR.0000000000000296 [PubMed 26373316]Balevic SJ, Smith PB, Testoni D, et al. Cefazolin pharmaco*kinetics in premature infants. J Perinatol. 2019;39(9):1213-1218. doi:10.1038/s41372-019-0368-z [PubMed 30944398]Baltimore RS, Gewitz M, Baddour LM, et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular and Stroke Nursing. Infective endocarditis in childhood: 2015 update: a scientific statement from the American Heart Association. Circulation. 2015;132(15):1487-1515. doi:10.1161/CIR.0000000000000298 [PubMed 26373317]Barshak MB. Antimicrobial approach to intra-abdominal infections in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.Based on expert opinion.Bellouard R, Deschanvres C, Deslandes G, et al. Population pharmaco*kinetic study of cefazolin dosage adaptation in bacteremia and infective endocarditis based on a nomogram. Antimicrob Agents Chemother. 2019;63(10):e00806-19. doi:10.1128/AAC.00806-19 [PubMed 31307987]Berbari E, Baddour LM. Prosthetic joint infection: Treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 16, 2022.Berbari EF, Kanj SS, Kowalski TJ, et al; Infectious Diseases Society of America. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis. 2015;61(6):e26-e46. doi:10.1093/cid/civ482 [PubMed 26229122]Berríos-Torres SI, Umscheid CA, Bratzler DW, et al; Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017 [published correction appears in JAMA Surg. 2017;152(8):803]. JAMA Surg. 2017;152(8):784-791. [PubMed 28467526]Bhalodi AA, Housman ST, Shepard A, Nugent J, Nicolau DP. Tissue pharmaco*kinetics of cefazolin in patients with lower limb infections. Antimicrob Agents Chemother. 2013;57(11):5679-5683. doi:10.1128/AAC.01348-13 [PubMed 24041887]Bianchini S, Rigotti E, Monaco S, et al. Surgical antimicrobial prophylaxis in abdominal surgery for neonates and paediatrics: a RAND/UCLA appropriateness method consensus study. Antibiotics (Basel). 2022;11(2):279. doi:10.3390/antibiotics11020279 [PubMed 35203881]Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinís MÁ. Augmented renal clearance in critically ill patients: a systematic review. Clin Pharmaco*kinet. 2018;57(9):1107-1121. doi:10.1007/s40262-018-0636-7 [PubMed 29441476]Bookstaver PB, Bland CM, Griffin B, Stover KR, Eiland LS, McLaughlin M. A review of antibiotic use in pregnancy. Pharmacotherapy. 2015;35(11):1052-1062. doi:10.1002/phar.1649 [PubMed 26598097]Bookstaver PB, Williamson JC, Tucker BK, Raad II, Sherertz RJ. Activity of novel antibiotic lock solutions in a model against isolates of catheter-related bloodstream infections. Ann Pharmacother. 2009;43(2):210-219. doi: 10.1345/aph.1L145. [PubMed 19193593]Bradley JS, Byington CL, Shah SS, et al. “The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America”, Clin Infect Dis, 2011, 53(7):e25-76. [PubMed 21880587]Bradley JS, Nelson JD, Barnett E, et al. Nelson's Pediatric Antimicrobial Therapy. 25th ed. American Academy of Pediatrics; 2019.Bradley JS, Nelson JD, Barnett ED, et al, eds. Nelson's Pediatric Antimicrobial Therapy. 28th ed. American Academy of Pediatrics; 2022: 97-102.Bratzler DW, Dellinger EP, Olsen KM, et al; American Society of Health-System Pharmacists; Infectious Diseases Society of America; Surgical Infection Society; Society for Healthcare Epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. [PubMed 23327981]Bunke CM, Aronoff GR, Luft FC. Pharmaco*kinetics of common antibiotics used in continuous ambulatory peritoneal dialysis. Am J Kidney Dis. 1983;3(2):114-117. doi:10.1016/s0272-6386(83)80025-0 [PubMed 6613991]Burkart JM. Microbiology and therapy of peritonitis in peritoneal dialysis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 21, 2022.Cefazolin for Injection Pharmacy Bulk Package [prescribing information]. Lake Zurich, IL: Fresenius Kabi; January 2019.Cefazolin for Injection [prescribing information]. Schaumburg, IL: Sagent Pharmaceuticals Inc; July 2020.Cefazolin in dextrose Duplex container [prescribing information]. Bethlehem, PA: B. Braun Medical Inc; November 2020.Cefazolin Sodium in Dextrose injection Galaxy container [prescribing information]. Deerfield, IL: Baxter Healthcare Corporation; July 2021.Cefazolin [prescribing information]. Weston, FL: Apotex Corp; January 2022.Chu VH. Staphylococcal toxic shock syndrome. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 11, 2022.Craig WA. Pharmaco*kinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1-12. doi:10.1086/516284 [PubMed 9455502]Craig WA. Post-antibiotic effects in experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man. J Antimicrob Chemother. 1993;31(suppl D):149-158. doi:10.1093/jac/31.suppl_d.149 [PubMed 8335516]Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163(11):978-985. doi:10.1001/archpediatrics.2009.188 [PubMed 19884587]Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. Use of cephalosporins during pregnancy and in the presence of congenital abnormalities: a population-based, case-control study. Am J Obstet Gynecol. 2001;184(6):1289-1296. doi:10.1067/mob.2001.113905 [PubMed 11349204]Dallmann A, Mian P, Van den Anker J, Allegaert K. Clinical pharmaco*kinetic studies in pregnant women and the relevance of pharmacometric tools. CurrPharmDes. 2019;25(5):483-495. doi:10.2174/1381612825666190320135137 [PubMed 30894099]De co*ck RF, Smits A, Allegaert K, et al. Population pharmaco*kinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates. J Antimicrob Chemother. 2014;69(5):1330-1338. doi:10.1093/jac/dkt527 [PubMed 24492261]Deguchi Y, Koshida R, Nakashima E, et al. Interindividual changes in volume of distribution of cefazolin in newborn infants and its prediction based on physiological pharmaco*kinetic concepts. J Pharm Sci. 1988;77(8):674-678. doi:10.1002/jps.2600770807 [PubMed 3210156]Donnelly RF. Stability of cefazolin sodium in polypropylene syringes and polyvinylchloride minibags. Can J Hosp Pharm. 2011;64(4):241-245. [PubMed 22479065]Douglas A, Udy AA, Wallis SC, et al. Plasma and tissue pharmaco*kinetics of cefazolin in patients undergoing elective and semielective abdominal aortic aneurysm open repair surgery. Antimicrob Agents Chemother. 2011;55(11):5238-5242. [PubMed 21859939]Duff P. Prevention of infection after cesarean delivery. Clin Obstet Gynecol. 2019;62(4):758-770. doi:10.1097/GRF.0000000000000460 [PubMed 31107253]Edwards FH, Engelman RM, Houck P, et al, “The Society of Thoracic Surgeons Practice Guideline Series: Antibiotic Prophylaxis in Cardiac Surgery, Part I: Duration,” Ann Thorac Surg, 2006, 81(1):397-404. [PubMed 16368422]Eley VA, Christensen R, Ryan R, et al. Prophylactic cefazolin dosing in women with body mass index >35 kg·m-2 undergoing cesarean delivery: a pharmaco*kinetic study of plasma and interstitial fluid. Anesth Analg. 2020;131(1):199-207. doi:10.1213/ANE.0000000000004766 [PubMed 32250982]Elkomy MH, Sultan P, Drover DR, Epshtein E, Galinkin JL, Carvalho B. Pharmaco*kinetics of prophylactic cefazolin in parturients undergoing cesarean delivery. Antimicrob Agents Chemother. 2014;58(6):3504-3513. [PubMed 24733461]Engelman R, Shahian D, Shemin R, et al, “The Society of Thoracic Surgeons Practice Guideline Series: Antibiotic Prophylaxis in Cardiac Surgery, Part II: Antibiotic Choice,” Ann Thorac Surg, 2007, 83(4):1569-76. [PubMed 17383396]Fowler VG, Holland TL. Clinical approach to Staphylococcus aureus bacteremia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 7, 2021.Girand HL, McNeil JC. Lock therapy for intravascular non-hemodialysis catheter-related infection. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 18, 2020.Goldenberg DL, Sexton DJ. Septic arthritis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 17, 2019.Groff SM, Fallatah W, Yang S, et al. Effect of maternal obesity on maternal-fetal transfer of preoperative cefazolin at cesarean section. J PediatrPharmacolTher. 2017;22(3):227-232. doi:10.5863/1551-6776-22.3.227 [PubMed 28638306]Guilhaumou R, Benaboud S, Bennis Y, et al. Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR). Crit Care. 2019;23(1):104. doi:10.1186/s13054-019-2378-9 [PubMed 30925922]Gupta K, Hooton TM, Naber KG, et al; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. doi: 10.1093/cid/ciq257. [PubMed 21292654]Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29(5):562-577. [PubMed 19397464]Hillis LD, Smith PK, Anderson JL, et al, “2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 124(23):2610-42. [PubMed 22064600]Hiner LB, Baluarte HJ, Polinsky MS, Gruskin AB. Cefazolin in children with renal insufficiency. J Pediatr. 1980;96(2):335-339. doi:10.1016/s0022-3476(80)80842-0 [PubMed 7351609]Ho VP, Nicolau DP, Dakin GF, et al. Cefazolin Dosing for Surgical Prophylaxis in Morbidly Obese Patients. Surg Infect. 2012;13(1):33-37. [PubMed 22316145]Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: update to practice management guidelines for prophylactic antibiotic use in open fractures. J Trauma. 2011;70(3):751-754. doi: 10.1097/TA.0b013e31820930e5. [PubMed 21610369]Hooton TM, Bradley SF, Cardenas DD, et al; Infectious Diseases Society of America. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663. doi: 10.1086/650482. [PubMed 20175247]Hsieh CC, Lee CH, Hong MY, et al. Propensity score-matched analysis comparing the therapeutic efficacies of cefazolin and extended-spectrum cephalosporins as appropriate empirical therapy in adults with community-onset Escherichia coli, Klebsiella spp. and Proteus mirabilis bacteraemia. Int J Antimicrob Agents. 2016;48(6):712-718. doi: 10.1016/j.ijantimicag.2016.09.015. [PubMed 27836382]Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. [PubMed 10891521]Jevsevar DS and Abt E, "The New AAOS-ADA Clinical Practice Guideline on Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures," J Am Acad Orthop Surg, 2013, 21(3):195-7. [PubMed 23457071]Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society [published corrections appear in Clin Infect Dis. 2017;64(9):1298; Clin Infect Dis. 2017;65(8):1435; Clin Infect Dis. 2017;65(12):2161]. Clin Infect Dis. 2016;63(5):e61-e111. doi: 10.1093/cid/ciw353. [PubMed 27418577]Klaus JR, Knodel LC, Kavanagh RE. Administration guidelines for parenteral drug therapy. Part I: pediatric patients. J Pharm Technol. 1989;5(3):101-128. [PubMed 10318297]Klompas M. Treatment of hospital-acquired and ventilator-associated pneumonia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 20, 2022.Koshida R, Nakashima E, Ichimura F, et al. Comparative distribution kinetics of cefazolin and tobramycin in children. J Pharmacobiodyn. 1987;10(9):436-442. doi:10.1248/bpb1978.10.436 [PubMed 3437384]Kram JJF, Greer DM, Cabrera O, Burlage R, Forgie MM, Siddiqui DS. Does current cefazolin dosing achieve adequate tissue and blood concentrations in obese women undergoing cesarean section? Eur J Obstet Gynecol Reprod Biol. 2017;210:334-341. doi:10.1016/j.ejogrb.2017.01.022 [PubMed 28122314]Kuypers D, Vanwalleghem J, Maes B, Messiaen T, Vanrenterghem Y, Peetermans WE. Cefazolin serum concentrations with fixed intravenous dosing in patients on chronic hemodialysis treatment. Nephrol Dial Transplant. 1999;14(8):2050-2051. doi:10.1093/ndt/14.8.2050 [PubMed 10462306]La Rosa M, Omere C, Redfern T, et al. The impact of low-dose versus high-dose antibiotic prophylaxis regimens on surgical site infection rates after cesarean delivery. Arch Gynecol Obstet. 2020;301(1):69-73. doi:10.1007/s00404-019-05370-y [PubMed 31811413]Lamont HF, Blogg HJ, Lamont RF. Safety of antimicrobial treatment during pregnancy: a current review of resistance, immunomodulation and teratogenicity. Expert Opin Drug Saf. 2014;13(12):1569-1581. doi:10.1517/14740338.2014.939580 [PubMed 25189188]Levison ME, Levison SP, Ries K, Kaye D. Pharmacology of cefazolin in patients with normal and abnormal renal function. J Infect Dis. 1973;128(suppl):S354-S357. doi:10.1093/infdis/128.supplement_2.s354 [PubMed 4744017]Li J, Echevarria KL, Hughes DW, Cadena JA, Bowling JE, Lewis JS 2nd. Comparison of cefazolin versus oxacillin for treatment of complicated bacteremia caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2014;58(9):5117-5124. doi:10.1128/AAC.02800-14 [PubMed 24936596]Li PK, Szeto CC, Piraino B, et al. ISPD peritonitis recommendations: 2016 update on prevention and treatment [published correction appears in Perit Dial Int. 2018;38(4):313]. Perit Dial Int. 2016;36(5):481-508. doi: 10.3747/pdi.2016.00078. [PubMed 27282851]Li PK, Szeto CC, Piraino B, International Society for Peritoneal Dialysis (ISPD), et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int. 2010;30(4):393-423. doi: 10.3747/pdi.2010.00049. [PubMed 20628102]Mancini A, Todd L. Inconsistencies in ISPD peritonitis recommendations: 2016 update on prevention and treatment and the ISPD catheter-related infection recommendations: 2017 update. Perit Dial Int. 2018;38(4):309-310. doi: 10.3747/pdi.2018.00026. [PubMed 29987068]Marshall WF and Blair JE, “The Cephalosporins,” Mayo Clin Proc, 1999, 74(2):187-95. [PubMed 10069359]Marx MA, Frye RF, Matzke GR, Golper TA. Cefazolin as empiric therapy in hemodialysis-related infections: efficacy and blood concentrations. Am J Kidney Dis. 1998;32(3):410-414. doi:10.1053/ajkd.1998.v32.pm9740156 [PubMed 9740156]Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society revised guidelines on the management of intra-abdominal infection. Surg Infect (Larchmt). 2017;18(1):1-76. doi:10.1089/sur.2016.261 [PubMed 28085573]Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America [published corrections appear in Clin Infect Dis. 2010;50(7):1079; Clin Infect Dis. 2010;50(3):457]. Clin Infect Dis. 2009;49(1):1-45. [PubMed 19489710]Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Resp Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST. [PubMed 31573350]Meyrier A, Fekete T. Acute bacterial prostatitis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.Millar LK, Wing DA, Paul RH, Grimes DA. Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial. Obstet Gynecol. 1995;86(4, pt 1):560-564. [PubMed 7675380]Miller MA, Fish DN, Barber GR, et al. A comparison of safety and outcomes with cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bloodstream infections [published online ahead of print August 18, 2018]. J Microbiol Immunol Infect. doi:10.1016/j.jmii.2018.07.006 [PubMed 30190234]Moehring R, Anderson DJ. Gram-negative bacillary bacteremia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 2, 2019.Muanda FT, Sheehy O, Bérard A. Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study. Br J Clin Pharmacol. 2017a;83(11):2557-2571. doi:10.1111/bcp.13364 [PubMed 28722171]Muanda FT, Sheehy O, Bérard A. Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ. 2017b;189(17):E625-E633. doi:10.1503/cmaj.161020 [PubMed 28461374]Murray MT, Corda R, Turcotte R, Bacha E, Saiman L, Krishnamurthy G. Implementing a standardized perioperative antibiotic prophylaxis protocol for neonates undergoing cardiac surgery. Ann Thorac Surg. 2014;98(3):927-933. doi:10.1016/j.athoracsur.2014.04.090 [PubMed 25038006]Nahata MC, Durrell DE, Ginn-Pease ME, King DR. Pharmaco*kinetics and tissue concentrations of cefazolin in pediatric patients undergoing gastrointestinal surgery. Eur J Drug Metab Pharmaco*kinet. 1991;16(1):49-52. doi:10.1007/BF03189874 [PubMed 1936061]Osmon DR, Aaron JT. Osteomyelitis in adults: Treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 28, 2019.Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guideline by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25. [PubMed 23223583]Pemberton JH. Acute colonic diverticulitis: Medical management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.Pevzner L, Swank M, Krepel C, Wing DA, Chan K, Edmiston CE Jr. Effects of maternal obesity on tissue concentrations of prophylactic cefazolin during cesarean delivery. Obstet Gynecol. 2011;117(4):877-882. [PubMed 21422859]Philipson A, Stiernstedt G, and Ehrnebo M, "Comparison of the Pharmaco*kinetics of Cephradine and Cefazolin in Pregnant and Non-Pregnant Women," Clin Pharmaco*kinet, 1987, 12(2):136-44. [PubMed 3829560]Refer to manufacturer's labeling.Roberts JA, Udy AA, Jarrett P, et al. Plasma and target-site subcutaneous tissue population pharmaco*kinetics and dosing simulations of cefazolin in post-trauma critically ill patients. J Antimicrob Chemother. 2015;70(5):1495-1502. doi:10.1093/jac/dku564 [PubMed 25608584]Robinson DC, Cookson TL, and Grisafe JA, “Concentration Guidelines for Parenteral Antibiotics in Fluid-Restricted Patients,” Drug Intell Clin Pharm, 1987, 21(12):985-9. [PubMed 3428165]Ross JJ. Septic arthritis of native joints. Infect Dis Clin North Am. 2017;31(2):203-218. doi: 10.1016/j.idc.2017.01.001. [PubMed 28366221]Sakata Y. The pharmaco*kinetic studies of cephalothin, cefazolin and cefmetazole in the neonates and the premature babies. Kurume Med J. 1980;27(4):275-298. doi:10.2739/kurumemedj.27.275 [PubMed 6946258]Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: The APPAC randomized clinical trial. JAMA. 2015;313(23):2340-2348. doi: 10.1001/jama.2015.6154. [PubMed 26080338]Salvador E, Oualha M, Bille E, et al. Population pharmaco*kinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus. Clin Microbiol Infect. 2021;27(3):413-419. doi:10.1016/j.cmi.2020.04.022 [PubMed 32360445]Sawyer RG, Claridge JA, Nathens AB, et al; STOP-IT Trial Investigators. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996-2005. doi:10.1056/NEJMoa1411162 [PubMed 25992746]Scheld WM, Spyker DA, Donowitz GR, Bolton WK, Sande MA. Moxalactam and cefazolin: comparative pharmaco*kinetics in normal subjects. Antimicrob Agents Chemother. 1981;19(4):613-619. doi:10.1128/aac.19.4.613 [PubMed 6454387]Schliamser SE, Cars O, Norrby SR. Neurotoxicity of beta-lactam antibiotics: predisposing factors and pathogenesis. J Antimicrob Chemother. 1991;27(4):405-425. doi:10.1093/jac/27.4.405 [PubMed 1856121]Schmitt SK. Osteomyelitis associated with open fractures in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 12, 2020.Schmitz ML, Blumer JL, Cetnarowski W, Rubino CM. Determination of appropriate weight-based cutoffs for empiric cefazolin dosing using data from a phase 1 pharmaco*kinetics and safety study of cefazolin administered for surgical prophylaxis in pediatric patients aged 10 to 12 years. Antimicrob Agents Chemother. 2015;59(7):4173-4180. doi:10.1128/AAC.00082-15 [PubMed 25941220]Smits A, Kulo A, Verbesselt R, et al. Cefazolin plasma protein binding and its covariates in neonates. Eur J Clin Microbiol Infect Dis. 2012;31(12):3359-3365. doi:10.1007/s10096-012-1703-x [PubMed 22833246]Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infections in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;15;50(2):133-164. [PubMed 20034345]Sowinski KM, Mueller BA, Grabe DW, et al. Cefazolin dialytic clearance by high-efficiency and high-flux hemodialyzers. Am J Kidney Dis. 2001;37(4):766-776. [PubMed 11273877]Spelman D, Baddour LM. Acute cellulitis and erysipelas in adults: Treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 17, 2022.Stevens DL. Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 11, 2022.Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America [published online June 18, 2014]. Clin Infect Dis. 2014;59(2):e10-e52. doi: 10.1093/cid/ciu296. [PubMed 24947530]Stitely M, Sweet M, Slain D, Alons L, Holls W, Hochberg C, Briggs F. Plasma and tissue cefazolin concentrations in obese patients undergoing cesarean delivery and receiving differing pre-operative doses of drug. Surg Infect (Larchmt). 2013;14(5):455-459. [PubMed 23859672]Stryjewski ME, Szchech LA, Benjamin DK Jr, et al. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Inf Dis. 2007;44(2):191-196. [PubMed 17173215]Szeto CC, Li PK. Concerns regarding inconsistencies within and between ISPD recommendations for peritonitis and catheter-related infections-in reply. Perit Dial Int. 2018;38(4):311-312. doi: 10.3747/pdi.2018.00046. [PubMed 29987069]Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis. 2005;41(8):1159-1166. [PubMed 16163635]Turnidge JD; Subcommittee on Antimicrobial Susceptibility Testing of the Clinical and Laboratory Standards Institute. Cefazolin and enterobacteriaceae: rationale for revised susceptibility testing breakpoints. Clin Infect Dis. 2011;52(7):917-924. doi: 10.1093/cid/cir031. [PubMed 21427400]Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis. 1998;27(1):10-22. doi:10.1086/514622 [PubMed 9675443]Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmaco*kinet. 2010;49(1):1-16. doi:10.2165/11318140-000000000-00000 [PubMed 20000886]Veltri MA, Neu AM, Fivush BA, Parekh RS, Furth SL. Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special considerations in pediatric patients. Paediatr Drugs. 2004;6(1):45-65. doi:10.2165/00148581-200406010-00004 [PubMed 14969569]Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmaco*kinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158(4):831-847. doi:10.1093/infdis/158.4.831 [PubMed 3139779]Vollmer CM, Zakko SF, Afdhal NH. Treatment of acute calculous cholecystitis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 16, 2021.Warady BA, Bakkaloglu S, Newland J, et al. Consensus guidelines for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update. Perit Dial Int. 2012;32(suppl 2):S32-S86. [PubMed 22851742]Wilson W, Taubert KA, Gewitz M, et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116(15):1736-1754. [PubMed 17446442]Wilson WR, Gewitz M, Lockhart PB, et al; American Heart Association Young Hearts Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Cardiovascular and Stroke Nursing; and the Council on Quality of Care and Outcomes Research. Prevention of viridans group streptococcal infective endocarditis: a scientific statement from the American Heart Association. Circulation. 2021;143(20):e963-e978. doi:10.1161/CIR.0000000000000969 [PubMed 33853363]Wing DA, Hendershott CM, Debuque L, Millar LK. A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Obstet Gynecol. 1998;92(2):249-253. [PubMed 9699761]Wong G, Briscoe S, McWhinney B, et al. Therapeutic drug monitoring of β-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. J Antimicrob Chemother. 2018;73(11):3087-3094. doi:10.1093/jac/dky314 [PubMed 30137377]World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the eleventh WHO model list of essential drugs. 2002. http://www.who.int/maternal_child_adolescent/documents/55732/en/Yahav D, Franceschini E, Koppel F, et al; Bacteremia Duration Study Group. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: a non-inferiority randomized controlled trial [published online ahead of print December 11, 2018]. Clin Infect Dis. doi:10.1093/cid/ciy1054 [PubMed 30535100]Yoshioka H, Cho K, Takimoto M, et al. Transfer of Cefazolin Into Human Milk. J Pediatr. 1979;94(1):151-152. [PubMed 758399]Young OM, Shaik IH, Twedt R, et al. Pharmaco*kinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. Am J Obstet Gynecol. 2015;213(4):541. [PubMed 26103528]Zelenitsky SA, Beahm NP, Iacovides H, Ariano RE, Zhanel G. Limitations of ceftriaxone compared with cefazolin against MSSA: an integrated pharmacodynamic analysis. J Antimicrob Chemother. 2018;73(7):1888-1894. doi:10.1093/jac/dky120 [PubMed 29635472]Zeller V, Durand F, Kitzis MD, et al. Continuous cefazolin infusion to treat bone and joint infections: clinical efficacy, feasibility, safety, and serum and bone concentrations. Antimicrob Agents Chemother. 2009;53(3):883-887. doi:10.1128/AAC.00389-08 [PubMed 19075069]Topic 13124 Version 365.0

CloseImmune globulin (Intravenous, subcutaneous, and intramuscular): Pediatric drug informationImmune globulin (Intravenous, subcutaneous, and intramuscular): Pediatric drug information(For additional information see "Immune globulin (Intravenous, subcutaneous, and intramuscular): Drug information" and see "Immune globulin (Intravenous, subcutaneous, and intramuscular): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Special AlertsExpiration Date Extension for AscenivJune 2022The FDA has approved an extension of the expiration date of ADMA Biologics' Asceniv (immune globulin) 10% liquid from 24 to 36 months when stored at 2 to 8°C (36 to 46°F). The new expiration date is valid for 6 Asceniv lots that were manufactured and distributed in 2019 and 2020. Future lots will be labeled according to the new dating period.Further information, including the impacted lots, may be found at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/expiration-date-extension-6-asceniv-immune-globulin-intravenous-human-slra-10-liquid-lots.Expiration Date Extension for BivigamMay 2022The FDA has approved an extension of the expiration date of ADMA Biologics’ Bivigam (immune globulin) intravenous liquid 10% from 24 to 36 months when stored at 2 to 8°C (36 to 46°F). The new expiration date is valid for 120 Bivigam lots that were manufactured and distributed in 2020 to 2022. Future lots will be labeled according to the new dating period.Further information, including the impacted lots, may be found at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/expiration-date-extension-120-bivigam-immune-globulin-intravenous-human-10-liquid-lots-manufactured.Withdrawal of Select Immune Globulin Intravenous and Subcutaneous ProductsMarch 2022The FDA along with manufacturers of affected products have voluntarily withdrawn certain lots of immune globulin intravenous (IGIV) and immune globulin subcutaneous (IGSC) due to a higher rate of allergic/hypersensitivity-type reactions, some clinically significant.Further information on affected products and lot numbers is available at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/voluntary-lot-withdrawals-immune-globulin-intravenous-igiv-and-immune-globulin-subcutaneous-igscExpiration Date Extension for CutaquigJanuary 2021The FDA has approved an extension of the expiration date of Octapharma’s Cutaquig (immune globulin) subcutaneous injection from 24 to 36 months when stored at 2 to 8°C (36 to 46°F). The new expiration date is valid for 42 Cutaquig lots that were manufactured and distributed in 2019 to 2020. The 6-month shelf life for Cutaquig stored at room temperature up to 25°C (77°F) is unchanged, and the expiration date extension does not apply to lots of Cutaquig that have already been stored at 25°C.For additional information and the list of lots, please refer to https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/expiration-date-extension-42-cutaquig-immune-globulin-subcutaneous-human-hipp-165-solution-lots.ALERT: US Boxed WarningThrombosis:Thrombosis may occur with immune globulin products. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.Renal dysfunction and acute renal failure (excluding Cutaquig, Cuvitru, Hizentra, HyQvia, GamaSTAN, and Xembify):Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients with immune globulin intravenous (IGIV) products. Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. (Note: The following IV products do not contain sucrose: Asceniv, Bivigam, Flebogamma DIF, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam 5%, Octagam 10%, Panzyga, and Privigen.) For patients at risk of renal dysfunction or acute renal failure, administer IGIV products at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration.Brand Names: USAsceniv;Bivigam;Carimune NF [DSC];Cutaquig;Cuvitru;Flebogamma DIF;GamaSTAN;Gammagard;Gammagard S/D Less IgA;Gammaked;Gammaplex;Gamunex-C;Hizentra;Hyqvia;Octagam;Panzyga;Privigen;XembifyBrand Names: CanadaCutaquig;Cuvitru;Gamastan S/D [DSC];Gammagard;Gammagard S/D;Gamunex;Hizentra;IGIVnex;Iveegam Immuno;Octagam;Panzyga;PrivigenTherapeutic CategoryBlood Product Derivative;Immune GlobulinDosing: NeonatalNote: Not all products are interchangeable with regards to route of administration; consult manufacturers' labeling for additional information. Consider osmolarity and concentration during product selection; infuse as slowly as indication and stability allow (see "Immune Globulin Product Comparison" section in Appendix for details). Dosage expressed as mg/kg or mL/kg dependent upon route of administration; use extra caution to ensure accuracy.Immune thrombocytopeniaImmune thrombocytopenia (ITP):Acute: Carimune NF 6%, Gammaked, Gamunex C: IV: 400 mg/kg/day for 2 to 5 consecutive days or 1,000 mg/kg/day for 1 to 2 days.Isoimmune hemolytic diseaseIsoimmune hemolytic disease (Rh-incompatibility): IV: GA ≥35 weeks: 500 to 1,000 mg/kg/dose once over 2 hours; if needed, dose may be repeated in 12 hours; most effective when administered as soon as possible after diagnosis (Ref).Measles, prophylaxisMeasles, prophylaxis (Ref):Preexposure prophylaxis (eg, during an outbreak, travel to endemic area): Immunocompromised patients: IV: ≥400 mg/kg/dose within 3 weeks before anticipated exposure.Postexposure prophylaxis: Any neonate without evidence of measles immunity:IM: 0.5 mL/kg/dose within 6 days of exposure. Note: Not all immune globulin preparations may be administered by the IM route; of the products currently available on the market, GamaSTAN may be given IM; consult product labeling for additional information as market availability may change. Note: GamaSTAN manufacturer labeling suggests a lower IM dose; however, this dosing was based on previous immune globulin donor potency concentrations; recent data indicates that potency from current donor populations has decreased (ie, measles immunity now from vaccinations instead of immunity from disease) requiring a higher IM immune globulin dose (0.5 mL/kg) in all patients without evidence of measles immunity to ensure adequate serum titers.IV: 400 mg/kg/dose within 6 days of exposure.Myasthenia gravisMyasthenia gravis (severe exacerbation): IV: 400 to 1,000 mg/kg/dose once daily over 2 to 5 days for a total dose of 2,000 mg/kg; if additional therapy required, dose should be based on clinical response and titrated to minimum effective dose (Ref).Myocarditis, acuteMyocarditis, acute: IV: 2,000 mg/kg as a single dose. A cohort study of 21 young patients, including neonates, showed improvement in LVF recovery and survival at 1 year as compared to untreated historical cohort (Ref); efficacy results are variable (Ref); the largest data analysis did not show clear clinical benefit nor positive impact on survival (Ref).Sepsis, adjunctive treatmentSepsis, adjunctive treatment: IV: Limited data available; efficacy results variable: Usual dose: 500 to 1,000 mg/kg/dose once daily for 1 to 3 days (Ref). The largest trial, INIS (n=3,493), reported no difference in outcomes (including incidence of subsequent sepsis, death, or major disability at 2 years) between treatment and control groups using 500 mg/kg/day for 2 days (Ref).Dosing: PediatricNote: Not all products are interchangeable with regards to route of administration; consult manufacturers' labeling for additional information. Product-specific dosing is provided where applicable; approval ages vary by product; see manufacturers' labeling. Some clinicians use ideal body weight or an adjusted ideal body weight in morbidly obese patients to calculate an IVIG dose (Ref). Dosage expressed as mg/kg or mL/kg and is dependent upon route of administration; use extra caution to ensure accuracy.Acute disseminated encephalomyelitisAcute disseminated encephalomyelitis (ADEM): Limited data available: Children and Adolescents: IV: 1,000 mg/kg/dose once daily for 2 days (Ref).Colitis due to Clostridioides difficile, chronicColitis due to Clostridioidesdifficile, chronic: Limited data available: Infants and Children: IV: 400 mg/kg/dose every 3 weeks resulted in resolution of colitis symptoms during treatment; duration of therapy was unclear (n=5; age range: 6 to 37 months) (Ref).Dermatomyositis, refractoryDermatomyositis, refractory: Limited data available: Children: IV: 1,000 mg/kg/dose once daily for 2 days; Note: If maintenance therapy is required, the dose and frequency should be based on clinical response and doses should not exceed 2,000 mg/kg per treatment course (Ref).Guillain-Barré syndromeGuillain-Barré syndrome: Limited data available: Various regimens have been used:Children: IV: 1,000 mg/kg/dose once daily for 2 days (Ref) or 400 mg/kg/dose once daily for 5 days (Ref).Hematopoietic cell transplantation with hypogammaglobulinemia, prevention of bacterial infectionHematopoietic cell transplantation (HCT) with hypogammaglobulinemia (IgG <400 mg/dL), prevention of bacterial infection: Limited data available (Ref): Note: Increase dose or frequency to maintain IgG concentration >400 mg/dL.Within first 100 days after HCT: Infants and Children (Allogeneic HCT recipients): IV: 400 mg/kg/dose once monthly.Adolescents: IV: 500 mg/kg/dose once weekly.>100 days after HCT: Infants, Children, and Adolescents: IV: 500 mg/kg/dose every 3 to 4 weeks.Hepatitis A, prophylaxisHepatitis A, prophylaxis: Limited data available:Preexposure prophylaxis upon travel into endemic areas (Ref): Note: Hepatitis A vaccine preferred for pediatric patients ≥6 months (Ref):Infants, Children, and Adolescents: GamaSTAN:Anticipated duration of risk ≤1 month: IM: 0.1 mL/kg/dose as a single dose.Anticipated duration of risk 1 to 2 months: IM: 0.2 mL/kg/dose as a single dose.Anticipated duration of risk ≥2 months: IM: 0.2 mL/kg/dose every 2 months.Postexposure prophylaxis (Ref): Note: Hepatitis A vaccine preferred for pediatric patients ≥12 months (Ref):Infants: GamaSTAN: IM: 0.1 mL/kg/dose as a single dose given within 14 days of exposure and prior to manifestation of disease.Children and Adolescents: GamaSTAN: IM: 0.1 mL/kg/dose as a single dose given within 14 days of exposure and prior to manifestation of disease; not needed if at least 1 dose of hepatitis A vaccine was given previously or as part of postexposure prophylaxis unless patient has chronic liver disease or is immunocompromised.Bacterial infection prophylaxis in patients with HIV and hypogammaglobulinemiaBacterial infection prophylaxis in patients with HIV and hypogammaglobulinemia: Limited data available (Ref):Infants and Children:Primary prophylaxis for serious bacterial infection in patients with hypogammaglobulinemia (IgG <400 mg/dL): IV: 400 mg/kg/dose every 2 to 4 weeks.Secondary prophylaxis for invasive bacterial infections: Should only be used if subsequent infections are frequent severe infections (>2 infections during a 1-year period): IV: 400 mg/kg/dose every 2 to 4 weeks.Immune thrombocytopeniaImmune thrombocytopenia (ITP): Carimune NF 6%: Infants, Children, and Adolescents:Acute therapy: IV: 400 mg/kg/dose once daily for 2 to 5 days to maintain platelet count ≥30,000/mm3 and/or to control significant bleeding. If platelet response is adequate (30,000 to 50,000/mm3) after the first 2 doses, then may discontinue therapy.Chronic therapy: IV: 400 mg/kg/dose as a single infusion to maintain platelet count ≥30,000/mm3 and/or to control significant bleeding; may increase to 800 to 1,000 mg/kg/dose if response inadequate.Flebogamma DIF 10%: Children ≥2 years and Adolescents: Chronic therapy: IV: 1,000 mg/kg/dose once daily for 2 consecutive days.Gammaked, Gamunex-C: Infants, Children, and Adolescents: Acute or chronic therapy: IV: 400 mg/kg/dose once daily for 5 consecutive days or 1,000 mg/kg/dose once daily for 2 consecutive days; if an adequate platelet response is observed after the initial 1,000 mg/kg/dose, then the subsequent dose may be held.Privigen: Adolescents ≥15 years: Chronic therapy: IV: 1,000 mg/kg/dose once daily for 2 days.Kawasaki disease, treatmentKawasaki disease, treatment: Limited data available: Note: Use in combination with aspirin; may consider the addition of corticosteroids in patients at high risk for IVIG resistance or developing coronary artery aneurysms (Ref).Infants and Children: IV: 2,000 mg/kg as a single dose infused over 8 to 12 hours; usually administered within 10 days of disease onset; however, may be administered >10 days from onset in patients with delayed diagnosis or with persistent symptoms of systemic inflammation with persistent fever and/or coronary artery aneurysms. If signs and symptoms persist ≥36 hours after completion of the infusion, retreatment with a second dose of 1,000 or 2,000 mg/kg infusion may be considered with or without corticosteroids; a lower second dose has been suggested to minimize risk for adverse drug reactions (eg, hemolytic anemia) (Ref). Note: A maximum dose has not been defined; a reasonable maximum dose of 100 to 140 g/dose has been suggested during times of drug shortages or when cost is a consideration (Ref).Measles, prophylaxisMeasles, prophylaxis: Note: Route of administration varies with product; verify route prior to administration.ACIP recommendations (Ref): Infants, Children, and Adolescents:Preexposure prophylaxis (eg, during an outbreak, travel to endemic area): Note: Indicated for patients already receiving immune globulin therapy.IV: ≥400 mg/kg/dose within 3 weeks before anticipated exposure.SUBQ: 200 mg/kg/dose once weekly for 2 consecutive weeks prior to anticipated exposure. Note: Not all immune globulin preparations may be administered by the SUBQ route; consult product labeling for additional information as market availability may change.Postexposure prophylaxis (in any person without evidence of measles immunity):Infants, Children, and Adolescents:IM: 0.5 mL/kg/dose (maximum dose: 15 mL/dose) within 6 days of exposure; in adults, doses >10 mL should be split into multiple injections and administered at different sites; in pediatric patients, may also split doses <10 mL based on patient size. Note: Not all immune globulin preparations may be administered by the IM route; of the products currently available on the market, GamaSTAN may be given IM; consult product labeling for additional information as market availability may change. GamaSTAN manufacturer labeling suggests a lower IM dose; however, this dosing was based on previous immune globulin donor potency concentrations; recent data indicates that potency from current donor populations has decreased (ie, measles immunity now from vaccinations instead of immunity from disease) requiring a higher IM immune globulin dose (0.5 mL/kg) in all patients without evidence of measles immunity to ensure adequate serum titers.IV: 400 mg/kg/dose within 6 days of exposure.Product-specific dosing:Cutaquig: SUBQ infusion: Patients with primary humoral immunodeficiency: Children ≥2 years and Adolescents:Preexposure prophylaxis: SUBQ: Increase dose to ≥245 mg/kg/dose once weekly or equivalent if dosing is not on a weekly schedule (if current dose is less).Cuvitru: SUBQ infusion: Patients with primary humoral immunodeficiency: Children ≥2 years and Adolescents:Preexposure prophylaxis: SUBQ: Increase dose to ≥230 mg/kg/dose once weekly or equivalent if dosing is not on a weekly schedule (if current dose is less).Flebogamma DIF 5%, Gammagard Liquid, Gammagard S/D, Gammaplex 5% and 10%: IV: Patients with primary humoral immunodeficiency: Children ≥2 years and Adolescents:Preexposure prophylaxis: IV: Increase dose to ≥530 mg/kg every 3 to 4 weeks (if current dose is less).Postexposure prophylaxis: IV: 400 mg/kg once as soon as possible and within 6 days of exposure.GamaSTAN: IM: Infants, Children, and AdolescentsImmunocompromised:Postexposure prophylaxis: IM: 0.5 mL/kg immediately; maximum dose: 15 mL/dose.Immunocompetent: Postexposure prophylaxis: IM: 0.25 mL/kg within 6 days of exposure. Note: CDC/ACIP recommend 0.5 mL/kg/dose for all patients (Ref).Gammaked, Gamunex-C: IV: Children ≥2 years and Adolescents:Preexposure prophylaxis: IV: Increase dose to ≥400 mg/kg every 3 to 4 weeks just prior to expected exposure (if current dose is less).Postexposure prophylaxis: IV: 400 mg/kg once as soon as possible after exposure.Hizentra: SUBQ infusion: Patients with primary humoral immunodeficiency: Children ≥2 years and Adolescents:Preexposure prophylaxis: SUBQ:Patients receiving weekly or more frequent dosing receiving <200 mg/kg weekly: Increase dose to ≥200 mg/kg/dose weekly for 2 consecutive weeks.Patients receiving biweekly dosing: Increase dose to ≥400 mg/kg once (if current dose is less).Postexposure prophylaxis (regardless of prior dosing schedule): SUBQ: 400 mg/kg administered as soon as possible after exposure.Octagam 5%: IV: Patients with primary humoral immunodeficiency: Children ≥6 years and Adolescents:Preexposure prophylaxis: IV: Increase dose to ≥530 mg/kg every 3 to 4 weeks (if current dose is less).Postexposure prophylaxis: IV: 400 mg/kg once as soon as possible and within 6 days of exposure.Privigen: IV: Patients with primary humoral immunodeficiency: Children ≥3 years and Adolescents:Preexposure prophylaxis: IV: Increase dose to ≥530 mg/kg every 3 to 4 weeks (if current dose is less).Postexposure prophylaxis: IV: 400 mg/kg once as soon as possible and within 6 days of exposure.Multiple sclerosisMultiple sclerosis (relapsing-remitting, when other therapies cannot be used): Limited data available:Children and Adolescents: Dosage regimen variable; optimal dose not established: IV: 1,000 mg/kg/dose once monthly, with or without an induction of 400 mg/kg/day for 5 days (Ref).Multisystem inflammatory syndrome in children associated with SARS-CoV-2Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: Limited data available:Note: Recommended for initial therapy in combination with glucocorticoids (ie, methylprednisolone) (Ref).Infants, Children, and Adolescents: IV: 2,000 mg/kg once, infused over ~12 hours; maximum dose: 100 g (Ref). Note: If cardiac function is impaired or patient is fluid overloaded, consider slowing administration rate (eg, ≥16 hours) or splitting into 2 infusions (1,000 mg/kg/dose daily for 2 days); monitor fluid status closely (Ref).Myasthenia gravis, severe exacerbationMyasthenia gravis, severe exacerbation: Limited data available: Children: IV: 400 to 1,000 mg/kg/dose once daily over 2 to 5 days for a total dose of 2,000 mg/kg; if additional therapy required, dose should be based on clinical response and titrated to minimum effective dose (Ref).Myocarditis, acuteMyocarditis, acute: Limited data available: Infants, Children, and Adolescents: IV: 2,000 mg/kg as a single dose. A cohort study of 21 children showed improvement in LVF recovery and survival at 1 year as compared to untreated historical cohort (Ref); efficacy results are variable (Ref); the largest data analysis did not show clear clinical benefit nor positive impact on survival (Ref).Primary immunodeficiency disordersPrimary immunodeficiency disorders: Adjust dose/frequency based on desired IgG concentration and clinical response; a trough IgG concentration of ≥500 mg/dL has been recommended by some experts (Ref); consult product specific labeling for appropriate age groups.IV infusion:Asceniv: Children ≥12 years and Adolescents: IV: 300 to 800 mg/kg every 3 to 4 weeks.Bivigam: Children ≥6 years and Adolescents: IV: 300 to 800 mg/kg every 3 to 4 weeks.Carimune NF: Infants, Children, and Adolescents: IV: 400 to 800 mg/kg/dose every 3 to 4 weeks.Flebogamma 5% DIF, Gammagard Liquid, Gammagard S/D, Gammaked, Gamunex-C, Panzyga: Children ≥2 years and Adolescents: IV: 300 to 600 mg/kg/dose every 3 to 4 weeks.Gammaplex 5% and 10%: Children ≥2 years and Adolescents: IV: 300 to 800 mg/kg every 3 to 4 weeks.Octagam 5%: Children ≥6 years and Adolescents: IV: 300 to 600 mg/kg/dose every 3 to 4 weeks.Privigen: Children ≥3 years and Adolescents: IV: 200 to 800 mg/kg/dose every 3 to 4 weeks.SUBQ infusion:Cutaquig, Cuvitru: Children ≥2 years and Adolescents:Patients switching from IGIV therapy: SUBQ infusion: Begin 1 week after last immune globulin IV dose. Use the following equations to calculate initial dose:Initial weekly dosing: Dose (grams) = (IV dose [grams] divided by IV dose interval [weeks]), then multiply this dose by 1.3 (dose adjustment factor). Note: To convert the dose (in grams) to mL, multiply the calculated dose (in grams) by 5 (for Cuvitru) or by 6 (for Cutaquig).Biweekly dosing (grams): Multiply the calculated weekly dose by 2.Frequent dosing (2 to 7 times per week) (grams): Divide the calculated weekly dose by the desired number of times per week.Note: For subsequent dose adjustments, refer to product labeling.Patients switching from another IG SubQ product: SUBQ infusion:Weekly dosing (grams): Weekly dose is the same as the prior immune globulin subcutaneous weekly dose.Biweekly dosing (grams): Multiply the calculated weekly dose by 2.Frequent dosing (2 to 7 times per week) (grams): Divide the calculated weekly dose by the desired number of administration times per week.Note: For subsequent dose adjustments, refer to product labeling.Gammagard Liquid, Gammaked, Gamunex-C: Children ≥2 years and Adolescents: SUBQ infusion: Begin 1 week after last IV dose. Use the following equation to calculate initial dose:Initial weekly dose: Dose (grams) = (1.37 x IV dose [grams]) divided by (IV dose interval [weeks]); Note: For subsequent doses, refer to product labeling. Note: To convert the dose (in grams) to mL, multiply the calculated dose (in grams) by 10.Hizentra: Children ≥2 years and Adolescents: SUBQ infusion: For weekly dosing or frequent (up to daily), begin 1 week after last IV or SUBQ infusion. For biweekly dosing, begin 1 or 2 weeks after last IV infusion or 1 week after the last SUBQ weekly infusion. Note: Patient should have received an IV immune globulin routinely for at least 3 months before switching to SUBQ. Use the following equation to calculate initial dose:Initial weekly dose: Dose (grams) = (Previous IV dose [grams]) divided by (IV dose interval [weeks]) then multiply by 1.37; if switching from a different SUBQ formulation to Hizentra, maintain previous weekly SUBQ dose initially. Note: To convert the dose (in grams) to mL, multiply the calculated dose (in grams) by 5.Note: Provided the total weekly dose is maintained, any dosing interval from daily up to biweekly (every 2 weeks) may be used. Use the following calculations to calculate frequent or biweekly dosing:Biweekly dose (grams): Dose = Calculated or previous weekly SUBQ dose (grams) multiplied by 2.Frequent (2 to 7 times per week) dosing: Dose (grams) = Calculated or previous weekly dose (grams) divided by the desired number of times per week (eg, for 3 times per week dosing, divide weekly dose by 3).Note: For subsequent doses refer to product labeling.Xembify: Children ≥2 years and Adolescents:Patients switching from another IG SUBQ product: SUBQ infusion: Weekly dose is the same as the prior immune globulin subcutaneous weekly dose (grams).Note: For subsequent dose adjustments, refer to product labeling.Patients switching from IGIV therapy: SUBQ infusion: Begin treatment 1 week after patient's last immune globulin IV.Initial weekly dosing (grams): Previous IV dose (grams) divided by IV dose interval (weeks) then multiply by 1.37. Note: To convert the dose (in grams) to mL, multiply the calculated dose (in grams) by 5.Note: For subsequent dose adjustments, refer to product labeling.Frequent (2 to 7 times per week) dosing (grams): Divide the calculated weekly dose by the desired number of times per week.Rubella, prophylaxis during pregnancyRubella, prophylaxis during pregnancy (postexposure): GamaSTAN: Adolescents: IM: 0.55 mL/kg/dose as a single dose within 72 hours of exposure (Ref); Note: Not recommended for routine use; may reduce, but not eliminate, risk for rubella. In adults, total dose volumes >10 mL should be split into multiple injections given at different sites.Stevens-Johnson syndrome/toxic epidermal necrolysisStevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): Limited data available:Infants, Children, and Adolescents: IV: Usual dose: 1,500 to 2,000 mg/kg total dose as a single dose or divided over 2 to 4 days; dosing based on retrospective reviews and case reports; efficacy results are variable (Ref).Varicella-zoster, postexposure prophylaxisVaricella-zoster, postexposure prophylaxis (independent of HIV-status):Infants, Children, and Adolescents: Note: Use only if varicella-zoster immune globulin is unavailable.IV: 400 mg/kg as a single infusion as soon as possible and within 10 days of exposure; ideally within 96 hours of exposure (Ref).IM: GamaSTAN: 0.6 to 1.2 mL/kg/dose as a single dose within 72 hours of exposure (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricIV: Use with caution due to risk of immune globulin-induced renal dysfunction; the rate of infusion and concentration of solution should be minimized. Discontinue if renal function deteriorates during treatment.IM: There are no dosage adjustments provided in the manufacturer's labeling.SubQ infusion: There are no dosage adjustments provided in the manufacturer's labeling; consider lower, more frequent dosing.Dosing: Hepatic Impairment: PediatricIM, IV, SubQ infusion: There are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Immune globulin (Intravenous, subcutaneous, and intramuscular): Drug information")Note: Always administer each initial IV dose under medical supervision. Route of administration: Not all products are interchangeable with regard to route of administration; consult manufacturer labeling. Several intravenous immune globulin (IVIG) 10% formulations FDA-approved for IV administration only may be administered as a SUBQ infusion based on clinical judgment and patient tolerability. In contrast, do not give higher concentration SUBQ products (eg, 20% [Cuvitru, Hizentra, Xembify]) or IM products (eg, 16% [GamaSTAN {Canadian product}]) intravenously. Dosing: Dosage is expressed as mg/kg or mL/kg and is dependent upon route of administration; use extra caution to ensure accuracy. Product-specific dosing is provided where applicable. Pretreatment: Ensure adequate hydration when using formulations containing certain stabilizers (eg, sucrose) and for patients with risk factors for thrombosis and/or renal complications (eg, preexisting renal insufficiency, diabetes, >65 years of age, heart disease, paraproteinemia, concomitant nephrotoxic agents) (Ref). Many patients do not require premedication prior to receiving IVIG; however, some clinicians may consider administering premedication (eg, acetaminophen, a nonsteroidal anti-inflammatory drug, a glucocorticoid, and/or diphenhydramine), especially if there have been prior reactions or other reasons for special concern (Ref).Antibody-mediated rejection, treatmentAntibody-mediated rejection, treatment (off-label use):Note: Optimal dose, frequency, and duration are unknown and vary based on institutional protocols. Dose may require large volume of fluid. These are only example regimens; dosing is center dependent.Heart transplantation: IV: 2 g/kg divided into 2 or 4 doses and given on consecutive days as part of an appropriate combination regimen; if plasmapheresis is utilized, administer 100 mg/kg after each session. Regimen may be re-dosed monthly, if necessary, based on response (Ref).Kidney transplantation: Antibody-mediated rejection <1 year after transplant: IV: 1 to 2.4 g/kg in divided doses over 1 to 3 consecutive days as part of an appropriate combination regimen (maximum total daily dose: 1 g/kg); with plasmapheresis, give 100 mg/kg after each session and remaining total dose after final session over 1 to 2 days (Ref).Antibody-mediated rejection >1 year after transplant: IV: 200 mg/kg every 2 weeks for 3 doses as part of an appropriate combination regimen (Ref).Lung transplantation: IV: 500 mg/kg to 2 g/kg as part of an appropriate combination regimen (doses >1 g/kg are typically divided into 2 doses and given over 2 days). This regimen may be re-dosed monthly, if necessary, based on response (Ref).Antiviral prophylaxisAntiviral prophylaxis:Hepatitis A, prophylaxis (adjunctive agent):Note: Hepatitis A vaccine alone is preferred for most individuals; IVIG may be administered in combination with hepatitis A vaccine (at a different anatomical site) in high-risk settings, or alone in individuals who are allergic to hepatitis A vaccine (Ref).Preexposure prophylaxis upon travel into endemic areas (alternative agent) (GamaSTAN, GamaSTAN S/D [Canadian product]):Anticipated risk of exposure <1 month: IM: 0.1 mL/kg (Ref).Anticipated risk of exposure 1 to 2 months: IM: 0.2 mL/kg (Ref).Anticipated risk of exposure ≥2 months: IM: 0.2 mL/kg every 2 months (Ref).Postexposure prophylaxis (alternative agent) (GamaSTAN, GamaSTAN S/D [Canadian product]):IM: 0.1 mL/kg given as soon as possible within 14 days of exposure and/or prior to manifestation of disease; not needed if at least 1 dose of hepatitis A vaccine was given at ≥1 month before exposure, unless patient has HIV infection (Ref).Measles, prophylaxis:Measles, preexposure prophylaxis in patients with primary humoral immunodeficiency at risk of measles exposure (eg, during an outbreak, travel to endemic area) who are currently receiving immune globulin therapy:IV:Patients receiving Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex 5%, Gammaplex 10%, Gamunex-C, Flebogamma DIF 5%, Flebogamma DIF 10%, Octagam 5%, or Privigen:If prior routine dose is <400 mg/kg (Gammaked only) or <530 mg/kg (other products): Give at least 400 mg/kg (Gammaked only) or at least 530 mg/kg (other products) as soon as possible before expected exposure followed by resumption of prior dosing in 3 to 4 weeks.Patients receiving Panzyga:If prior dose <530 mg/kg: Increase dose to at least 530 mg/kg immediately before expected exposure; increased dose provides adequate serum level for at least 22 days.If prior dose ≥530 mg/kg: Maintain current dose.SUBQ:Patients receiving Cutaquig:If prior weekly dose <245 mg/kg: Increase dose to 245 mg/kg weekly.If prior weekly dose ≥245 mg/kg: Maintain current dose.Patients receiving Cuvitru:If prior weekly (or weekly equivalent) dose <230 mg/kg: Increase dose to at least 230 mg/kg weekly or the weekly equivalent of 230 mg/kg for dosing intervals other than weekly.Patients receiving Hizentra:If prior dosing is weekly or more frequent: Ensure total weekly dose of ≥200 mg/kg for 2 consecutive weeks followed by resumption of prior dosing schedule.If prior dosing is biweekly: Administer at least 400 mg/kg once followed by resumption of prior dosing schedule.Measles, postexposure prophylaxis in patients with primary humoral immunodeficiency currently receiving SUBQ or IV immune globulin therapy; patients who are immunocompromised without evidence of immunity; and pregnant or severely immunocompromised patients without evidence of measles immunity (Ref):IV: 400 mg/kg as a single dose as soon as possible and within 6 days of exposure (Ref). For patients with primary humoral immunodeficiency currently receiving SUBQ or IV immune globulin therapy, resume prior dosing schedule.SUBQ (Hizentra only): 400 mg/kg as a SUBQ infusion as soon as possible and within 6 days of exposure followed by resumption of prior dosing schedule (Ref). Note: This regimen is generally used for patients with primary humoral immunodeficiency currently receiving Hizentra.Varicella, postexposure prophylaxis (alternative agent): Note: Varicella zoster immune globulin is preferred; IVIG may be used if varicella zoster immune globulin is unavailable (Ref).IV: 400 mg/kg administered as a single dose within 10 days but, ideally, within 96 hours of exposure (Ref).IM (GamaSTAN, GamaSTAN S/D [Canadian product]): 0.6 to 1.2 mL/kg once within 72 hours of exposure. Note: For patients at risk of thrombosis, administer at the lower end of the recommended dosage range (Ref).Chronic inflammatory demyelinating polyneuropathyChronic inflammatory demyelinating polyneuropathy:IV:Initial: 2 g/kg administered in divided doses over 2 to 5 consecutive days (eg, 400 mg/kg once daily for 5 days) followed by maintenance dosing (maximum total daily dose: 1 g/kg) (Ref).Maintenance: 1 g/kg administered as a single infusion over 1 day or divided into 2 doses over 2 consecutive days, every 3 weeks (Ref). Continue maintenance therapy for 2 to 3 months before determining response to therapy. Further tapering of dose or frequency and the duration of maintenance therapy are individualized depending upon clinical response (Ref).SUBQ (alternative route): Note: May be used as maintenance therapy for patients who respond to initial IVIG therapy (Ref). Begin maintenance therapy 1 week after last IVIG infusion.Maintenance: 200 to 400 mg/kg/week administered in 1 or 2 sessions over 1 or 2 consecutive days (Ref). For worsening symptoms, consider restarting IVIG using dosing above.Dermatomyositis/Polymyositis, severe, life-threatening or refractoryDermatomyositis/Polymyositis, severe, life-threatening or refractory:Note: For dermatomyositis, use in combination with other agents (Ref).IV: 1 g/kg per day on 2 consecutive days every 4 weeks (total monthly dose: 2 g/kg) (Ref). For patients who develop intolerable adverse effects, some experts give 1 g/kg per day once every 2 weeks. Dosing interval may be lengthened once complete clinical response is achieved (Ref).SUBQ (alternative route): 500 mg/kg once weekly (total monthly dose: 2 g/kg) (Ref).Duration: Full clinical effect may take up to 6 months. Relapse may occur upon treatment discontinuation; continued treatment may be necessary to maintain control (Ref).Encephalomyelitis, acute disseminatedEncephalomyelitis, acute disseminated (off-label use):Note: Reserve for patients in whom first-line therapy with high-dose glucocorticoids has failed while evaluating for alternative diagnoses (Ref).IV: 400 mg/kg once daily for 5 days (Ref).Guillain-Barré syndromeGuillain-Barré syndrome (off-label use): Note: Initiate IVIG within 4 weeks of symptom onset (Ref).IV: 400 mg/kg once daily for 5 days (Ref). Re-treatment is not recommended due to increased risk of adverse effects without additional benefit (Ref).Hypogammaglobulinemia, prophylaxis against bacterial infectionHypogammaglobulinemia, prophylaxis against bacterial infection:Acquired secondary to malignancy: Note: Reserve for patients who have had recurrent infections and have a low serum IgG (eg, <300 to 500 mg/dL); routine prophylaxis not recommended and thresholds for treatment vary (Ref).IV: Initial: 200 to 400 mg/kg given as a single dose once every 3 to 4 weeks. Adjust dose or frequency to maintain IgG concentration >500 to 700 mg/dL and/or based on response to therapy (Ref).Hematopoietic cell transplantation (off-label use):Note: Reserve for patients who have had recurrent infections and have a low serum IgG (eg, <300 to 500 mg/dL); routine prophylaxis not recommended and thresholds for treatment vary (Ref).≤100 days post–hematopoietic cell transplantation: IV: 500 mg/kg administered as a single dose once weekly (Ref).>100 days post–hematopoietic cell transplantation: IV: 500 mg/kg administered as a single dose every 3 to 4 weeks (Ref).Note: Adjust dose or frequency to maintain IgG concentration >500 to 700 mg/dL and/or based on patient's response to therapy (Ref).Primary humoral immunodeficiency disorders:IV: 400 to 600 mg/kg as a single dose once every 3 to 4 weeks; adjust dose based on clinical condition and response (see "Note" below). Dosage range: 200 to 800 mg/kg (Ref). Consider using lower concentrations (eg, Carimune NF 3%) in previously untreated patients; may use higher concentrations if tolerated.SUBQ: 100 to 200 mg/kg once weekly; adjust dose based on clinical condition and response (see "Note" below). Dosage range: 200 to 800 mg/kg (Ref). May facilitate absorption by administering along with hyaluronidase (Ref).HyQvia: See manufacturer's labeling for initial ramp-up schedule (initiating treatment with a full monthly dose has not been evaluated).Note: Consistent IgG trough concentrations are typically achieved after 3 to 6 months of regular therapy. Adjust dose to maintain goal IgG trough 500 to 800 mg/dL; occasionally, a goal of >1 g/dL is required (Ref). Refer to "Switching from IV to SUBQ infusion dosing or switching between SUBQ products" below for dosing and administration recommendations when switching between products.Immune thrombocytopeniaImmune thrombocytopenia:Immune thrombocytopenia (adjunctive or alternative agent):Note: For patients who require a rapid increase in platelet count, those who do not respond to glucocorticoids, and those who cannot tolerate glucocorticoids. IVIG may also be used for patients with critical bleeding or a need for urgent surgery or procedures (eg, pregnancy) (Ref).IV: 1 g/kg once daily for 1 or 2 days; second dose may be withheld if adequate platelet response (eg, platelets >50,000/mm3) in 24 hours (Ref). Alternative dosing: 400 mg/kg once daily for 5 days (Ref).Fetal and neonatal alloimmune thrombocytopenia (maternal administration): IV: 1 to 2 g/kg per week, with or without glucocorticoids (doses >1 g/kg are typically divided into 2 doses and given over 2 days). Dose is dependent upon gestational age and risk (Ref).Lambert-Eaton myasthenic syndromeLambert-Eaton myasthenic syndrome (off-label use): IV: 2 g/kg administered in divided doses over 2 to 5 consecutive days (eg, 400 mg/kg once daily for 5 days) (maximum total daily dose: 1 g/kg) (Ref). For patients who respond to initial therapy, IVIG may be repeated every 4 to 12 weeks for symptom recurrence (Ref).Multifocal motor neuropathyMultifocal motor neuropathy: Initial: IV: 2 g/kg administered in divided doses over 2 to 5 consecutive days (eg, 400 mg/kg once daily for 5 days) (maximum total daily dose: 1 g/kg) (Ref).Maintenance: Note: Dosing is individualized and based on clinical response.IV: 1 to 2 g/kg every 2 to 6 weeks. If initial dose was administered over 5 days and was well tolerated, maintenance dose may be administered over a shorter duration (eg, total dose of 2 g/kg administered as 1 g/kg daily for 2 consecutive days) (Ref).Myasthenia gravis, acute exacerbationMyasthenia gravis, acute exacerbation (off-label use): IV: 2 g/kg per treatment course, administered in divided doses over 2 to 5 consecutive days (eg, 400 mg/kg once daily for 5 days or 1 g/kg once daily for 2 days) (maximum total daily dose: 1 g/kg) (Ref). Note: A single dose of 1 g/kg may have similar efficacy to 1 g/kg given on 2 consecutive days (Ref).Parvovirus B19 infection, treatment, immunocompromised hostParvovirus B19 infection, treatment, immunocompromised host (off-label use): Solid organ transplant: IV: 400 mg/kg once daily for 5 days in combination with a reduction of immunosuppression, if possible (Ref).Patients with HIV: Note: Optimal dose not well-defined.Initial: IV: 400 mg/kg once daily for 5 to 10 days or 1 g/kg once daily for 2 days (Ref).Maintenance: Note: For patients with a CD4 count <100 cells/mm3 to prevent relapse (Ref).IV: 400 mg/kg once every 4 weeks (Ref).Pemphigus foliaceus and vulgaris, refractoryPemphigus foliaceus and vulgaris, refractory (off-label use): IV: 2 g/kg administered in divided doses over 2 to 5 consecutive days (eg, 400 mg/kg once daily for 5 days); may repeat every 4 to 6 weeks based on clinical response (Ref).Toxic shock syndrome, streptococcalToxic shock syndrome, streptococcal (adjunctive agent) (off-label use): IV: 1 g/kg on day 1, followed by 500 mg/kg once daily on days 2 and 3 (Ref).Warm autoimmune hemolytic anemiaWarm autoimmune hemolytic anemia (adjunctive agent) (off-label use): Note: May be used for patients who are improving but remain transfusion-dependent 2 weeks after starting first-line therapies (Ref).IV: 500 mg/kg once daily for 4 days or 1 g/kg once daily for 2 days (Ref).Switching from IV to SUBQ infusion dosing or switching between SUBQ products:Switching from IV to SUBQ infusion dosing:Cutaquig, Cuvitru:SUBQ infusion: Begin treatment 1 week after patient's last IVIG dose.Initial weekly dose (grams): Divide the previous IVIG dose (grams) by the number of weeks between IV doses, then multiply this dose by 1.3 (dose adjustment factor).Every-2-week dosing (grams): Multiply the calculated weekly dose by 2.Frequent (2 to 7 injections per week) dosing (grams): Divide the calculated weekly dose by the desired number of injections per week.Note: For subsequent dose adjustments, refer to product labeling.Gammagard Liquid, Gammaked, Gamunex-C:SUBQ infusion: Begin 1 week after last IV dose. Use the following equation to calculate initial dose:Initial weekly dose (grams) = [1.37 × previous IVIG dose (grams)] divided by [number of weeks between IV doses].Note: For subsequent dose adjustments, refer to product labeling.Hizentra:SUBQ infusion: For weekly or frequent (up to daily) dosing, begin 1 week after last IVIG dose. For every-2-week dosing, begin 1 or 2 weeks after last IVIG dose. Note: Patient should have received IVIG routinely for at least 3 months before switching to SUBQ. Use the following equation to calculate initial weekly dose:Initial weekly dose (grams) = [1.37 × previous IVIG dose (grams)] divided by [number of weeks between IV doses]. To convert the dose (in grams) to mL, multiply the calculated dose (in grams) by 5.Note: Provided the total weekly dose is maintained, any dosing interval from daily up to every 2 weeks may be used. Use the following calculations to calculate frequent or every-2-week dosing:Every-2-week dosing (grams): Multiply the calculated or previous weekly dose by 2.Frequent (2 to 7 injections per week) dosing (grams): Divide the calculated or previous weekly dose by the desired number of injections per week.Note: For subsequent dose adjustments, refer to product labeling.HyQvia:SUBQ infusion: For patients previously on another IVIG treatment, administer the first dose ~1 week after the last infusion of previous treatment.Administer the same dose and frequency as the previous IVIG treatment after the initial dose ramp-up. For subsequent dose adjustments, refer to product labeling.Xembify:SUBQ infusion: Begin treatment 1 week after patient's last IVIG dose.Initial weekly dose (grams): [1.37 × previous IVIG dose (grams)] divided by [number of weeks between IV doses].Frequent (2 to 7 injections per week) dosing (grams): Divide the calculated weekly dose by the desired number of injections per week.Note: For subsequent dose adjustments, refer to product labeling.Switching between SUBQ products:Cutaquig:SUBQ infusion: Begin treatment 1 week after patient's last SUBQ immune globulin dose regardless of prior treatment regimen/frequency.Initial weekly dose (grams): Use the same dose as the prior SUBQ immune globulin treatment (grams).Every-2-week dosing (grams): Multiply the calculated weekly dose by 2.Frequent (2 to 7 injections per week) dosing (grams): Divide the calculated weekly dose by the desired number of administration injections per week.Note: For subsequent dose adjustments, refer to product labeling.Cuvitru:SUBQ infusion: Begin treatment 1 week after patient's last SUBQ immune globulin dose regardless of prior treatment regimen/frequency.Weekly dosing (grams): Weekly dose is the same as the prior immune globulin SUBQ weekly dose. If switching from HyQvia, divide the previous HyQvia dose (grams) by the number of weeks between HyQvia doses, then multiply this dose by 1.3 (dose adjustment factor).Every-2-week dosing (grams): Multiply the calculated weekly dose by 2.Frequent (2 to 7 injections per week) dosing (grams): Divide the calculated weekly dose by the desired number of administration injections per week.Note: For subsequent dose adjustments, refer to product labeling.Hizentra:SUBQ infusion: For weekly or frequent (up to daily) dosing, begin 1 week after last SUBQ infusion. For every-2-week dosing, begin 1 week after the last SUBQ weekly infusion. Note: Use the following equation to calculate initial weekly dose:Initial weekly dose: Use previous weekly SUBQ dose initially.Note: Provided the total weekly dose is maintained, any dosing interval from daily up to every 2 weeks may be used. Use the following conversions to calculate dosing:Every-2-week dosing (grams): Multiply the calculated or previous weekly dose by 2.Frequent (2 to 7 injections per week) dosing (grams): Divide the calculated or previous weekly dose by the desired number of injections per week.Note: For subsequent dose adjustments, refer to product labeling.HyQvia:SUBQ infusion: Begin treatment 1 week after patient's last infusion of their previous treatment regardless of prior treatment regimen/frequency.See manufacturer's labeling for initial ramp-up schedule (initiating treatment with a full monthly dose has not been evaluated).Xembify:SUBQ infusion: Weekly dose is the same as the prior immune globulin SUBQ weekly dose (grams).Note: For subsequent dose adjustments, refer to product labeling.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultIV: Use with caution due to risk of immune globulin-induced renal dysfunction; the rate of infusion and concentration of solution should be minimized. Discontinue if renal function deteriorates during treatment.IM: There are no dosage adjustments provided in the manufacturer's labeling.SUBQ infusion: There are no dosage adjustments provided in the manufacturer's labeling; consider lower, more frequent dosing.Dosing: Hepatic Impairment: AdultIM, IV, SUBQ infusion: There are no dosage adjustments provided in the manufacturer's labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productInjectable, Intramuscular [preservative free]: GamaSTAN: 15% to 18% [150 to 180 mg/mL] (2 mL, 10 mL)Kit, Subcutaneous: Hyqvia: 10 g immune globulin (human)/100 mL with an 800 unit hyaluronidase vial, 5 g immune globulin (human)/50 mL with a 400 unit hyaluronidase vial, 2.5 g immune globulin (human)/25 mL with a 200 unit hyaluronidase vial, 20 g immune globulin (human)/200 mL with a 1,600 unit hyaluronidase vial, 30 g immune globulin (human)/300 mL with a 2,400 unit hyaluronidase vial [contains albumin human, edetate (edta) disodium dihydrate]Solution, Injection [preservative free]: Gammagard: 1 g/10 mL (10 mL); 2.5 g/25 mL (25 mL); 5 g/50 mL (50 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL); 30 g/300 mL (300 mL) [latex free]Gammaked: 1 g/10 mL (10 mL); 5 g/50 mL (50 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL) [latex free]Gamunex-C: 1 g/10 mL (10 mL); 2.5 g/25 mL (25 mL); 5 g/50 mL (50 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL); 40 g/400 mL (400 mL) [latex free]Solution, Intravenous [preservative free]: Asceniv: 5 g/50 mL (50 mL) [contains polysorbate 80]Bivigam: 10 g/100 mL (100 mL) [latex free, sugar free; contains polysorbate 80]Bivigam: 5 g/50 mL (50 mL) [contains polysorbate 80]Bivigam: 5 g/50 mL (50 mL [DSC]) [sugar free; contains polysorbate 80]Flebogamma DIF: 0.5 g/10 mL (10 mL); 5 g/50 mL (50 mL); 5 g/100 mL (100 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL); 20 g/400 mL (400 mL); 10 g/200 mL (200 mL); 2.5 g/50 mL (50 mL) [contains polyethylene glycol (macrogol)]Gammaplex: 5 g/50 mL (50 mL); 5 g/100 mL (100 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL); 20 g/400 mL (400 mL); 10 g/200 mL (200 mL) [contains polysorbate 80]Octagam: 1 g/20 mL (20 mL); 2 g/20 mL (20 mL); 5 g/50 mL (50 mL); 5 g/100 mL (100 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL); 25 g/500 mL (500 mL [DSC]); 30 g/300 mL (300 mL); 10 g/200 mL (200 mL); 2.5 g/50 mL (50 mL) [sucrose free]Panzyga: Immune globulin (human)-ifas 1 g/10mL (10 mL); Immune globulin (human)-ifas 30 g/300 mL (300 mL); Immune globulin (human)-ifas 20 g/200 mL (200 mL); Immune globulin (human)-ifas 2.5 g/25 mL (25 mL); Immune globulin (human)-ifas 10 g/100 mL (100 mL); Immune globulin (human)-ifas 5 g/50 mL (50 mL) [latex free]Panzyga: Immune globulin (human)-ifas 1 g/10mL (10 mL); Immune globulin (human)-ifas 5 g/50 mL (50 mL); Immune globulin (human)-ifas 10 g/100 mL (100 mL); Immune globulin (human)-ifas 2.5 g/25 mL (25 mL); Immune globulin (human)-ifas 20 g/200 mL (200 mL); Immune globulin (human)-ifas 30 g/300 mL (300 mL)Privigen: 5 g/50 mL (50 mL); 10 g/100 mL (100 mL); 20 g/200 mL (200 mL); 40 g/400 mL (400 mL)Solution, Subcutaneous [preservative free]: Cutaquig: 1 g/6 mL (6 mL); 1.65 g/10 mL (10 mL); 2 g/12 mL (12 mL); 3.3 g/20 mL (20 mL); 4 g/24 mL (24 mL); 8 g/48 mL (48 mL) [latex free; contains polysorbate 80]Cuvitru: 1 g/5 mL (5 mL); 2 g/10 mL (10 mL); 4 g/20 mL (20 mL); 8 g/40 mL (40 mL); 10 g/50 mL (50 mL)Hizentra: 1 g/5 mL (5 mL); 2 g/10 mL (10 mL); 4 g/20 mL (20 mL); 10 g/50 mL (50 mL) [contains polysorbate 80]Xembify: Immune globulin (human)-klhw 1 g/5 mL (5 mL); Immune globulin (human)-klhw 2 g/10 mL (10 mL); Immune globulin (human)-klhw 4 g/20 mL (20 mL); Immune globulin (human)-klhw 10 g/50 mL (50 mL) [latex free; contains polysorbate 80]Solution Prefilled Syringe, Subcutaneous: Hizentra: 1 g/5 mL (5 mL); 2 g/10 mL (10 mL) [contains polysorbate 80]Solution Prefilled Syringe, Subcutaneous [preservative free]: Hizentra: 4 g/20 mL (20 mL) [contains polysorbate 80]Solution Reconstituted, Intravenous [preservative free]: Carimune NF: 6 g (1 ea [DSC]); 12 g (1 ea [DSC])Gammagard S/D Less IgA: 5 g (1 ea); 10 g (1 ea) [contains albumin human, polyethylene glycol (macrogol), polysorbate 80]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productInjectable, Intramuscular: Gamastan S/D: 15% to 18% [150 to 180 mg/mL] ([DSC])Solution, Intravenous: Gammagard: 10% (10 mL, 25 mL, 50 mL, 100 mL, 200 mL, 300 mL)Gamunex: 10% (25 mL, 50 mL, 100 mL, 200 mL, 400 mL)Octagam: 5% (50 mL, 100 mL, 200 mL); 10% (20 mL, 50 mL, 100 mL, 200 mL)Panzyga: 100 mg/mL (10 mL, 25 mL, 50 mL, 100 mL, 200 mL, 300 mL)Privigen: 10% (25 mL, 50 mL, 100 mL, 200 mL, 400 mL)Solution, Subcutaneous: Cutaquig: 165 mg/mL (6 mL, 12 mL, 24 mL, 48 mL) [contains polysorbate 80]Hizentra: 200 mg/mL (5 mL, 10 mL, 15 mL, 20 mL) [contains polysorbate 80]Generic: 200 mg/mL (5 mL, 10 mL, 20 mL, 40 mL, 50 mL)Solution Prefilled Syringe, Subcutaneous: Hizentra: 4 g/20 mL (20 mL) [contains polysorbate 80]Solution Reconstituted, Intravenous: Gammagard S/D: 5 g (1 ea); 10 g (1 ea) [contains albumin human, polyethylene glycol (macrogol), polysorbate 80]IGIVnex: 10 g (10 mL, 25 mL, 50 mL, 100 mL, 200 mL)Iveegam Immuno: 1 g (1 ea); 7.5 g (1 ea); 10 g (1 ea)Dosage Forms ConsiderationsCarimune NF may contain a significant amount of sodium and also contains sucrose.Cutaquig contains maltose.Gammagard S/D may contain a significant amount of sodium and also contains glucose.Octagam contains maltose.Hyqvia Kit is supplied with a Hyaluronidase (Human Recombinant) component intended for injection prior to Immune Globulin administration to improve dispersion and absorption of the Immune Globulin.Administration: PediatricParenteral: Note: If plasmapheresis employed for treatment of condition, administer immune globulin after completion of plasmapheresis session.IV: Infuse over 2 to 24 hours with initial infusion administered slowly and titrated as tolerated; administer in separate infusion line from other medications; if using primary line, flush with NS or D5W (product specific; consult product prescribing information) prior to administration. Decrease dose, rate, and/or concentration of infusion in patients who may be at risk of renal failure. Decreasing the rate or stopping the infusion may help relieve some adverse effects (flushing, changes in pulse rate, changes in blood pressure). Epinephrine should be available during administration.For initial treatment, a lower concentration and/or a slower rate of infusion should be used. Initial rate of administration and titration is specific to each IVIG product. Refrigerated products should be warmed to room temperature prior to infusion. Some products require filtration; refer to individual product labeling. Antecubital veins should be used, especially with concentrations ≥10% to prevent injection site discomfort.Asceniv 10%: Primary humoral immunodeficiency: Initial (first 15 minutes): 0.5 mg/kg/minute (0.3 mL/kg/hour); if tolerated, increase every 15 minutes up to 8 mg/kg/minute (4.8 mL/kg/hour).Bivigam 10%: Primary humoral immunodeficiency: Initial rate: 0.5 mg/kg/minute (0.3 mL/kg/hour) for 10 minutes; if tolerated, increase every 20 minutes by 0.8 mg/kg/minute (0.48 mL/kg/hour) up to 6 mg/kg/minute (3.6 mL/kg/hour).Carimune NF: Primary humoral immunodeficiency or immune thrombocytopenia: Initial rate: 0.5 mg/kg/minute for 30 minutes; if tolerated, increase to 1 mg/kg/minute, if tolerated after 30 minutes, may increase gradually up to 3 mg/kg/minute; rate in mL/kg/hour varies based on concentration; refer to product labeling.Flebogamma DIF 5%: Primary humoral immunodeficiency: Initial rate: 0.5 mg/kg/minute (0.6 mL/kg/hour) for the first 30 minutes; if tolerated, increase slowly up to 5 mg/kg/minute (6 mL/kg/hour).Flebogamma DIF 10%: Primary humoral immunodeficiency or immune thrombocytopenia: Initial rate: 1 mg/kg/minute (0.6 mL/kg/hour) for first 30 minutes; if tolerated, increase slowly up to 8 mg/kg/minute (4.8 mL/kg/hour).Gammagard Liquid 10%: Primary humoral immunodeficiency: Initial rate: 0.8 mg/kg/minute (0.5 mL/kg/hour) for 30 minutes; if tolerated, increase every 30 minutes up to 8 mg/kg/minute (5 mL/kg/hour).Gammagard S/D: 5% solution: Initial rate: 0.5 mL/kg/hour; if tolerated, may increase to a maximum rate of 4 mL/kg/hour. If 5% solution is tolerated at maximum rate, may administer 10% solution with an initial rate of 0.5 mL/kg/hour; if tolerated, may increase to a maximum rate of 8 mL/kg/hour.Gammaked 10%:CIDP: Initial rate: 2 mg/kg/minute (1.2 mL/kg/hour) for 30 minutes; if tolerated, increase gradually up to 8 mg/kg/minute (4.8 mL/kg/hour).Primary humoral immunodeficiency or ITP: Initial rate: 1 mg/kg/minute (0.6 mL/kg/hour) for 30 minutes; if tolerated, increase gradually up to 8 mg/kg/minute (4.8 mL/kg/hour).Gammaplex 5%: Primary humoral immunodeficiency or ITP: Initial rate: 0.5 mg/kg/minute (0.6 mL/kg/hour) for 15 minutes; if tolerated, increase every 15 minutes up to 4 mg/kg/minute (4.8 mL/kg/hour).Gammaplex 10%: Primary humoral immunodeficiency or ITP: Initial rate: 0.5 mg/kg/minute (0.3 mL/kg/hour) for 15 minutes; if tolerated, increase every 15 minutes up to 8 mg/kg/minute (4.8 mL/kg/hour).Gamunex-C 10%:CIDP: Initial rate: 2 mg/kg/minute (1.2 mL/kg/hour) for 30 minutes; if tolerated, increase gradually up to 8 mg/kg/minute (4.8 mL/kg/hour).Primary humoral immunodeficiency or ITP: Initial rate: 1 mg/kg/minute (0.6 mL/kg/hour) for 30 minutes; if tolerated, increase gradually up to 8 mg/kg/minute (4.8 mL/kg/hour).Octagam 5%: Primary humoral immunodeficiency: Initial rate: 0.5 mg/kg/minute (0.6 mL/kg/hour) for 30 minutes; if tolerated, double the infusion rate every 30 minutes up to a maximum rate of <3.33 mg/kg/minute (4.2 mL/kg/hour).Panzyga 10%: Primary humoral immunodeficiency: Initial (first 30 minutes): 1 mg/kg/minute (0.6 mL/kg/hour); if tolerated, increase gradually every 15 to 30 minutes up to 8 mg/kg/minute (4.8 mL/kg/hour) in treatment-naive patients or if it has been >8 weeks since last infusion or up to 12 to 14 mg/kg/minute (7.2 to 8.4 mL/kg/hour) in treatment-experienced patients.Privigen 10%:ITP: Initial rate: 0.5 mg/kg/minute (0.3 mL/kg/hour); if tolerated, increase gradually up to 4 mg/kg/minute (2.4 mL/kg/hour).Primary humoral immunodeficiency: Initial rate: 0.5 mg/kg/minute (0.3 mL/kg/hour); if tolerated, increase gradually up to 8 mg/kg/minute (4.8 mL/kg/hour).CIDP: Initial rate: 0.5 mg/kg/minute (0.3 mL/kg/hour); if tolerated, increase gradually up to 8 mg/kg/minute (4.8 mL/kg/hour).IM: Administer IM in the anterolateral aspects of the upper thigh or deltoid muscle of the upper arm. Avoid gluteal region due to risk of injury to sciatic nerve. Divide doses >10 mL (adult) and inject in multiple sites; in pediatric patients, consider splitting doses <10 mL based on patient size.SUBQ infusion: Initial dose should be administered in a health care setting capable of providing monitoring and treatment in the event of hypersensitivity. Using aseptic technique, follow the infusion device manufacturer's instructions for filling the reservoir and preparing the pump. Remove air from administration set and needle by priming. Dose may be infused into multiple sites simultaneously. After administration sites are clean and dry, insert subcutaneous needle and prime administration set. Attach sterile needle to administration set, gently pull back on the syringe to assure a blood vessel has not been inadvertently accessed; if blood is present, remove and discard needle and tubing; repeat process using a new needle and tubing and different injection site. Repeat for each injection site; deliver the dose following instructions for the infusion device. Rotate the site(s) between successive infusions. Treatment may be transitioned to the home/home care setting in the absence of adverse reactions.Cutaquig:Injection sites: Abdomen, thigh, upper arm, and/or upper leg/hip area (avoid areas that are scarred, tattooed, injured, or inflamed); ≤6 simultaneous injection sites (spaced ≥2 inches apart).Recommended infusion rate:Children ≥2 years and Adolescents <18 years: First 2 infusions: ≤15 mL/hour per injection site; subsequent infusions: Gradually increase as tolerated by ~5 to 10 mL/hour per injection site every 2 to 4 weeks to maximum rate of 25 mL/hour per injection site.Adolescents ≥18 years: First 2 infusions: ≤20 mL/hour per injection site; subsequent infusions: Gradually increase as tolerated by ~10 mL/hour per injection site every 2 to 4 weeks to a maximum rate of 52 mL/hour per injection site.Recommended infusion volume:Children ≥2 to 6 years: First 2 infusions: ≤10 mL per injection site; subsequent infusions: Gradually increase as tolerated by ~5 to 10 mL per infusion site every 2 to 4 weeks up to a maximum of 15.5 mL per injection site.Children >6 years and Adolescents <17 years: First 2 infusions: ≤15 mL per injection site; subsequent infusions: Gradually increase as tolerated by ~5 to 10 mL per infusion site every 2 to 4 weeks up to a maximum of 29 mL per injection site.Adolescents ≥17 years: First 2 infusions: ≤25 mL per injection site; subsequent infusions: Gradually increase as tolerated by ~10 mL per infusion site every 2 to 4 weeks up to a maximum of 40 mL per site.Cuvitru: Note: It is recommended that infusion be complete within 2 hours of preparation.Injection sites: Abdomen, thighs, upper arms, or lateral hip (avoid bony areas, visible blood vessels, and areas that are scarred, inflamed, or infected); ≤4 simultaneous injection sites (spaced 4 inches apart or more).Maximum infusion rate: 10 to 20 mL/hour per injection site (first 2 infusions); may be increased to 60 mL/hour per injection site (as tolerated) for subsequent infusions.Maximum infusion volume:Patients <40 kg: 20 mL per injection site (first 2 infusions); may increase to 60 mL per site for subsequent infusions.Patients ≥40 kg: 60 mL per injection site.Gammagard Liquid:Injection sites: Abdomen, thighs, upper arms, or lower back (avoid bony areas, visible blood vessels, and areas that are scarred, inflamed, or infected); ≤8 simultaneous injection sites (spaced ≥2 inches apart).Recommended infusion rate:<40 kg: Initial infusion: 15 mL/hour per injection site; subsequent infusions: 15 to 20 mL/hour per injection site; maximum: 160 mL/hour for all simultaneous sites combined.≥40 kg: Initial infusion: 20 mL/hour per injection site; subsequent infusions: 20 to 30 mL/hour per injection site; maximum: 240 mL/hour for all simultaneous sites combined.Maximum infusion volume:<40 kg: 20 mL per injection site.≥40 kg: 30 mL per injection site.Gammaked, Gamunex-C:Injection sites: Abdomen, thighs, upper arms, and/or lateral hip; ≤6 simultaneous injection sites (spaced ≥2 inches apart) (≤8 sites may be used in adults).Recommended infusion rate:<25 kg: 10 mL/hour per infusion site.≥25 kg: Initial: 15 mL/hour per infusion site; may increase up to 20 mL/hour per infusion site.Hizentra:Injection sites: Abdomen, thigh, upper arm, and/or lateral hip (avoid scars, stretch marks, and areas that are tender, bruised, red, or hard); ≤8 simultaneous injection sites (spaced ≥2 inches apart).Maximum infusion rate: First infusion: 15 mL/hour per injection site (primary humoral immunodeficiency) or 20 mL/hour per injection site (CIDP); subsequent infusions: 25 mL/hour per injection site (primary humoral immunodeficiency) or 50 mL/hour per injection site (CIDP).Maximum infusion volume: First infusions: 15 mL per injection site (primary humoral immunodeficiency) or 20 mL per injection site (CIDP); subsequent infusions: 25 mL per injection site (primary humoral immunodeficiency) or 50 mL per injection site (CIDP).HyQvia: Administer the two components of HyQvia (immune globulin and hyaluronidase) sequentially, beginning with the hyaluronidase; do not use either component alone. Infusion pump capable of infusing rates up to 300 mL/hour/site required; must also have the ability to titrate the flow rate. Use a 24-gauge subcutaneous needle set labeled for high flow rates. Infusion site leakage can occur; consider using longer needles (14 mm or 12 mm) and/or more than one infusion site. Initiate the infusion of the full dose of the immune globulin through the same subcutaneous needle set within ~10 minutes of hyaluronidase infusion. For each full or partial vial of immune globulin used, administer the entire contents of the hyaluronidase vial. A second site can be used based on tolerability and total volume; if a second site is used, it should be placed on the opposite side of the body; administer half of total volume of the hyaluronidase in each site. Flush the infusion line with NS or D5W if required.Injection sites: Middle to upper abdomen or thigh (avoid bony prominences or areas that are scarred, inflamed, or infected).Volume per site:<40 kg: ≤300 mL per injection site.≥40 kg: ≤600 mL per injection site.Infusion rate:Immune globulin:First 2 infusions:<40 kg: 5 mL/hour for 5 to 15 minutes; 10 mL/hour for 5 to 15 minutes; 20 mL/hour for 5 to 15 minutes; 40 mL/hour for 5 to 15 minutes; then 80 mL/hour for remainder of infusion.≥40 kg: 10 mL/hour for 5 to 15 minutes; 30 mL/hour for 5 to 15 minutes; 60 mL/hour for 5 to 15 minutes; 120 mL/hour for 5 to 15 minutes; then 240 mL/hour for remainder of infusion.Next 2 or 3 infusions:<40 kg: 10 mL/hour for 5 to 15 minutes; 20 mL/hour for 5 to 15 minutes; 40 mL/hour for 5 to 15 minutes; 80 mL/hour for 5 to 15 minutes; then 160 mL/hour for remainder of infusion.≥40 kg: 10 mL/hour for 5 to 15 minutes; 30 mL/hour for 5 to 15 minutes; 120 mL/hour for 5 to 15 minutes; 240 mL/hour for 5 to 15 minutes; then 300 mL/hour for remainder of infusion.Xembify: Note: It is recommended that infusion be complete within 2 hours of preparation to avoid the potential formation of particles caused by siliconized syringes.Injection sites: Abdomen, thigh, upper arm, sides, back, and/or lateral hip (avoid bony prominence or areas that are scarred, inflamed, or infected); ≤6 simultaneous injection sites (spaced ≥2 inches apart).Maximum infusion rate: 25 mL/hour per injection site.Maximum infusion volume: 25 mL per injection site.Administration: AdultNote: If plasmapheresis employed for treatment of condition, administer immune globulin after completion of plasmapheresis session.IM: Administer IM in the anterolateral aspects of the upper thigh or deltoid muscle of the upper arm. Avoid gluteal region due to risk of injury to sciatic nerve. Divide doses >10 mL and inject in multiple sites.GamaSTAN and GamaSTAN S/D [Canadian product] are for IM administration only.IV infusion: Infuse over 2 to 24 hours; administer in separate infusion line from other medications; if using primary line, flush with NS or D5W (product specific; consult product prescribing information) prior to administration. Decrease dose, rate and/or concentration of infusion in patients who may be at risk of renal failure. Decreasing the rate or stopping the infusion may help relieve some adverse effects (flushing, changes in pulse rate, changes in blood pressure). Epinephrine should be available during administration. For initial treatment or in elderly patients, a lower concentration and/or a slower rate of infusion should be used. Initial rate of administration and titration is specific to each IGIV product. Refrigerated product should be warmed to room temperature prior to infusion. Some products require filtration; refer to individual product labeling. Antecubital veins should be used, especially with concentrations ≥10% to prevent injection-site discomfort.Asceniv: Primary humoral immunodeficiency: Initial (first 15 minutes): 0.5 mg/kg/minute (0.3 mL/kg/hour); Maintenance: Increase every 15 minutes (if tolerated) up to 8 mg/kg/minute (4.8 mL/kg/hour).Bivigam 10%: Primary humoral immunodeficiency: Initial (first 10 minutes): 0.5 mg/kg/minute (0.3 mL/kg/hour); Maintenance: Increase every 20 minutes (if tolerated) by 0.8 mg/kg/minute (0.48 mL/kg/hour) up to 6 mg/kg/minute (3.6 mL/kg/hour).Carimune NF: Refer to product labeling.Flebogamma DIF 5%: Primary humoral immunodeficiency: Initial: 0.5 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Increase slowly (if tolerated) up to 5 mg/kg/minute (6 mL/kg/hour).Flebogamma DIF 10%: Primary humoral immunodeficiency or immune thrombocytopenia: Initial: 1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Increase slowly (if tolerated) up to 8 mg/kg/minute (4.8 mL/kg/hour).Gammagard Liquid 10%:Multifocal motor neuropathy: Initial: 0.8 mg/kg/minute (0.5 mL/kg/hour); Maintenance: Increase gradually (if tolerated) up to 9 mg/kg/minute (5.4 mL/kg/hour).Primary humoral immunodeficiency: Initial (first 30 minutes): 0.8 mg/kg/minute (0.5 mL/kg/hour); Maintenance: Increase every 30 minutes (if tolerated) up to: 8 mg/kg/minute (5 mL/kg/hour).Gammagard S/D [Canadian product]: 5% solution: Initial: 0.5 mL/kg/hour; may increase (if tolerated) to a maximum rate of 4 mL/kg/hour. If 5% solution is tolerated at maximum rate, may administer 10% solution with an initial rate of 0.5 mL/kg/hour; may increase (if tolerated) to a maximum rate of 8 mL/kg/hour.Gammaked 10%:Chronic inflammatory demyelinating polyneuropathy (CIDP): Initial (first 30 minutes): 2 mg/kg/minute (1.2 mL/kg/hour); Maintenance: Increase gradually (if tolerated) to a maximum of 8 mg/kg/minute (4.8 mL/kg/hour).Primary humoral immunodeficiency or immune thrombocytopenia (ITP): Initial (first 30 minutes): 1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Increase gradually (if tolerated) to a maximum of 8 mg/kg/minute (4.8 mL/kg/hour).Gammaplex 5%: Primary humoral immunodeficiency or ITP: Initial (first 15 minutes): 0.5 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Increase every 15 minutes (if tolerated) up to 4 mg/kg/minute (4.8 mL/kg/hour).Gammaplex 10%: Primary humoral immunodeficiency or ITP: Initial (first 15 minutes): 0.5 mg/kg/minute (0.3 mL/kg/hour); Maintenance: Increase every 15 minutes (if tolerated) up to 8 mg/kg/minute (4.8 mL/kg/hour).Gamunex-C 10%:CIDP: Initial (first 30 minutes): 2 mg/kg/minute (1.2 mL/kg/hour); Maintenance: Increase gradually (if tolerated) to a maximum of 8 mg/kg/minute (4.8 mL/kg/hour).Primary humoral immunodeficiency or ITP: Initial (first 30 minutes): 1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Increase gradually (if tolerated) to a maximum of 8 mg/kg/minute (4.8 mL/kg/hour).Octagam 5%: Primary humoral immunodeficiency: Initial (first 30 minutes): 0.5 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Double infusion rate (if tolerated) every 30 minutes up to a maximum rate of <3.33 mg/kg/minute (4.2 mL/kg/hour).Octagam 10%: ITP: Initial (first 30 minutes):1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Double infusion rate (if tolerated) every 30 minutes up to a maximum rate of 12 mg/kg/minute (7.2 mL/kg/hour).Panzyga:CIDP: Initial (first 30 minutes): 1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: Increase gradually (if tolerated) every 15 to 30 minutes up to 12 mg/kg/minute (7.2 mL/kg/hour).ITP: Initial (first 30 minutes): 1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: May increase gradually (if tolerated) every 15 to 30 minutes up to 8 mg/kg/minute (4.8 mL/kg/hour).Primary humoral immunodeficiency: Initial (first 30 minutes): 1 mg/kg/minute (0.6 mL/kg/hour); Maintenance: May increase gradually (if tolerated) every 15 to 30 minutes up to 14 mg/kg/minute (8.4 mL/kg/hour).Privigen 10%:ITP: Initial: 0.5 mg/kg/minute (0.3 mL/kg/hour); Maintenance: Increase gradually (if tolerated) up to 4 mg/kg/minute (2.4 mL/kg/hour).CIDP/Primary humoral immunodeficiency: Initial: 0.5 mg/kg/minute (0.3 mL/kg/hour); Maintenance: Increase gradually (if tolerated) up to 8 mg/kg/minute (4.8 mL/kg/hour).SUBQ infusion: Initial dose should be administered in a health care setting capable of providing monitoring and treatment in the event of hypersensitivity. Using aseptic technique, follow the infusion device manufacturer's instructions for filling the reservoir and preparing the pump. Remove air from administration set and needle by priming. After the administration sites are clean and dry, insert subcutaneous needle and prime administration set. Attach sterile needle to administration set, gently pull back on the syringe to assure a blood vessel has not been inadvertently accessed (do not use needle and tubing if blood present). Repeat for each injection site; deliver the dose following instructions for the infusion device. Rotate the site(s) between successive infusions. Treatment may be transitioned to the home/home care setting in the absence of adverse reactions.Cutaquig:Injection sites: Abdomen, thigh, upper arm, and/or upper leg/hip; ≤6 simultaneous injection sites (spaced ≥2 inches apart).Maximum infusion rate: 20 mL/hour per injection site (first 2 infusions); may be increased to 52 mL/hour per injection site (as tolerated) for subsequent infusions.Maximum infusion volume: 25 mL per injection site (first 2 infusions); may increase to 40 mL per site for subsequent infusions.Cuvitru: Note: Manufacturer recommends to complete administration within 2 hours due to the potential formation of particles caused by siliconized syringes.Injection sites: Abdomen, thigh, upper arm, lateral hip (avoid bony prominences); ≤4 simultaneous injection sites (spaced ≥4 inches apart).Maximum infusion rate: 10 to 20 mL/hour per injection site (first 2 infusions); may be increased to 60 mL/hour per injection site (as tolerated) for subsequent infusions.Maximum infusion volume:Patients <40 kg: 20 mL per injection site (first 2 infusions); may increase to 60 mL per site for subsequent infusions.Patients ≥40 kg: 60 mL per injection site.Gammagard Liquid:Injection sites: Abdomen, thigh, upper arm, lower back (avoid bony prominences); ≤8 simultaneous injection sites (spaced ≥2 inches apart).Initial infusion rate:<40 kg: 15 mL/hour per injection site (maximum volume: 20 mL per injection site).≥40 kg: 20 mL/hour per injection site (maximum volume: 30 mL per injection site).Maintenance infusion rate:<40 kg: 15 to 20 mL/hour per injection site (maximum volume: 20 mL per injection site).≥40 kg: 20 to 30 mL/hour per injection site (maximum volume: 30 mL per injection site).Gammaked, Gamunex-C:Injection sites: Abdomen, thigh, upper arm, lateral hip; ≤8 simultaneous injection sites (spaced ≥2 inches apart).Recommended infusion rate: 20 mL/hour per infusion site.Hizentra:Injection sites: Abdomen, thigh, upper arm, lateral hip; ≤8 simultaneous injection sites in parallel (spaced ≥2 inches apart).Maximum infusion rate: First infusion: 15 mL/hour per injection site (primary humoral immunodeficiency) or 20 mL/hour per injection site (CIDP); subsequent infusions: 25 mL/hour per injection site (primary humoral immunodeficiency) or 50 mL/hour per injection site (CIDP).Maximum infusion volume: First infusion: 15 mL per injection site (primary humoral immunodeficiency) or 20 mL per injection site (CIDP); subsequent infusions: 25 mL per injection site (primary humoral immunodeficiency) or 50 mL per injection site (CIDP).HyQvia: Infuse the two components of HyQvia (immune globulin and hyaluronidase) sequentially, beginning with hyaluronidase; do not use either component alone. Infusion pump capable of infusing rates up to 300 mL/hour/site is required; must also have the ability to titrate the flow rate. Use a 24 gauge subcutaneous needle set labeled for high flow rates. Infusion site leakage can occur; consider using longer needles (14 mm or 12 mm) and/or more than one infusion site. Initiate the infusion of the full dose of the immune globulin through the same subcutaneous needle set within ~10 minutes of hyaluronidase infusion. For each full or partial vial of immune globulin used, administer the entire contents of the hyaluronidase vial. A second site can be used based on tolerability and total volume; if a second site is used, administer half of total volume of the hyaluronidase in each site. Flush the infusion line with NS or D5W if required.Injection sites: Middle to upper abdomen or thigh (avoid bony prominences, or areas that are scarred, inflamed, or infected). If two sites are used simultaneously, the two infusion sites should be on opposite sides of the body.Volume per site:<40 kg: ≤300 mL per injection site.≥40 kg: ≤600 mL per injection site.Infusion rate:Hyaluronidase: ~1 to 2 mL/minute, or as tolerated.Immune globulin:First 2 infusions:<40 kg: 5 mL/hour for 5 to 15 minutes; 10 mL/hour for 5 to 15 minutes; 20 mL/hour for 5 to 15 minutes; 40 mL/hour for 5 to 15 minutes; then 80 mL/hour for remainder of infusion.≥40 kg: 10 mL/hour for 5 to 15 minutes; 30 mL/hour for 5 to 15 minutes; 60 mL/hour for 5 to 15 minutes; 120 mL/hour for 5 to 15 minutes; then 240 mL/hour for remainder of infusion.Next 2 or 3 infusions:<40 kg: 10 mL/hour for 5 to 15 minutes; 20 mL/hour for 5 to 15 minutes; 40 mL/hour for 5 to 15 minutes; 80 mL/hour for 5 to 15 minutes; then 160 mL/hour for remainder of infusion.≥40 kg: 10 mL/hour for 5 to 15 minutes; 30 mL/hour for 5 to 15 minutes; 120 mL/hour for 5 to 15 minutes; 240 mL/hour for 5 to 15 minutes; then 300 mL/hour for remainder of infusion.Xembify: Note: Manufacturer recommends to complete administration within 2 hours due to the potential formation of particles caused by siliconized syringes.Injection sites: Abdomen, thigh, upper arm, sides, back, lateral hip (avoid bony prominences or areas that are scarred, inflamed, or infected); ≤6 simultaneous injection sites (spaced ≥2 inches apart).Maximum infusion rate: 25 mL/hour per injection site.Maximum infusion volume: 25 mL per injection site.Storage/StabilityStability is dependent upon the manufacturer and brand. Do not freeze (do not use if previously frozen). Do not shake. Do not heat (do not use if previously heated).Asceniv: Store under refrigeration at 2°C to 8°C (36°F to 46°F).Bivigam: Store under refrigeration at 2°C to 8°C (36°F to 46°F).Carimune NF: Prior to reconstitution, store at or below 30°C (86°F). Following reconstitution in a sterile laminar air flow environment, store under refrigeration.Cutaquig: Store at 2°C to 8°C (36°F to 46°F) for up to 36 months from the date of manufacture or at room temperature (≤25°C [≤77°F]) for up to 9 months; do not return vial to refrigerator after it has been stored at room temperature. Keep in original carton to protect from light.Cuvitru: Store at 2°C to 8°C (36°F to 46°F) for up to 36 months or at room temperature (≤25°C [≤77°F]) for up to 24 months; do not return vial to refrigerator after it has been stored at room temperature. Keep in original carton to protect from light.Flebogamma DIF: Store at 2°C to 25°C (36°F to 77°F). Keep in original carton to protect from light.GamaSTAN: Store at 2°C to 8°C (36°F to 46°F).GamaSTAN S/D [Canadian product]: Store under refrigeration at 2°C to 8°C (36°F to 46°F).Gammagard Liquid: Prior to use, may store at 2°C to 8°C (36°F to 46°F) for up to 36 months or at ≤ 25°C (≤77°F) for up to 24 months.Gammagard S/D: Store at ≤25°C (≤77°F) for up to 24 months. May store diluted solution under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 24 hours if originally prepared in a sterile laminar air flow environment.Gammaked: Store at 2°C to 8°C (36°F to 46°F); may be stored at ≤25°C (≤77°F) for up to 6 months.Gammaplex: Store at 2°C to 25°C (36°F to 77°F). Keep in original carton to protect from light.Gamunex-C: Store at 2°C to 8°C (36°F to 46°F) for up to 36 months from the date of manufacture; within this time, may store for up to 6 months at ≤25°C (≤77°F); after storage at ≤25°C (≤77°F) the product must be used or discarded. Protect from light.Hizentra: Store at ≤25°C (≤77°F). Keep in original carton to protect from light.HyQvia: Store at 2°C to 8°C (36°F to 46°F) for up to 36 months; may store at ≤25°C (≤77°F) for up to 3 months during the first 24 months from the date of manufacture (after 3 months at room temperature, discard); do not return vial to refrigerator after it has been stored at room temperature.Octagam 5%: Store at 2°C to 8°C (36°F to 46°F) for 36 months from the date of manufacture; within the first 24 months, may store at ≤25°C (≤77°F); after storage at ≤25°C (≤77°F), the product must be used or discarded.Octagam 10%: Store at 2°C to 8°C (36°F to 46°F) for 24 months from the date of manufacture; within these first 12 months, may store up to 9 months at ≤25°C (77°F); after storage at ≤25°C (77°F), the product must be used or discarded.Panzyga: Store at 2°C to 8°C (36°F to 46°F) for up to 36 months from the date of manufacture; within this time, may store up to 12 months at ≤25°C (≤77°F); after storage at ≤25°C (≤77°F) the product must be used or discarded. Protect from light.Privigen: Store at ≤25°C (≤77°F). Protect from light.Xembify: Store at 2°C to 8°C (36°F to 46°F); may be stored at ≤25°C (≤77°F) for up to 6 months; after storage at ≤25°C (≤77°F) the product must be used or discarded. Administer within 8 hours after beginning infusion preparation (ie, once transferred from the vial into a syringe).UseTreatment of primary humoral immunodeficiency syndromes (may include but not limited to: Congenital agammaglobulinemia, severe combined immunodeficiency syndromes [SCIDS], common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome); acute and chronic immune thrombocytopenia (ITP); chronic inflammatory demyelinating polyneuropathy (CIDP); and multifocal motor neuropathy. Prevention of coronary artery aneurysms associated with Kawasaki syndrome (in combination with aspirin).Adjunctive treatment of bacterial infection in patients with hypogammaglobulinemia and/or recurrent bacterial infections with B-cell chronic lymphocytic leukemia (CLL); and serious infection in immunoglobulin deficiency (select agammaglobulinemias).To provide passive immunity for prophylaxis in the following susceptible individuals: Hepatitis A (preexposure and postexposure [within 14 days and prior to manifestation of disease]); measles (postexposure [within 6 days] in an unvaccinated or nonimmune person); rubella (postexposure during early pregnancy); and varicella zoster (immunosuppressed patients when varicella zoster immune globulin is unavailable).See table for product specific indications, FDA approved age ranges, and routes of administration.ProductIndicationFDA Approval AgesRoute(s)AscenivPrimary immunodeficiency (treatment)≥12 years and adultsIntravenousBivigamPrimary immunodeficiency (treatment)≥6 years and adultsIntravenousCarimune NFPrimary immunodeficiency (treatment)Pediatric patients (age not specified) and adultsIntravenousAcute and chronic ITP (treatment)CutaquigPrimary immunodeficiency (treatment)≥2 years and adultsSubcutaneousCuvitruPrimary immunodeficiency (treatment)≥2 years and adultsSubcutaneousFlebogamma 5% DIFPrimary immunodeficiency (treatment)≥2 years and adultsIntravenousFlebogamma 10% DIFPrimary immunodeficiency (treatment)AdultsIntravenousChronic ITP (treatment)≥2 years and adultsGamaSTANPassive immunity - Hepatitis AAdultsIntramuscularPassive immunity - MeaslesPediatric patients (age not specified) and adultsPassive immunity - RubellaAdultsPassive immunity - VaricellaAdultsGammagard LiquidPrimary immunodeficiency (treatment)≥2 years and adultsIntravenous, SubcutaneousMultifocal motor neuropathy (MMN)AdultsIntravenousGammagard S/DPrimary immunodeficiency (treatment)≥2 years and adultsIntravenousB-cell chronic lymphocytic leukemia (CLL)AdultsChronic ITP (treatment)AdultsKawasaki syndromePediatric patients (age not specified)GammakedPrimary immunodeficiency (treatment)≥2 years and adultsIntravenous, SubcutaneousAcute and chronic ITP (treatment)Pediatric patients (age not specified) and adultsIntravenousChronic inflammatory demyelinating polyneuropathy (CIDP)AdultsIntravenousGammaplex 5%Primary immunodeficiency (treatment)≥2 years and adultsIntravenousChronic ITP (treatment)AdultsGammaplex 10%Primary immunodeficiency (treatment)≥2 years and adultsIntravenousChronic ITP (treatment)AdultsGamunex-CPrimary immunodeficiency (treatment)≥2 years and adultsIntravenous, SubcutaneousAcute and chronic ITP (treatment)Pediatric patients (age not specified) and adultsIntravenousChronic inflammatory demyelinating polyneuropathy (CIDP)AdultsIntravenousHizentraPrimary immunodeficiency (treatment)≥2 years and adultsSubcutaneousChronic inflammatory demyelinating polyneuropathy (CIDP)AdultsSubcutaneousHyQviaPrimary immunodeficiency (treatment), in conjunction with recombinant human hyaluronidaseAdultsSubcutaneousOctagam 5%Primary immunodeficiency (treatment)6 to 16 years and adultsIntravenousOctagam 10%Chronic ITP (treatment)AdultsIntravenousPanzygaPrimary immunodeficiency (treatment)≥2 years and adultsIntravenousChronic ITP (treatment)AdultsIntravenousPrivigenPrimary immunodeficiency (treatment)≥3 years and adultsIntravenousChronic ITP (treatment)≥15 years and adultsChronic inflammatory demyelinating polyneuropathy (CIDP)AdultsXembifyPrimary immunodeficiency (treatment)≥2 years and adultsSubcutaneousHas also been used for acute disseminated encephalomyelitis (ADEM), acute myocarditis, chronic Clostridioides difficile colitis, Guillain-Barré syndrome, hematopoietic stem cell transplantation with hypogammaglobulinemia, isoimmune hemolytic disease (Rh-incompatibility), multiple sclerosis, multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, myasthenia gravis, neonatal sepsis, pediatric HIV infection and associated thrombocytopenia, refractory dermatomyositis, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and refractory polymyositis.Medication Safety IssuesSound-alike/look-alike issues: Gamimune N may be confused with CytoGamImmune globulin (intravenous) may be confused with hepatitis B immune globulinPrivigen (immune globulin) may be confused with Albuminar-25 (albumin) due to similar packaging Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse effects are reported as class effects rather than for specific products in adult and pediatric patients.>10%:Cardiovascular: Chest pain, decreased heart rate, hypertension, hypotension, increased heart rate, tachycardiaDermatologic: Dermatitis, ecchymoses, injection site pruritusGastrointestinal: Abdominal pain, diarrhea, nausea, upper abdominal pain, viral gastroenteritis, vomitingHematologic & oncologic: Anemia, hemolysis, positive direct Coombs testHepatic: Increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum bilirubin (increased direct serum bilirubin or increased indirect serum bilirubin)Immunologic: Antibody developmentLocal: Bruising at injection site, erythema at injection site, injection site nodule, irritation at injection site, pain at injection site, swelling at injection siteNervous system: Chills, dizziness, fatigue, headache, increased body temperature, pain, rigorsNeuromuscular and skeletal: Asthenia, back pain, limb pain, myalgiaRespiratory: Asthma, bronchitis, cough, epistaxis, nasal congestion, nasopharyngitis, pharyngitis, rhinitis, sinusitis (including acute sinusitis), upper respiratory tract infection, wheezingMiscellaneous: Fever1% to 10%:Cardiovascular: Chest discomfort, flushing, heart murmur, peripheral edemaDermatologic: Allergic dermatitis, eczema, erythema of skin, hyperhidrosis, pruritus, skin rash, urticaria, xerodermaEndocrine & metabolic: Dehydration, increased lactate dehydrogenase, thyroiditisGastrointestinal: Abdominal distention, aphthous stomatitis, dyspepsia, flatulence, gastritis, stomach discomfortGenitourinary: Cystitis, dysuria, urinary tract infectionHematologic & oncologic: Bruise, hematoma, hemolytic anemia, leukopenia, neutropeniaHepatic: Increased serum aspartate aminotransferaseHypersensitivity: Hypersensitivity reactionInfection: Influenza, viral infectionLocal: Induration at injection site, inflammation at injection siteNervous system: Depression, falling, fibromyalgia syndrome (exacerbation), hypertonia, lethargy, malaise, migraine, myasthenia, sensation of cold, vertigoNeuromuscular & skeletal: Arthralgia, joint effusion, joint swelling, muscle spasm, musculoskeletal pain, neck painOtic: OtalgiaRespiratory: Dyspnea, flu-like symptoms, oropharyngeal pain, pharyngolaryngeal pain, pneumonia, viral upper respiratory tract infection<1%:Cardiovascular: Transient ischemic attacksGastrointestinal: AnorexiaInfection: Subcutaneous abscessNervous system: Anxiety, aseptic meningitis, chronic inflammatory demyelinating polyneuropathy (exacerbation)Renal: NephrolithiasisFrequency not defined:Cardiovascular: Facial flushing, thrombosisDermatologic: Cellulitis, diaphoresis, localized erythema, papule of skin, urticaria at injection siteGenitourinary: Proximal tubular nephropathyHematologic & oncologic: Exacerbation of autoimmune pure red cell aplasia, hyperproteinemia, increased serum immunoglobulins (hyperviscosity), local hemorrhageLocal: Hematoma at injection site, local irritation, residual mass at injection siteNervous system: DrowsinessNeuromuscular & skeletal: Lower limb crampOphthalmic: Blurred visionRenal: Increased blood urea nitrogen, increased serum creatinine, renal tubular necrosisRespiratory: Bronchopneumonia, non-cardiogenic pulmonary edemaPostmarketing:Cardiovascular: Acute myocardial infarction, angina pectoris, arterial thrombosis, bradycardia, cerebrovascular accident, circulatory shock, deep vein thrombosis, edema, facial edema, hot and cold flashes, oxygen saturation decreased, palpitations, peripheral vascular insufficiency, phlebitis, pulmonary embolism, syncope, thromboembolism, thrombophlebitis, venous thrombosis (retinal vein thrombosis)Dermatologic: Alopecia, bullous dermatitis, epidermolysis, erythema multiforme, erythematous rash, exfoliation of skin, pallor, rash at injection site, skin discoloration, skin ulceration at injection site, Stevens-Johnson syndromeEndocrine & metabolic: Decreased haptoglobins, hypervolemia, hyponatremia (Daphnis 2007; Nguyen 2006; Steinberger 2003), pseudohyponatremia (Daphnis 2007; Nguyen 2006; Steinberger 2003), translocational hyponatremia (Daphnis 2007; Nguyen 2006; Steinberger 2003)Gastrointestinal: Oral paresthesiaGenitourinary: Hematuria, hemoglobinuria, osmotic nephrosis, urine discolorationHematologic & oncologic: Acute intravascular hemolysis, decreased neutrophils, disseminated intravascular coagulation, increased hemoglobin, lymphadenopathy, pancytopenia, thrombocytopeniaHepatic: Hepatic insufficiency, hepatitis (noninfectious)Hypersensitivity: Anaphylactic shock, anaphylaxis, angioedema, nonimmune anaphylaxisLocal: Tissue necrosis at injection site, warm sensation at injection siteNervous system: Agitation, burning sensation, coma, confusion, hypoesthesia, loss of consciousness, nervousness, paresthesia, restlessness, seizure, speech disturbance, voice disorderNeuromuscular & skeletal: Laryngospasm, muscle rigidity, polymyositis, tremorOphthalmic: Eye pain, photophobia, visual disturbanceRenal: Acute kidney injury, renal failure syndrome, renal insufficiency, renal painRespiratory: Acute respiratory distress syndrome, apnea, bronchospasm, cyanosis, hyperventilation, hypoxemia, hypoxia, pharyngeal edema, pulmonary edema, respiratory failure, transfusion-related acute lung injuryContraindicationsHypersensitivity to immune globulin or any component of the formulation; IgA deficiency (with anti-IgA antibodies and history of hypersensitivity [excluding Gammagard S/D]); hyperprolinemia (Hizentra, Privigen); hypersensitivity to corn (Octagam 5%); hereditary intolerance to fructose (Gammaplex 5%); infants/neonates for whom sucrose or fructose tolerance has not been established (Gammaplex 5%); hypersensitivity to hyaluronidase, human albumin, or any component of the hyaluronidase formulation (HyQvia).Canadian labeling: Additional contraindications (not in US labeling): GamaSTAN S/D: Severe thrombocytopenia or coagulation disorders where IM injections are contraindicated.Documentation of allergenic cross-reactivity for immune globulins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Anaphylaxis/hypersensitivity reactions: Hypersensitivity and anaphylactic reactions can occur (some severe); patients with known antibodies to IgA are at greater risk; a severe fall in blood pressure may rarely occur with anaphylactic reaction; discontinue therapy and institute immediate treatment (including epinephrine 1 mg/mL) should be available.• Aseptic meningitis: Aseptic meningitis syndrome (AMS) has been reported with immune globulin administration; may occur with high doses (≥1 g/kg) and/or rapid infusion. Syndrome usually appears within several hours to 2 days following treatment; usually resolves within several days after product is discontinued. Female patients or patients with a migraine history may be at higher risk for AMS.• Hematoma: Do not administer subcutaneously for the treatment of immune thrombocytopenia because of the risk of hematoma formation.• Hemolysis: Intravenous immune globulin has been associated with antiglobulin hemolysis (acute or delayed). Cases of hemolysis-related renal impairment/failure or disseminated intravascular coagulation have been reported. Risk factors associated with hemolysis include high doses (≥2 g/kg) given either as a single administration or divided over several days, underlying associated inflammatory conditions, and non-O blood type (FDA 2012). An underlying inflammatory state (eg, elevated C-reactive protein or erythrocyte sedimentation rate) may also increase the risk. Closely monitor patients for signs of hemolytic anemia, particularly in patients with preexisting anemia and/or cardiovascular or pulmonary compromise.• Hereditary fructose intolerance: Immune globulin may contain sorbitol. The presence of sorbitol presents a risk to those with hereditary fructose intolerance (HFI). The incidence of HFI is estimated at 1 in 20,000 births and is usually diagnosed at the time of weaning when fructose or sucrose is introduced into the diet. Clinical symptoms include recurrent vomiting, abdominal pain, and hypoglycemia. Immune globulin containing sorbitol must not be administered to patients with HFI.• Hyperproteinemia: Hyperproteinemia, increased serum viscosity, and hyponatremia may occur; distinguish hyponatremia from pseudohyponatremia to prevent volume depletion, a further increase in serum viscosity and a higher risk of thrombotic events.• Hypertension: Elevations of blood pressure (systolic ≥180 mm Hg and/or diastolic >120 mm Hg) have been observed during and/or shortly following infusion of Panzyga and Privigen, which resolved with either observation or changes in oral antihypertensive therapy.• Infusion reactions: Patients should be monitored for adverse events during and after the infusion. Stop administration with signs of infusion reaction (fever, chills, nausea, vomiting, and rarely shock). Risk may be increased with initial treatment, when switching brands of immune globulin, and with treatment interruptions of >8 weeks.• Pulmonary edema: Monitor for transfusion-related acute lung injury (TRALI); noncardiogenic pulmonary edema has been reported with immune globulin use. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, and fever in the presence of normal left ventricular function. Usually occurs within 1 to 6 hours after infusion.• Renal dysfunction and acute renal failure: [US Boxed Warning]: IV administration only: Acute renal dysfunction (increased serum creatinine, oliguria, acute renal failure, osmotic nephrosis) can rarely occur and has been associated with fatalities in predisposed patients. Patients predisposed to renal dysfunction include elderly patients, patients with renal disease, diabetes mellitus, hypovolemia, volume depletion, sepsis, paraproteinemia, and nephrotoxic medications due to risk of renal dysfunction. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. (Note: The following IV products do not contain sucrose: Asceniv, Bivigam, Flebogamma DIF, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam 5%, Octagam 10%, Panzyga, and Privigen). In patients at risk of renal dysfunction or acute renal failure, ensure adequate hydration prior to administration; the dose, rate of infusion, and concentration of solution should be minimized. Assess renal function prior to treatment and periodically thereafter. Discontinue if renal function deteriorates.• Thromboembolic events: [US Boxed Warning]: Thrombosis may occur with immune globulin products even in the absence of risk factors for thrombosis. For patients at risk of thrombosis (eg, advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors), administer at the minimum dose and infusion rate practicable. Ensure adequate hydration before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity, such as those with cryoglobulins, fasting chylomicronemia/severe hypertriglyceridemia, or monoclonal gammopathies.Disease-related concerns:• Fluid overload: High-dose regimens (1 g/kg for 1 to 2 days) are not recommended for individuals with fluid overload or where fluid volume may be of concern.• IgA deficiency: Increased risk of hypersensitivity, especially in patients with anti-IgA antibodies; use is contraindicated in patients with IgA deficiency (with antibodies against IgA and history of hypersensitivity) or isolated IgA deficiency (GamaSTAN S/D [Canadian product]).• Renal impairment: Use with caution; ensure adequate hydration prior to administration; the rate of infusion and concentration of solution should be minimized.Special populations:• Older adult: Use with caution in elderly patients; may be at increased risk for renal dysfunction/failure and thromboembolic events.Dosage form specific issues:• Human plasma: Product of human plasma; may potentially contain infectious agents (eg, viruses, the variant Creutzfeldt Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt Jakob disease [CJD] agent) that could transmit disease, including unknown or emerging viruses and other pathogens. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.• L-proline: Hizentra and Privigen contain the stabilizer L-proline and are contraindicated in patients with hyperprolinemia.• Maltose: Some products may contain maltose, which may result in falsely elevated blood glucose readings. Maltose-containing products may be contraindicated with patients with corn allergy.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.• Skin testing: Skin testing should not be performed with GamaSTAN or GamaSTAN S/D [Canadian product] as local irritation can occur and be misinterpreted as a positive reaction.• Sodium: Some products may contain sodium.• Sorbitol: Some products may contain sorbitol; do not use immune globulin in patients with hereditary fructose intolerance.• Sucrose: Some products may contain sucrose.Other warnings/precautions:• Administration: Do not infuse into or around an infected area due to the risk of spreading a localized infection.• High-dose regimen: Consider risk versus benefit for high-dose regimen in patients with increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programEfgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapyEstrogen Derivatives: May enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapyRavulizumab: Immune Globulin may decrease the serum concentration of Ravulizumab.Management: Administer a supplemental dose of ravulizumab (600 mg) within 4 hours of completion of the immune globulin cycle. Risk D: Consider therapy modificationVaccines (Live): Immune Globulins may diminish the therapeutic effect of Vaccines (Live).Management: Live organism vaccination should be withheld for as long as 6 to 11 months following immune globulin administration. Recommendations vary by product and immune globulin dose, see full monograph for details. Risk D: Consider therapy modificationDietary ConsiderationsSome products may contain sodium.Pregnancy ConsiderationsPlacental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009). In a study of two women treated with IV immune globulin (IVIG) for common variable immunodeficiency, exogenous immune globulin was shown to cross the placenta similar to endogenous immune globulin (Palmeira 2012).IV immune globulin has been recommended for use in fetal-neonatal alloimmune thrombocytopenia and pregnancy-associated immune thrombocytopenia (ITP) (ACOG 207 2019; Anderson 2007; Neunert 2011); use is appropriate for ITP in cases refractory to corticosteroids, when side effects to corticosteroids are significant, or when a rapid increase in platelets is needed (ACOG 207 2019). Intravenous immune globulin is recommended to prevent measles in nonimmune women exposed during pregnancy (CDC 2013). May also be used in postexposure prophylaxis for rubella to reduce the risk of infection and fetal damage in exposed pregnant females who will not consider therapeutic abortion (per GamaSTAN product labeling; use for postexposure rubella prophylaxis is not currently recommended [CDC 2013]). IV immune globulin may be used when a prompt response for the treatment of myasthenia gravis is needed during pregnancy (Sanders 2016).HyQvia: Data collection to monitor pregnancy and infant outcomes following exposure to HyQvia is ongoing. Patients may enroll themselves in the HyQvia pregnancy registry by calling (866) 424-6724.Monitoring ParametersRenal function (prior to initial infusion and at appropriate intervals), urine output, IgG concentrations, hemoglobin and hematocrit, platelets (in patients with ITP); infusion- or injection-related adverse reactions, anaphylaxis, signs and symptoms of hemolysis; blood viscosity (in patients at risk for hyperviscosity); presence of antineutrophil antibodies (if TRALI is suspected); volume status; neurologic symptoms (if aseptic meningitis syndrome suspected); pulmonary adverse reactions; clinical response (as defined by disease state); monitor for fluid overload in patients with cardiac dysfunction being treated for multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 (ACR [Henderson 2022]; NIH 2022).For patients at high risk of hemolysis (dose ≥2,000 mg/kg, given as a single dose or divided over several days, and non-O blood type): Hemoglobin or hematocrit prior to and 36 to 96 hours postinfusion.SubQ infusion: Primary immunodeficiency: Monitor IgG trough levels every 2 to 3 months before/after conversion from IV; subcutaneous infusions provide more constant IgG levels than usual IV immune globulin treatments.Mechanism of ActionReplacement therapy for primary and secondary immunodeficiencies, and IgG antibodies against bacteria, viral, parasitic and mycoplasma antigens; interference with Fc receptors on the cells of the reticuloendothelial system for autoimmune cytopenias and ITP; provides passive immunity by increasing the antibody titer and antigen-antibody reaction potential Pharmaco*kinetics (Adult data unless noted)Onset of action: IV: Provides immediate antibody levels.Immune thrombocytopenia: Initial response: 1 to 3 days; Peak response: 2 to 7 days (Neunert 2011).Duration: IM, IV: Immune effect: 3 to 4 weeks (variable).Distribution: Vd: 0.05 to 0.13 L/kg.Intravascular portion (primarily): Healthy subjects: 41% to 57%; Patients with congenital humoral immunodeficiencies: ~70%.Half-life elimination: IM: ~23 days; SUBQ: ~59 days (HyQvia); IV: IgG (variable among patients): Healthy subjects: 14 to 24 days; Patients with congenital humoral immunodeficiencies: 26 to 40 days; hypermetabolism associated with fever and infection have coincided with a shortened half-life.Time to peak:Plasma: SUBQ: Cutaquig: ~2 days; Cuvitru: ~4.4 days; Gammagard Liquid: 2.9 days; Hizentra: 2.9 days; HyQvia: ~5 days; Xembify: ~3 days.Serum: IM: ~48 hours.Additional InformationIM: When administering immune globulin for hepatitis A prophylaxis, use should be considered for the following close contacts of persons with confirmed hepatitis A: Unvaccinated household and sexual contacts, persons who have shared illicit drugs, regular babysitters, staff and attendees of child care centers, food handlers within the same establishment (CDC 2006).DIF: Dual inactivation plus nanofiltration.NF: Nanofiltered.S/D: Solvent detergent treated.Octagam contains sodium 30 mmol/L.IgA content:Asceniv: ≤200 mcg/mL.Bivigam: ≤200 mcg/mL.Carimune NF: Manufacturer's labeling: Trace amounts; others have reported 1,000 to 2,000 mcg/mL in a 6% solution (Siegel 2011).Cutaquig: ≤600 mcg/mL.Cuvitru: Average 80 mcg/mL.Flebogamma 5% DIF: <50 mcg/mL.Flebogamma 10% DIF: <100 mcg/mL.GamaSTAN: Not specified.Gammagard Liquid: Average 37 mcg/mL.Gammagard S/D 5% solution: <1 mcg/mL (see Note).Gammaked: Average 46 mcg/mL.Gammaplex 5%: <10 mcg/mL.Gammaplex 10%: <20 mcg/mL.Gamunex-C: Average 46 mcg/mL.Hizentra: ≤50 mcg/mL.HyQvia: Average 37 mcg/mL.Octagam 5%: ≤200 mcg/mL.Octagam 10%: Average 106 mcg/mL.Panzyga 10%: Average 100 mcg/mL.Privigen: ≤25 mcg/mL.Xembify: Not specified.Note: Manufacturer has discontinued Gammagard S/D 5% solution; however, the lower IgA product may be available by special request for patients with known reaction to IgA or IgA deficiency with antibodies.Pricing: USKit (Hyqvia Subcutaneous)2.5 g/25 mL (per mL): $25.385 gm/50 mL (per mL): $25.3810 g/100 mL (per mL): $25.3820 g/200 mL (per mL): $25.3830 g/300 mL (per mL): $25.38Solution (Asceniv Intravenous)5 gm/50 mL (per mL): $111.26Solution (Bivigam Intravenous)5 gm/50 mL (per mL): $16.5210 g/100 mL (per mL): $16.52Solution (Cutaquig Subcutaneous)1GM/6ML (per mL): $38.871.65 g/10 mL (per mL): $38.482GM/12ML (per mL): $38.873.3 g/20 mL (per mL): $38.484GM/24ML (per mL): $38.878GM/48ML (per mL): $38.87Solution (Cuvitru Subcutaneous)1 g/5 mL (per mL): $48.402 g/10 mL (per mL): $48.404 g/20 mL (per mL): $48.408 g/40mL (per mL): $48.4010 gm/50 mL (per mL): $48.40Solution (Flebogamma DIF Intravenous)0.5 g/10 mL (per mL): $6.352.5 gm/50 mL (per mL): $6.355 g/100 mL (per mL): $6.355 gm/50 mL (per mL): $12.7110 g/100 mL (per mL): $12.7110 g/200 mL (per mL): $6.3520 g/200 mL (per mL): $12.7120 g/400 mL (per mL): $6.35Solution (Gammagard Injection)1 g/10 mL (per mL): $18.632.5 g/25 mL (per mL): $18.635 gm/50 mL (per mL): $18.6310 g/100 mL (per mL): $18.6320 g/200 mL (per mL): $18.6330 g/300 mL (per mL): $18.63Solution (Gammaked Injection)1 g/10 mL (per mL): $20.955 gm/50 mL (per mL): $20.9410 g/100 mL (per mL): $20.9420 g/200 mL (per mL): $20.94Solution (Gammaplex Intravenous)5 g/100 mL (per mL): $11.855 gm/50 mL (per mL): $23.7010 g/100 mL (per mL): $23.7010 g/200 mL (per mL): $11.8520 g/200 mL (per mL): $23.7020 g/400 mL (per mL): $11.85Solution (Gamunex-C Injection)1 g/10 mL (per mL): $16.412.5 g/25 mL (per mL): $16.415 gm/50 mL (per mL): $16.4110 g/100 mL (per mL): $16.4120 g/200 mL (per mL): $16.4140 g/400 mL (per mL): $16.41Solution (Hizentra Subcutaneous)1 g/5 mL (per mL): $49.492 g/10 mL (per mL): $49.494 g/20 mL (per mL): $49.4910 gm/50 mL (per mL): $49.49Solution (Octagam Intravenous)1 g/20 mL (per mL): $10.782 g/20 mL (per mL): $21.552.5 gm/50 mL (per mL): $10.785 g/100 mL (per mL): $10.785 gm/50 mL (per mL): $21.5510 g/100 mL (per mL): $21.5510 g/200 mL (per mL): $10.7820 g/200 mL (per mL): $21.5530 g/300 mL (per mL): $21.55Solution (Panzyga Intravenous)1 g/10 mL (per mL): $23.862.5 g/25 mL (per mL): $23.865 gm/50 mL (per mL): $23.8610 g/100 mL (per mL): $23.8620 g/200 mL (per mL): $23.8630 g/300 mL (per mL): $23.86Solution (Privigen Intravenous)5 gm/50 mL (per mL): $19.5110 g/100 mL (per mL): $19.5120 g/200 mL (per mL): $19.5140 g/400 mL (per mL): $19.51Solution (Xembify Subcutaneous)1 g/5 mL (per mL): $42.292 g/10 mL (per mL): $42.294 g/20 mL (per mL): $42.2910 gm/50 mL (per mL): $42.29Solution (reconstituted) (Gammagard S/D Less IgA Intravenous)5 g (per each): $1,244.0410 g (per each): $2,488.08Solution Prefilled Syringe (Hizentra Subcutaneous)1 g/5 mL (per mL): $49.492 g/10 mL (per mL): $49.494 g/20 mL (per mL): $49.49Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAllerglobuline (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Aragam (GB);Aunativ (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Beriglobin (AE, AT, BH, CH, CY, DE, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SE, SY, YE);Beriglobin P (AR);Beriglobina (BR, ES);Beriglobina P (CL);Endobulin (CZ, FI);Flebogamma (HK, IL, MY, SG, TH);Gamastan (HK);Gamastan Immune Globulin (IL);Gamimune (QA);Gamma 16 (IL);Gamma I.V. (IN, PH);Gammagard (BG, DK, ES, FR, GB, HN, IT, NL, PL, SE);Gammagard S/D (HK, IL, SA);Gammanorm (AE, FR, GB);Gammaplex (GB);Gammonativ (AE, BH, CY, DE, DK, EG, IQ, IR, JO, KW, LB, LY, NO, OM, QA, SA, SE, SY, YE);Gamunex (AE, CY, ID, IL);Gamunex C (SG);Gamunex-C (HK, MY, TH);Globuman Berna (PH);Hizentra (AR, AT, AU, BE, BR, CH, CZ, DE, DK, EC, EE, ES, FI, FR, GB, GR, HK, HR, HU, IE, JP, KR, LB, LT, LU, LV, NL, NO, NZ, PE, PL, PT, RO, SE, TR);Humaglobin (VN);Humoglob (PH);I.V.-Globulin SN (PH);IG Gamma (IL);IG Vena (HK, PH);Ig Vena NIV (ID);Immunorel (PH);Intragam P (AU, HK, ID);Intraglobin (CH, DE, IT);Intraglobin F (IL);Intratect (GB, HK, ID);IV Globulin-S (KR);Kiovig (AT, AU, BE, BG, CH, CZ, DE, DK, EE, FI, FR, GB, GR, HK, HN, IE, IL, IT, MT, NL, NO, PL, PT, RU, SE, SK, TR);Klovig (TH);Octagam (AT, AU, BE, BG, BH, BR, CH, CO, CZ, DE, DK, EE, FI, FR, GB, GR, HR, ID, IN, LB, LT, MT, MX, NL, NO, NZ, PH, PL, RO, SA, SE, SI, SK, TH, UY, VN);Panzyga (AT, AU, CZ, DK, ES, GB, HU, LT, LU, NO, PT, SK);Pentaglobin (AT, DE, SG, TH, VN);Privigen (IL, JP);Sandoglobulin (AE, BH, CZ, DK, EG, FI, GR, IL, LB, LK, NO, NZ, PK, QA);Sandoglobulina (CO, IT, PE);Subcuvia (FR, GB);Subgam (GB, IE);Tegeline (LB);Vena IG (LK);Vigam (TH)For country code abbreviations (show table)Abougergi MS and Kwon JH, "Intravenous Immunoglobulin for the Treatment of Clostridium difficile Infection: A Review," Dig Dis Sci, 2011, 56(1):19-26. [PubMed 20924675]Abraham D, Kalyanasundaram S, Krishnamurthy K. Refractory Kawasaki disease-a challenge for the pediatrician. SN Compr Clin Med. 2021;3(3):855-860. doi:10.1007/s42399-021-00775-w [PubMed 33532696]Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Amagai M, Ikeda S, Shimizu H, et al; Pemphigus Study Group. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009;60(4):595-603. doi:10.1016/j.jaad.2008.09.052 [PubMed 19293008]American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.American Academy of Pediatrics (AAP). In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2021 Report of the Committee on Infectious Diseases. 32nd ed. American Academy of Pediatrics; 2021.American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics. 2004;114(1):297-316. [PubMed 15231951]American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 207: thrombocytopenia in pregnancy. Obstet Gynecol. 2019;133(3):e181-e193. doi:10.1097/AOG.0000000000003100 [PubMed 30801473]Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. 2007;21(2)(suppl 1):s9-s56. [PubMed 17397769]Arnold DM. Immune thrombocytopenia (ITP) in adults: initial treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed October 5, 2021.Asceniv (immune globulin intravenous [human]) [prescribing information]. Boca Raton, FL: ADMA Biologics; April 2019.ASHP Commission on Therapeutics. ASHP Therapeutic Guidelines for Intravenous Immune Globulin. Am J Hosp Pharm. 1992;49(3):652-654. [PubMed 1598949]Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47(3):678-683. [PubMed 8797464]Ballow M, Shehata N. Overview of intravenous immune globulin (IVIG) therapy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed August 17, 2021.Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011;76(23):2017-2023. [PubMed 21562253]Based on expert opinion.Bassan H, Muhlbaur B, Tomer A, et al, "High-Dose Intravenous Immunoglobulin in Transient Neonatal Myasthenia Gravis," Pediatr Neurol, 1998, 18(2):181-3. [PubMed 9535308]Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(5 Suppl 1):S1-63. [PubMed 15945566]Bonilla FA, Khan DA, Ballas ZK, et al; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.e1-78. doi:10.1016/j.jaci.2015.04.049 [PubMed 26371839]Bivigam (immune globulin intravenous [human]) [prescribing information]. Boca Raton, FL: Biotest Pharmaceuticals Corporation; July 2019.Brennan J, Moore K, Sizemore L, et al. Notes from the field: acute hepatitis A virus infection among previously vaccinated persons with HIV infection - Tennessee, 2018. MMWR Morb Mortal Wkly Rep. 2019;68(14):328-329. doi:10.15585/mmwr.mm6814a3 [PubMed 30973852]British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574-596. doi:10.1046/j.1365-2141.2003.04131.x [PubMed 12588344]Brodsky RA. Warm autoimmune hemolytic anemia. N Engl J Med. 2019;381(7):647-654. doi:10.1056/NEJMcp1900554 [PubMed 31412178]Brugnara C, Brodsky RA. Warm autoimmune hemolytic anemia (AIHA) in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 25, 2022.Carimune (immune globulin intravenous [human]) [prescribing information]. Kankakee, IL: CSL Behring AG; November 2016.Carimune NF (immune globulin intravenous [human]) [prescribing information]. Kankakee, IL: CSL Behring LLC; May 2018.Cattalini M, Taddio A, Bracaglia C, et al. Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics. Ital J Pediatr. 2021;47(1):24. doi:10.1186/s13052-021-00980-2 [PubMed 33557873]Centers for Disease Control and Prevention (CDC). Control and prevention of rubella: evaluation and management of suspected outbreaks, rubella in pregnant women, and surveillance for congenital rubella syndrome. MMWR Recomm Rep. 2001;50(RR-12):1-23. [PubMed 11475328]Centers for Disease Control and Prevention (CDC). Hepatitis A Questions and Answers for Health Professionals. Updated October 2017. https://www.cdc.gov/hepatitis/hav/havfaq.htm. Accessed October 10, 2017.Centers for Disease Control and Prevention (CDC). Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1-23. http://www.cdc.gov/mmwr/PDF/rr/rr5507.pdf. [PubMed 16708058]Centers for Disease Control and Prevention (CDC). Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-04):1-34. [PubMed 23760231]Centers for Disease Control and Prevention (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm. [PubMed 6423951]Centers for Disease Control and Prevention (CDC). Updated dosing instructions for immune globulin (human) GamaSTAN S/D for hepatitis A virus prophylaxis. MMWR Morb Mortal Wkly Rep. 2017;66(36):959-960. [PubMed 28910270]Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices (ACIP). Update: prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2007;56(41):1080-1084. [PubMed 17947967]Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG. Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet. 1994;343(8905):1059-1063. [PubMed 7909099]Cherin P, Pelletier S, Teixeira A, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum. 2002;46(2):467-474. doi:10.1002/art.10053 [PubMed 11840450]Colvin MM, Cook JL, Chang P, et al; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiopulmonary Critical Care, Perioperative and Resuscitation; American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiovascular Disease in the Young; et al. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2015;131(18):1608-1639. [PubMed 25838326]Costanzo MR, Dipchand A, Starling R, et al; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914-956. doi:10.1016/j.healun.2010.05.034 [PubMed 20643330]Cutaquig (immune globulin subcutaneous human) [prescribing information]. Paramus, NJ: Octapharma USA Inc; October 2021.Cutaquig (immune globulin subcutaneous human) [prescribing information]. New York, NY: Pfizer Labs; November 2021.Cutaquig (immune globulin subcutaneous human) [product monograph]. Toronto, Ontario, Canada: Octapharma Canada Inc; June 2021.Cuvitru (immune globulin subcutaneous [human]) [prescribing information]. Lexington, MA: Baxalta US Inc; September 2021.Czernik A, Beutner EH, Bystryn JC. Intravenous immunoglobulin selectively decreases circulating autoantibodies in pemphigus. J Am Acad Dermatol. 2008;58(5):796-801. doi:10.1016/j.jaad.2008.01.007 [PubMed 18423257]Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. 1993;329(27):1993-2000. [PubMed 8247075]Danieli MG, Pettinari L, Moretti R, Logullo F, Gabrielli A. Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application. Autoimmun Rev. 2011;10(3):144-149. doi:10.1016/j.autrev.2010.09.004 [PubMed 20858553]Dantal J. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol. 2013;38(4):275-284. doi:10.1159/000354893 [PubMed 24051350]Daphnis E, Stylianou K, Alexandrakis M, et al. Acute renal failure, translocational hyponatremia and hyperkalemia following intravenous immunoglobulin therapy. Nephron Clin Pract. 2007;106(4):c143-c148. [PubMed 17596722]Darenberg J, Ihendyane N, Sjölin J, et al; StreptIg Study Group. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2003;37(3):333-340. doi:10.1086/376630 [PubMed 12884156]Djamali A, Brennan DC. Kidney transplantation in adults: prevention and treatment of antibody-mediated rejection of the renal allograft. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed February 24, 2021.Drucker NA, Colan SD, Lewis AB, et al, "Gamma-Globulin Treatment of Acute Myocarditis in the Pediatric Population," Circulation, 1994, 89(1):252-7. [PubMed 8281654]Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M; ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(suppl 6):vi50-vi54. doi:10.1093/annonc/mdr377 [PubMed 21908504]Eid AJ, Ardura MI; AST Infectious Diseases Community of Practice. Human parvovirus B19 in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13535. doi:10.1111/ctr.13535 [PubMed 30973192]El-Bayoumi MA, El-Refaey AM, Abdelkader AM, El-Assmy MM, Alwakeel AA, El-Tahan HM. Comparison of intravenous immunoglobulin and plasma exchange in treatment of mechanically ventilated children with Guillain Barré syndrome: a randomized study. Crit Care. 2011;15(4):R164. [PubMed 21745374]Elovaara I, Apostolski S, van Doorn P, et al; EFNS. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS Task Force on the Use of Intravenous Immunoglobulin in Treatment of Neurological Diseases. Eur J Neurol. 2008;15(9):893-908. [PubMed 18796075]English RF, Janosky JE, Ettedgui JA, et al, "Outcomes for Children With Acute Myocarditis," Cardiol Young, 2004, 14(5):488-93. [PubMed 15680069]FDA Safety Communication: updated information on the risks of thrombosis and hemolysis potentially related to administration of intravenous, subcutaneous and intramuscular human immune globulin products. November, 13, 2012. http://wayback.archive-it.org/7993/20170112095655/http:/www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm327934.htm.Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. 2007;21(2)(suppl 1):57-107. doi:10.1016/j.tmrv.2007.01.002 [PubMed 17397768]Flebogamma 5% DIF (immune globulin intravenous [human]) [prescribing information]. Barcelona, Spain: Instituto Grifols, SA; September 2019. [PubMed 23744661]Flebogamma 10% DIF (immune globulin intravenous [human]) [prescribing information]. Barcelona, Spain: Instituto Grifols; September 2019.Frickhofen N, Abkowitz JL, Safford M, et al. Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): a treatable cause of anemia in AIDS. Ann Intern Med. 1990;113(12):926-933. doi:10.7326/0003-4819-113-12-926 [PubMed 2173460]Gajdos P, Tranchant C, Clair B, et al; Myasthenia Gravis Clinical Study Group. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol. 2005;62(11):1689-1693. doi:10.1001/archneur.62.11.1689 [PubMed 16286541]Gale RP, Chapel HM, Bunch C, et al; Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med. 1988;319(14):902-907. doi:10.1056/NEJM198810063191403 [PubMed 2901668]GamaSTAN (immune globulin intramuscular [human]) [prescribing information]. Research Triangle Park, NC: Grifols Therapeutics Inc; February 2018.GamaSTAN S/D (immune globulin intramuscular [human]) [product monograph]. Mississauga, Ontario, Canada: Grifols Therapeutics Inc; February 2018.Gammagard Liquid (immune globulin intravenous and subcutaneous [human]) [prescribing information]. Lexington, MA: Baxalta US Inc; November 2020.Gammagard S/D (immune globulin intravenous [human]) [prescribing information]. Lexington, MA: Baxalta US Inc; March 2021.Gammagard S/D (immune globulin intravenous [human]) [product monograph]. Mississauga, Ontario: Baxalta Canada Corporation; December 2016.Gammaked (immune globulin intravenous and subcutaneous [human]) [prescribing information]. Research Triangle Park, NC: Grifols Therapeutics LLC; January 2020.Gammaplex 5% (immune globulin intravenous [human]) [prescribing information]. Durham, NC: BPL Inc; September 2019.Gammaplex 10% (immune globulin intravenous [human]) [prescribing information]. Durham, NC: BPL Inc; October 2019.Gamunex-C (immune globulin [human]) [prescribing information]. Research Triangle Park, NC: Grifols Therapeutics LLC; January 2020.Gamunex-C (immune globulin [human]) [prescribing information]. Research Triangle Park, NC: Grifols Therapeutics LLC; June 2018.Gershon AA, Piomelli S, Karpatkin M, Smithwick E, Steinberg S. Antibody to varicella-zoster virus after passive immunization against chickenpox. J Clin Microbiol. 1978;8(6):733-735. [PubMed 217893]Girish G, Chawla D, Agarwal R, et al, "Efficacy of Two Dose Regimes of Intravenous Immunoglobulin in Rh Hemolytic Disease of Newborn--a Randomized Controlled Trial," Indian Pediatr, 2008, 45(8):653-9. [PubMed 18723908]Gorelik M, Chung SA, Ardalan K, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of Kawasaki disease. Arthritis Care Res (Hoboken). 2022;74(4):538-548. doi:10.1002/acr.24838 [PubMed 35257507]Gottlieb F, Deutsch J. Red cell aplasia responsive to immunoglobulin therapy as initial manifestation of human immunodeficiency virus infection. Am J Med. 1992;92(3):331-333. doi:10.1016/0002-9343(92)90085-p [PubMed 1546732]Gottstein R, Cooke RW. Systematic Review of Intravenous Immunoglobulin in Haemolytic Disease of the Newborn. Arch Dis Child Fetal Neonatal Ed. 2003;88(1):F6-F10. [PubMed 12496219]Grindeland JW, Grindeland CJ, Moen C, Leedahl ND, Leedahl DD. Outcomes associated with standardized ideal body weight dosing of intravenous immune globulin in hospitalized patients: a multicenter study. Ann Pharmacother. 2020;54(3):205-212. doi:10.1177/1060028019880300 [PubMed 31578070]Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Front Immunol. 2018;9:1299. doi:10.3389/fimmu.2018.01299 [PubMed 29951056]Hachem RR, Yusen RD, Meyers BF, et al. Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation. J Heart Lung Transplant. 2010;29(9):973-980. doi:10.1016/j.healun.2010.05.006 [PubMed 20558084]Hahn AF, Bolton CF, Zochodne D, Feasby TE. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain. 1996;119(pt 4):1067-1077. doi:10.1093/brain/119.4.1067 [PubMed 8813271]Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398 [PubMed 29540348]Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology (ACR) clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: Version 3. Arthritis Rheumatol. Published online February 3, 2022. doi:10.1002/art.42062 [PubMed 35118829]Herzog S, Schmidt E, Goebeler M, Bröcker EB, Zillikens D. Serum levels of autoantibodies to desmoglein 3 in patients with therapy-resistant pemphigus vulgaris successfully treated with adjuvant intravenous immunoglobulins. Acta Derm Venereol. 2004;84(1):48-52. doi:10.1080/00015550310005861 [PubMed 15040478]HHS Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. December 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf.Hia CP, Yip WC, Tai BC, et al, "Immunosuppressive Therapy in Acute Myocarditis: An 18 Year Systematic Review," Arch Dis Child, 2004, 89(6):580-4. [PubMed 15155409]Hizentra (immune globulin) [prescribing information]. Kankakee, IL: CSL Behring LLC; April 2022.Hizentra (immune globulin) [product monograph]. Ottawa, Ontario, Canada: CSL Behring Canada, Inc; February 2020.Hodkinson JP. Considerations for dosing immunoglobulin in obese patients. Clin Exp Immunol. 2017;188(3):353-362. doi:10.1111/cei.12955 [PubMed 28263379]Hodkinson JP, Lucas M, Lee M, Harrison M, Lunn MP, Chapel H. Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients. Clin Exp Immunol. 2015;181(1):179-187. doi:10.1111/cei.12616 [PubMed 25731216]Hughes RA, Donofrio P, Bril V, et al; ICE Study Group. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 2008;7(2):136-144. doi:10.1016/S1474-4422(07)70329-0 [PubMed 18178525]HyQvia (immune globulin infusion 10% [human] with recombinant human hyaluronidase) [prescribing information]. Lexington, MA: Baxalta US Inc; March 2021.INIS Collaborative Group, Brocklehurst P, Farrell B, et al, "Treatment of Neonatal Sepsis With Intravenous Immune Globulin," N Engl J Med, 2011, 365(13):1201-11. [PubMed 21962214]Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia (CGSIGCLL). N Engl J Med. 1988;319(14):902-907. [PubMed 2901668]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-313. [PubMed 12534540]Jenson HB and Pollock BH, "Meta-Analyses of the Effectiveness of Intravenous Immune Globulin for Prevention and Treatment of Neonatal Sepsis," Pediatrics, 1997, 99(2):E2. [PubMed 9099759]Jordan JA. Treatment and prevention of parvovirus B19 infection. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed June 25, 2021.Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(suppl 3):S1-S155. doi:10.1111/j.1600-6143.2009.02834.x [PubMed 19845597]Klugman D, Berger JT, Sable CA, et al, "Pediatric Patients Hospitalized With Myocarditis: A Multi-institutional Analysis," Pediatr Cardiol, 2010, 31(2):222-8. [PubMed 19936586]Kobayashi T, Kobayashi T, Morikawa A, et al. Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease. J Pediatr. 2013;163(2):521-526. doi:10.1016/j.jpeds.2013.01.022 [PubMed 23485027]Koduri PR. Parvovirus B19-related anemia in HIV-infected patients. AIDS Patient Care STDS. 2000;14(1):7-11. doi:10.1089/108729100318082 [PubMed 12240888]Koduri PR, Kumapley R, Valladares J, Teter C. Chronic pure red cell aplasia caused by parvovirus B19 in AIDS: use of intravenous immunoglobulin--a report of eight patients. Am J Hematol. 1999;61(1):16-20. doi:10.1002/(sici)1096-8652(199905)61:1<16::aid-ajh4>3.0.co;2-y [PubMed 10331506]Koh MJ and Tay YK, "Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Asian Children," J Am Acad Dermatol, 2010, 62(1):54-60. [PubMed 19811851]Korinthenberg R, Schessl J, Kirschner J, Mönting JS. Intravenously administered immunoglobulin in the treatment of childhood Guillain-Barré syndrome: a randomized trial. Pediatrics. 2005;116(1):8-14. [PubMed 15995024]Lachiewicz AM, Srinivas ML. Varicella-zoster virus post-exposure management and prophylaxis: a review. Prev Med Rep. 2019;16:101016. doi:10.1016/j.pmedr.2019.101016 [PubMed 31890472]Lagasse C, Hatton RC, Pyles E. A survey of intravenous immune globulin (IVIG) dosing strategies. Ann Pharmacother. 2015;49(2):254-257. doi:10.1177/1060028014559095 [PubMed 25583939]Lange DJ, Robison-Papp J. Multifocal motor neuropathy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed January 25, 2022.Leung DY, Kelly CP, Boguniewicz M, et al, "Treatment With Intravenously Administered Gamma Globulin of Chronic Relapsing Colitis Induced by Clostridium difficile Toxin," J Pediatr, 1991, 118(4 Pt 1):633-7. [PubMed 1901084]Lewis RA, Ashok Muley S. Chronic inflammatory demyelinating polyneuropathy: treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed February 16, 2021.Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Marchioni E, Marinou-Aktipi K, Uggetti C, et al. Effectiveness of intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis. J Neurol. 2002;249(1):100-104. doi:10.1007/pl00007836 [PubMed 11954856]Marin M, Güris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1-40. [PubMed 17585291]McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki Disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927-e999. doi: 10.1161/CIR.0000000000000484. [PubMed 28356445]McFarland LV, Brandmarker SA, and Guandalini S, "Pediatric Clostridium difficile: A Phantom Menace or Clinical Reality?" J Pediatr Gastroenterol Nutr, 2000, 31(3):220-31. [PubMed 10997362]McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-04):1-34. [PubMed 23760231]Mendell JR, Barohn RJ, Freimer ML, et al; Working Group on Peripheral Neuropathy. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 2001;56(4):445-449. doi:10.1212/wnl.56.4.445 [PubMed 11222785]Miqdad AM, Abdelbasit OB, Shaheed MM, et al, "Intravenous Immunoglobulin G (IVIG) Therapy for Significant Hyperbilirubinemia in ABO Hemolytic Disease of the Newborn," J Matern Fetal Neonatal Med, 2004, 16(3):163-6. [PubMed 15590442]Morici MV, Galen WK, Shetty AK, et al, "Intravenous Immunoglobulin Therapy for Children With Stevens-Johnson Syndrome," J Rheumatol, 2000, 27(10):2494-7. [PubMed 11036849]Morrison VA. Prevention of infections in patients with chronic lymphocytic leukemia. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 25, 2022.Muchnik S, Losavio AS, Vidal A, Cura L, Mazia C. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve. 1997;20(6):674-678. doi:10.1002/(sici)1097-4598(199706)20:6<674::aid-mus3>3.0.co;2-5 [PubMed 9149073]Muley SA. Guillain-Barré syndrome in adults: treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed October 7, 2021.National Institutes of Health (NIH). COVID-19 Treatment Guidelines Panel. Therapeutic management of hospitalized pediatric patients with multisystem inflammatory syndrome in children (MIS-C) (with discussion on multisystem inflammatory syndrome in adults [MIS-A]). https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/hospitalized-pediatric-patients--therapeutic-management-of-mis-c/. Updated February 24, 2022. Accessed March 7, 2022.Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices, 2020. MMWR Recomm Rep. 2020;69(5):1-38. [PubMed 32614811]Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA; American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. [PubMed 21325604]Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866. doi:10.1182/bloodadvances.2019000966 [PubMed 31794604]Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324(23):1633-1639. doi:10.1056/NEJM199106063242305 [PubMed 1709446]Nguyen MK, Rastogi A, Kurtz I. True hyponatremia secondary to intravenous immunoglobulin. Clin Exp Nephrol. 2006;10(2):124-126. [PubMed 16791398]Nguyen TP, Nguyen TD, Zhu L, et al. Precision intravenous immunoglobulin dosing and clinical outcomes: a retrospective chart review. J Clin Neuromuscul Dis. 2021;23(1):18-23. doi:10.1097/CND.0000000000000359 [PubMed 34431797]NIH Consensus Conference. Intravenous immunoglobulin. Prevention and treatment of disease. JAMA. 1990;264(24):3189-3193. [PubMed 2255028]Octagam (immune globulin intravenous [human]) [prescribing information]. Hoboken, NJ: Octapharma USA Inc; October 2014.Octagam 5% (immune globulin intravenous [human]) [prescribing information]. Paramus, NJ: Octapharma USA Inc; April 2022.Octagam 5% (immune globulin intravenous [human]) [product monograph]. Toronto, Canada: Octapharma Canada Inc; November 2018.Octagam 10% (immune globulin intravenous [human]) [prescribing information]. Paramus, NJ: Octapharma USA Inc; June 2021.Octagam 10% (immune globulin intravenous [human]) [product monograph]. Toronto, Ontario, Canada: Octapharma Canada Inc; May 2022.Ohlsson A and Lacy J, "Intravenous Immunoglobulin for Suspected or Subsequently Proven Infection in Neonates," Cochrane Database Syst Rev, 2010, (3):CD001239. [PubMed 20238315]Orange JS. Immune globulin therapy in primary immunodeficiency. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed August 17, 2021.Pacheco LD, Berkowitz RL, Moise KJ Jr, Bussel JB, McFarland JG, Saade GR. Fetal and neonatal alloimmune thrombocytopenia: a management algorithm based on risk stratification. Obstet Gynecol. 2011;118(5):1157-1163. doi:10.1097/AOG.0b013e31823403f4 [PubMed 22015886]Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646. doi: 10.1155/2012/985646. [PubMed 22235228]Panzyga (immune globulin intravenous [human] - ifas) [prescribing information]. Paramus, NJ: Octapharma USA Inc; March 2021.Parks T, Wilson C, Curtis N, Norrby-Teglund A, Sriskandan S. Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: a systematic review and meta-analysis. Clin Infect Dis. 2018;67(9):1434-1436. doi:10.1093/cid/ciy401 [PubMed 29788397]Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012;78(13):1009-1015. [PubMed 22454268]Pecoraro A, Ricci S, Vultaggio A, Boggia GM, Spadaro G; SHIFT and IBIS Study Groups. Correlations among subcutaneous immunoglobulin dosage, immunoglobulin G serum pre-infusional levels and body mass index in primary antibody deficiency patients: a pooled analysis from the SHIFT/IBIS studies. Clin Drug Investig. 2020;40(3):279-286. doi:10.1007/s40261-020-00885-8 [PubMed 32036588]Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res B Dev Reprod Toxicol. 2009;86(4):328-344. doi: 10.1002/bdrb.20201. [PubMed 19626656]Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1-S46. doi:10.1016/j.jaci.2016.09.023 [PubMed 28041678]Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349(9047):225-230. [PubMed 9014908]Privigen (immune globulin intravenous [human]) [prescribing information]. Kankakee, IL: CSL Behring LLC; March 2022.Raphael JC, Chevret S, Harboun M, Jars-Guincestre MC; French Guillain-Barré Syndrome Cooperative Group. Intravenous immune globulins in patients with Guillain-Barré syndrome and contraindications to plasma exchange: 3 days versus 6 days. J Neurol Neurosurg Psychiatry. 2001;71(2):235-238. [PubMed 11459901]Refer to manufacturer's labeling.Rich MM, Teener JW, Bird SJ. Treatment of Lambert-Eaton syndrome with intravenous immunoglobulin. Muscle Nerve. 1997;20(5):614-615. doi:10.1002/(sici)1097-4598(199705)20:5<614::aid-mus13>3.0.co;2-w [PubMed 9140371]Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87(4):419-425. doi: 10.1212/WNL.0000000000002790. [PubMed 27358333]Sautenet B, Blancho G, Büchler M, et al. One-year results of the effects of rituximab on acute antibody-mediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation. 2016;100(2):391-399. doi:10.1097/TP.0000000000000958 [PubMed 26555944]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. [PubMed 7746084]Siegel J. IImmune globulins: therapeutic, pharmaceutical, cost and administration considerations. Pharmacy Practice News. 2011;20-27.Siegel J. Immunoglobulins and obesity. Pharmacy Practice News. 2010;37:1.Skeie GO, Apostolski S, Evoli A, et al; European Federation of Neurological Societies. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17(7):893-902. [PubMed 20402760]Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol. 2003;73(2):97-100. [PubMed 12749010]Stump SE, Schepers AJ, Jones AR, Alexander MD, Auten JJ. Comparison of weight-based dosing strategies for intravenous immunoglobulin in patients with hematologic malignancies. Pharmacotherapy. 2017;37(12):1530-1536. doi:10.1002/phar.2047 [PubMed 29028117]Sugunan S, Bindusha S, Geetha S, Niyas HR, Kumar AS. Clinical profile and short-term outcome of children with SARS-CoV-2 related multisystem inflammatory syndrome (MIS-C) treated with pulse methylprednisolone. Indian Pediatr. 2021;58(8):718-722. doi:10.1007/s13312-021-2277-4 [PubMed 33876782]Takemoto SK, Zeevi A, Feng S, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant. 2004;4(7):1033-1041. doi:10.1111/j.1600-6143.2004.00500.x [PubMed 15196059]Targoff IN. Treatment of recurrent and resistant dermatomyositis and polymyositis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed February 18, 2021.Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238. doi:10.1016/j.bbmt.2009.06.019 [PubMed 19747629]Tristani-Firouzi P, Petersen MJ, Saffle JR, et al, "Treatment of Toxic Epidermal Necrolysis With Intravenous Immunoglobulin in Children," J Am Acad Dermatol, 2002, 47(4):548-52. [PubMed 12271299]van Schaik IN, Bril V, van Geloven N, et al; PATH study group. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2018;17(1):35-46. doi:10.1016/S1474-4422(17)30378-2 [PubMed 29122523]van Schaik IN, Léger JM, Nobile-Orazio E, et al; Joint task force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision. J Peripher Nerv Syst. 2010;15(4):295-301. doi:10.1111/j.1529-8027.2010.00290.x [PubMed 21199100]Vleugels RA. Management of refractory cutaneous dermatomyositis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 24, 2022.Vo AA, Cam V, Toyoda M, Puliyanda DP, et al. Safety and adverse events profiles of intravenous gammaglobulin products used for immunomodulation: a single-center experience. Clin J Am Soc Nephrol. 2006;1(4):844-852. doi:10.2215/CJN.01701105 [PubMed 17699296]Waldman AT. Acute disseminated encephalomyelitis (ADEM) in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed March 29, 2021.Walgaard C, Jacobs BC, Lingsma HF, et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-283. doi:10.1016/S1474-4422(20)30494-4 [PubMed 33743237]Wasserman RL. Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases. Immunotherapy. 2017;9(12):1035-1050. doi:10.2217/imt-2017-0092 [PubMed 28871852]Watson JC, Hadler SC, Dykewicz CA, Reef S, Phillips L. Measles, mumps, and rubella--vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1998;47(RR-8):1-57. [PubMed 9639369]Weinberg DH. Lambert-Eaton myasthenic syndrome: treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed February 22, 2021.Wimperis J, Lunn M, Jones A, et al, National Health Service. Clinical Guidelines for the Use of Immunoglobulin Use: Second Edition Update, July 2011.Wingard JR. Prevention of infections in hematopoietic cell transplant recipients. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed June 25, 2021.Witt CA, Gaut JP, Yusen RD, et al. Acute antibody-mediated rejection after lung transplantation. J Heart Lung Transplant. 2013;32(10):1034-1040. doi:10.1016/j.healun.2013.07.004 [PubMed 23953920]World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the eleventh WHO model list of essential drugs. 2002. http://www.who.int/maternal_child_adolescent/documents/55732/en/. Accessed April 17, 2019.Xembify (immune globulin subcutaneous [human-klhw]) [prescribing information]. Research Triangle Park, NC: Grifols Therapeutics LLC; August 2020.Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007;68(11):837-841. [PubMed 17353471]Topic 83878 Version 386.0

CloseFentanyl: Pediatric drug informationFentanyl: Pediatric drug information(For additional information see "Fentanyl: Drug information" and see "Fentanyl: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningLife-threatening respiratory depression:Serious, life-threatening, or fatal respiratory depression has occurred with use of fentanyl, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of fentanyl or following a dose increase. The substitution of fentanyl buccal, intranasal, lozenge, or sublingual for any other fentanyl product may result in fatal overdose. Due to the risk of respiratory depression, fentanyl buccal, intranasal, lozenge, and sublingual are contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients; fentanyl transdermal is contraindicated for use as an as-needed analgesic, in nonopioid tolerant patients, in acute pain, and in postoperative pain. Only the patient should activate Ionsys dosing.Addiction, abuse, and misuse:Fentanyl exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing fentanyl, and monitor all patients regularly for the development of these behaviors and conditions.Accidental exposure:Accidental exposure of even one dose of fentanyl, especially by children, can result in a fatal overdose of fentanyl. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. Deaths due to a fatal overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal patch. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure. Fentanyl must be kept out of reach of children.Cytochrome P450 3A4 Interaction:The concomitant use of fentanyl with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl and any CYP3A4 inhibitor or inducer.Neonatal opioid withdrawal syndrome:Prolonged use of fentanyl during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.Risks from concomitant use with benzodiazepines or other CNS depressants:Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of fentanyl and benzodiazepine or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.Risk of medication errors (buccal, intranasal, lozenge, sublingual):Substantial differences exist in the pharmaco*kinetic profile of fentanyl buccal, intranasal, lozenge, and sublingual compared with other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose. When prescribing, do not convert patients on a mcg-per-mcg basis from any other fentanyl products to fentanyl buccal, intranasal, lozenge, or sublingual. When dispensing, do not substitute a fentanyl buccal, intranasal, lozenge, or sublingual prescription for other fentanyl products.REMS program:Buccal, intranasal, lozenge, sublingual: Because of the risk for misuse, abuse, addiction, and overdose, fentanyl buccal, intranasal, lozenge, and sublingual are available only through a restricted program required by the FDA, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program, outpatients, health care providers who prescribe to outpatients, pharmacies, and distributors must enroll in the program. Further information is available at http://www.TIRFREMSaccess.com or by calling 1-866-822-1483.Transdermal iontophoretic system (Ionsys): For use only in patients in the hospital. Discontinue treatment with before patients leave the hospital. Because of the risk of respiratory depression from accidental exposure, Ionsys is available through a restricted program called the Ionsys REMS Program. Healthcare facilities that dispense Ionsys must be certified in this program and comply with the REMS requirements.Transdermal (Duragesic): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.Exposure to heat (Duragesic only):Exposure of the fentanyl application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources.Brand Names: USAbstral [DSC];Actiq;Duragesic-100 [DSC];Duragesic-12 [DSC];Duragesic-25 [DSC];Duragesic-50 [DSC];Duragesic-75 [DSC];Fentora;Ionsys [DSC];Lazanda;SubsysBrand Names: CanadaFentaNYL Citrate SDZ;Fentora;MYLAN-FentaNYL Matrix [DSC];PMS-FentaNYL MTX;RAN-FentaNYL Matrix [DSC];SANDOZ FentaNYL;TEVA-FentaNYLTherapeutic CategoryAnalgesic, Opioid;General AnestheticDosing: NeonatalNote: Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance. Lower initial doses are recommended for nonventilated patients (Ref). Risk of chest wall rigidity is minimized when doses are administered over at least 1 to 2 minutes (Ref).Acute pain; opioid-naiveAcute pain; opioid-naive: Limited data available: Note: Lower initial doses are recommended for patients who are preterm, low birth weight, younger age, or nonventilated (Ref).Intermittent IV doses: Preterm and term neonates: IV: Initial: 1 to 3 mcg/kg/dose over at least 5 minutes; may repeat every 2 to 4 hours as needed (Ref).Continuous IV infusion: Note: Some experts recommend a loading dose of to achieve analgesic effects more rapidly (Ref).Preterm and term neonates: Loading dose (optional): 1 to 2 mcg/kg once over 5 to 30 minutes, followed by continuous IV infusion: 0.5 to 1 mcg/kg/hour; titrate to desired effect; usual initial range: 1 to 3 mcg/kg/hour; some patients require higher doses especially in the presence of opioid tolerance (Ref).Endotracheal intubation, premedicationEndotracheal intubation, premedication: Limited data available:Preterm and term neonates:IV, IM: 1 to 4 mcg/kg over 3 to 5 minutes (preferred); may be used in combination with other medications. Note: Risk of chest wall rigidity is minimized when doses are administered over at least 1 to 2 minutes (Ref).Intranasal (using parenteral preparation): 1 to 2 mcg/kg/dose usually 5 minutes prior to procedure; administration with a mucosal atomizer device (MAD) is preferred but use may be limited by the size of the patient and/or dose, in such cases administration without a MAD is appropriate (Ref); one study which used an initial dose of 1.5 mcg/kg allowed for a repeat dose after 5 minutes based on nursing’s clinical assessment with a maximum of 2 doses/procedure (Ref).Pain and sedation; critically ill patients in the ICUPain and sedation; critically ill patients in the ICU (including extracorporeal membrane oxygenation [ECMO]): Limited data available: Note: A multimodal approach (eg, a combination of pharmacologic and non-pharmacologic interventions) should typically be employed for pain control. Pain should be monitored using validated neonatal pain assessment tools (Ref).Preterm and term neonates: Initial IV bolus: 1 to 2 mcg/kg, then continuous IV infusion of 0.5 to 3 mcg/kg/hour; titrate carefully to effect; higher doses may be needed if tolerance develops or if patient is on ECMO (Ref). A pharmaco*kinetic study in neonates <32 weeks GA showed low clearance in the first few days of life followed by a rapid increase in clearance and recommended lower initial doses in the first few days of life to prevent accumulation; the authors suggested administering 50% of the recommended dose during the first 4 days of life, 75% of the recommended dose on day of life 5 to 9, then the full recommended dose on day of life ≥10 (Ref).Pain and sedation, hypoxic ischemic encephalopathy undergoing therapeutic hypothermiaPain and sedation, hypoxic ischemic encephalopathy (moderate to severe) undergoing therapeutic hypothermia: Limited data available:Term neonates: Initial IV bolus: 1 to 2 mcg/kg, then continuous IV infusion of 0.5 to 1 mcg/kg/hour; increase dose by 0.5 mcg/kg/hour as needed to clinical effect; maximum reported dose: 3 mcg/kg/hour (Ref).Procedural pain and sedationProcedural pain and sedation: Limited data available:Preterm and term neonates:IV: Usual dosage range: 1 to 3 mcg/kg/dose over at least 5 minutes; may repeat every 2 to 4 hours as needed; lower doses (0.5 to 1 mcg/kg/dose) have been recommended for patients not on mechanical ventilation (Ref).Intranasal (using parenteral preparation): 1 to 2 mcg/kg/dose prior to painful procedure; usually 5 minutes prior to procedure; administration with a mucosal atomizer device (MAD) is preferred but use may be limited by the size of the patient and/or dose, in such cases administration without a MAD is appropriate (Ref); one study which used an initial dose of 1.5 mcg/kg allowed for a repeat dose after 5 minutes based on nursing's clinical assessment with a maximum of 2 doses/procedure (Ref).Dosing: PediatricNote: Ionsys (transdermal device) and Abstral (sublingual tablets) have been discontinued in the United States for >1 year. Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance.Acute painAcute pain:Parenteral:Infants: Limited data available: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 2- to 4-hour intervals; in opioid-tolerant or younger infants, titration to higher doses may be required (up to 4 mcg/kg/dose) (Ref).Children: Limited data available in <2 years of age: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 30- to 60-minute intervals; in opioid-tolerant children, titration to higher doses may be required. Note: Usual adolescent starting dose is 25 to 50 mcg (Ref).Adolescents: Note: After the first dose, if severe pain persists and adverse effects are minimal at the time of expected peak effect, may repeat dose (Ref).<50 kg: Initial: IV: 0.5 to 1 mcg/kg/dose may repeat every 1 to 2 hours although some patients may require more frequent dosing (eg, 30-minute intervals) (Ref).≥50 kg: Initial: IV: 25 to 50 mcg every 1 to 2 hours although some patients may require more frequent dosing (eg, 30-minute intervals) (Ref).Intranasal (using parenteral preparation): Limited data available: Children ≥10 kg and Adolescents: Intranasal: Usual dose: 1.5 to 2 mcg/kg once; maximum dose: 100 mcg/dose (Ref); some studies that used an initial dose of 1.5 mcg/kg allowed for second dose of 0.5 to 0.75 mcg/kg, at the discretion of the physician, 10 to 20 minutes after the first dose (Ref).Procedural sedation and analgesiaProcedural sedation and analgesia:Parenteral:Infants and Children: Limited data available in <2 years of age: IM, IV: 1 to 2 mcg/kg/dose; administer 3 minutes before the procedure; maximum dose: 50 mcg/dose; may repeat 1/2 original dose every 3 to 5 minutes if necessary; titrate to effect (Ref).Adolescents: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg, repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5-minute intervals if needed. Note: Higher doses are used for major procedures.Intranasal (using parenteral preparation): Limited data available: Infants and Children weighing ≥10 kg and Adolescents: Intranasal: 1.5 to 2 mcg/kg administered 15 minutes prior to procedure; maximum dose: 100 mcg/dose (Ref).Anesthesia, general; adjunctAnesthesia, general; adjunct:Children 2 to 12 years: IM, IV: 2 to 3 mcg/kg/dose; Note: An IV should be in place with general anesthesia so the IM route is rarely used but still maintained as an option in the manufacturer's labeling.Adolescents:Low dose: IV: 0.5 to 2 mcg/kg/dose depending on the indication.Moderate dose: IV: Initial: 2 to 20 mcg/kg/dose; Maintenance (bolus or infusion): 1 to 2 mcg/kg/hour. Discontinuing fentanyl infusion 30 to 60 minutes prior to the end of surgery will usually allow adequate ventilation upon emergence from anesthesia. For "fast-tracking" and early extubation following major surgery, total fentanyl doses are limited to 10 to 15 mcg/kg.High dose: IV: 20 to 50 mcg/kg/dose; Note: High-dose fentanyl as an adjunct to general anesthesia is rarely used, but is still described in the manufacturer's label.Anesthesia, general without additional anesthetic agentsAnesthesia, general without additional anesthetic agents: Adolescents: IV: 50 to 100 mcg/kg/dose with O2 and skeletal muscle relaxant.Anesthesia, regional; adjunctAnesthesia, regional; adjunct: Adolescents: IM, IV: 50 to 100 mcg; Note: An IV should be in place with regional anesthesia so the IM route is rarely used but still maintained as an option in the manufacturer's labeling.Cancer pain; breakthroughCancer pain; breakthrough: Note: For use in patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Patients must remain on around-the-clock opioids during use.Transmucosal lozenge (eg, Actiq):Adolescents ≥16 years:Initial: 200 mcg (consumed over 15 minutes) for all patients; if after 30 minutes from the start of the lozenge (ie, 15 minutes following the completion of the lozenge), the pain is unrelieved, a second 200 mcg dose may be given over 15 minutes. A maximum of 1 additional dose can be given per pain episode; must wait at least 4 hours before treating another episode. To limit the number of units in the home during titration, only prescribe an initial titration supply of six 200 mcg lozenges. Note: Do not convert patients from any other fentanyl product to Actiq on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 200 mcg; individually titrate to provide adequate analgesia while minimizing adverse effects.Dose titration: Dose titration should be done if patient requires more than 1 dose/breakthrough pain episode for several consecutive episodes. From the initial dose, closely follow patients and modify the dose until patient reaches a dose providing adequate analgesia using a single dosage unit per breakthrough cancer pain episode. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses. If adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given for that episode; must wait at least 4 hours before treating another episode.Maintenance dose: Once titrated to an effective dose, patients should generally use a single dosage unit per breakthrough pain episode. During any pain episode, if adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given over 15 minutes for that episode; must wait at least 4 hours before treating another episode. Consumption should be limited to ≤4 units per day (once an effective breakthrough dose is found). If adequate analgesia is not provided after treating several episodes of breakthrough pain using the same dose, increase dose to next highest lozenge strength (initially dispense no more than 6 units of the new strength). Consider increasing the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day and have their long-term opioid re-evaluated. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses.Chronic pain, moderate to severeChronic pain, moderate to severe (opioid-tolerant):Transdermal patch (eg, Duragesic): Note: For use in patients who are opioid-tolerant receiving at least 60 mg oral morphine equivalents per day. Discontinue or taper all other around-the-clock or extended-release opioids when initiating therapy with fentanyl transdermal patch:Children ≥2 years and Adolescents:Initial: 25 mcg/hour system or higher based on previous opioid dosing. To convert patients from oral or parenteral opioids to transdermal patch, a 24-hour analgesic requirement should be calculated (based on prior opioid use). Using the following tables, the appropriate initial dose can be determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage equivalent and titrated to minimize adverse effects and provide analgesia. Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily fentanyl requirement and provide breakthrough pain relief with rescue medication (eg, immediate release opioid) than to overestimate requirements. With the initial application, the absorption of transdermal fentanyl requires several hours to reach plateau; therefore, transdermal fentanyl is inappropriate for management of acute pain. Change patch every 72 hours.Conversion from continuous infusion of fentanyl: In patients who have adequate pain relief with a fentanyl infusion, fentanyl may be converted to transdermal dosing at a rate equivalent to the intravenous rate. Based on experience in adults, a two-step taper of the infusion to be completed over 12 hours may be considered (Ref) after the patch is applied. The infusion is decreased to 50% of the original rate 6 hours after the application of the first patch, and subsequently discontinued twelve hours after application.Titration: Short-acting agents may be required until analgesic efficacy is established and/or as supplements for “breakthrough” pain. The amount of supplemental doses should be closely monitored. Appropriate dosage increases may be based on daily supplemental dosage using the ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage.Frequency of adjustment: The dosage should not be titrated more frequently than every 3 days after the initial dose or every 6 days thereafter. Titrate dose based on the daily dose of supplemental opioids required by the patient on the second or third day of the initial application. Note: Upon discontinuation, ~17 hours are required for a 50% decrease in fentanyl levels.Frequency of application: The majority of patients may be controlled on every 72-hour administration; however, a small number of adult patients have required every 48-hour administration.Discontinuation: When discontinuing transdermal fentanyl and not converting to another opioid, use a gradual downward titration, such as decreasing the dose by 50% every 6 days, to reduce the possibility of withdrawal symptoms.Dose conversion guidelines for transdermal fentanyl from other opioids (see tables).Note: The conversion factors in these tables are only to be used for the conversion from current opioid therapy to Duragesic patch. Conversion factors in this table cannot be used to convert from Duragesic to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). US and Canadian dose conversion guidelines differ; consult table for US recommendations. The Canadian product is not approved in pediatric patients. These are not tables of equianalgesic doses.US Labeling: Dose Conversion Guidelines: Recommended Initial Duragesic Dose Based Upon Daily Oral Morphine DoseaOral 24-Hour Morphine(mg/day)Duragesic Doseb,c(mcg/hour)aThe table should NOT be used to convert from transdermal fentanyl (Duragesic) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.bPediatric patients initiating therapy on a 25 mcg/hour Duragesic system should be opioid-tolerant and receiving at least 60 mg oral morphine equivalents per day.cA fentanyl 37.5 mcg/hour transdermal system is also available and may be considered during conversion from prior opioids or dose titration.60 to 13425135 to 22450225 to 31475315 to 404100405 to 494125495 to 584150585 to 674175675 to 764200765 to 854225855 to 944250945 to 1,0342751,035 to 1,124300US Labeling: Dose Conversion GuidelinesaCurrent AnalgesicDaily Dosage(mg/day)aThe table should NOT be used to convert from transdermal fentanyl (Duragesic) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.Morphine (IM/IV)10 to 2223 to 3738 to 5253 to 67Oxycodone (oral)30 to 6767.5 to 112112.5 to 157157.5 to 202Codeine (oral)150 to 447---Hydromorphone (oral)8 to 1717.1 to 2828.1 to 3939.1 to 51Hydromorphone (IV)1.5 to 3.43.5 to 5.65.7 to 7.98 to 10Meperidine (IM)75 to 165166 to 278279 to 390391 to 503Methadone (oral)20 to 4445 to 7475 to 104105 to 134Duragesic (fentanyl transdermal) recommended dose (mcg/hour) 25 mcg/hour50 mcg/hour75 mcg/hour100 mcg/hourContinuous analgesia/sedationContinuous analgesia/sedation: Infants and Children: Limited data available in <2 years of age: Initial IV bolus: 1 to 2 mcg/kg followed by continuous IV infusion at initial rate: 1 mcg/kg/hour; titrate to effect; usual range: 1 to 3 mcg/kg/hour; some patients may require higher rates (5 mcg/kg/hour) (Ref).Adolescents:≤50 kg: Initial IV bolus: 0.5 to 2 mcg/kg followed by continuous IV infusion at initial rate: 0.5 to 2 mcg/kg/hour based on expert recommendations for children and pediatric patients ≤50 kg (Ref).>50 kg: Initial IV bolus: 25 to 100 mcg/dose followed by continuous IV infusion at initial rate: 25 to 200 mcg/hour based on expert recommendations for pediatric patients and experience in adult patients (Ref).Endotracheal intubation, emergent Endotracheal intubation, emergent: Limited data available: Infants and Children: IV: 1 to 5 mcg/kg/dose (Ref).Patient-controlled analgesiaPatient-controlled analgesia (PCA): Limited data available:Note: PCA has been used in children as young as 5 years; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed (Ref):Children ≥5 years and Adolescents; opioid-naive: IV:Patient weight ≤50 kg:Usual concentration: Determined by weight; some centers use the following:Children <12 kg: 10 mcg/mL.Children 12 to 30 kg: 25 mcg/mL.Children >30 kg: 50 mcg/mL.Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose; usual range: 0.5 to 1 mcg/kg/dose.Lockout: Usual initial: 5 doses/hour.Lockout interval: Range: 6 to 8 minutes.Usual basal rate: 0 to 0.5 mcg/kg/hour.Patient weight >50 kg:Usual concentration: 50 mcg/mL.Demand dose: Usual initial: 20 mcg; usual range: 10 to 50 mcg.Lockout interval: Usual initial: 6 minutes; usual range: 5 to 8 minutes.Usual basal rate: ≤50 mcg/hour.Preoperative sedation Preoperative sedation: Adolescents <18 years: IM, IV: 50 to 100 mcg administered 30 to 60 minutes prior to surgery or slow IV: 25 to 50 mcg given shortly before induction (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricInjection: There are no dosage adjustments provided in the manufacturer's labeling; however, the following guidelines have been used by some clinicians (Ref):Infants, Children, and Adolescents: The following assumes dosages of 0.5 to 2 mcg/kg/dose or 1 to 5 mcg/kg/hour in normal renal function: IV:GFR >50 mL/minute/1.73 m2: No adjustment required.GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of usual dose.GFR <10 mL/minute/1.73 m2: Administer 50% of usual dose.Intermittent hemodialysis: Administer 50% of usual dose.Peritoneal dialysis (PD): Administer 50% of usual dose.Continuous renal replacement therapy (CRRT): Administer 75% of usual dose.Transdermal (patch): Pediatric patients ≥2 years: Degree of impairment (ie, CrCl) not defined in manufacturer's labeling.Mild to moderate impairment: Initial: Reduce dose by 50%.Severe impairment: Use not recommended.Transmucosal (lozenge [eg, Actiq]) and nasal spray: Adolescents ≥16 years: Although fentanyl pharmaco*kinetics may be altered in renal disease, fentanyl can be used successfully in the management of breakthrough cancer pain. Use with caution; reduce initial dose and titrate to reach clinical effect with careful monitoring of patients, especially those with severe renal disease.Dosing: Hepatic Impairment: PediatricInjection: There are no dosage adjustments provided in the manufacturer's labeling.Transdermal (patch): Pediatric patients ≥2 years:Mild to moderate impairment: Initial: Reduce dose by 50%.Severe impairment: Use not recommended.Transmucosal (lozenge [eg, Actiq]): Adolescents ≥16 years: Although fentanyl pharmaco*kinetics may be altered in hepatic disease, fentanyl can be used successfully in the management of breakthrough cancer pain. Use with caution; reduce initial dose and titrate to reach clinical effect with careful monitoring of patients, especially those with severe hepatic disease.Dosing: Adult(For additional information see "Fentanyl: Drug information")Note: Ionsys (transdermal device) and Abstral (sublingual tablets) have been discontinued in the United States for >1 year.Note: When used for managing severe pain, opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for pain. Maximize nonopioid analgesia, if appropriate, prior to initiation of opioid analgesia (Ref). Dosing provided is based on typical doses and some patients may require higher or lower doses. Individualize dosing and dosing intervals based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, cachexia, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time. For acute non–cancer-related pain severe enough to require an opioid, do not prescribe fentanyl for use on an outpatient basis; consider the use of other oral opioids. Before starting opioid therapy for chronic pain, establish realistic treatment goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh risks (Ref).Acute pain, patient-controlled analgesiaAcute pain, patient-controlled analgesia (alternative agent): Note: Generally, fentanyl is the preferred opioid for patients with severe kidney or hepatic dysfunction and/or for patients who are unable to tolerate morphine or hydromorphone (Ref). For use in ICU, postoperative, or other closely monitored settings. IV:Example IV Patient-Controlled Analgesia Initial Dose Ranges for Opioid-Naive Patientsaa For use to maintain pain control after initial pain control achieved. May adjust dosing and provide rescue bolus doses (eg, 5 to 20 mcg) if analgesia is inadequate (Mariano 2019).b The use of a continuous background infusion for patient-controlled analgesia is generally not recommended for most patients because of the risk of respiratory depression, and use should be limited to carefully selected patients who are opioid tolerant and/or receiving care in a critical care unit, or if required to maintain baseline opioid dosing during intervals when oral or transdermal opioid administration is not possible (Arnold 2019; Mariano 2019).Usual concentration10 mcg/mLDemand doseUsual range: 5 to 20 mcgBasal doseIn general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)bLockout interval4 to 10 minutesMaximum cumulative dose75 mcg within 1 hour (or 300 mcg within a 4-hour period)Acute postoperative painAcute postoperative pain: Postoperative recovery/Postanesthesia care unit (ie, immediate postoperative period): IV: 25 to 50 mcg every 5 minutes (moderate pain) or 50 to 100 mcg every 2 to 5 minutes (severe pain) until pain is relieved or unwanted side effects appear; after initial pain control, readdress postoperative analgesic regimen to optimize comfort (Ref).IM: 50 to 100 mcg every 1 to 2 hours as needed. Note: IM route should only be used if IV administration is not available (eg, loss of IV access).Transdermal device (Ionsys): Note: For hospital use only by patients under medical supervision for whom alternative treatments are inadequate and only after patients have been titrated to an acceptable level of analgesia using another opioid analgesic.Apply 1 device to chest or upper outer arm only. Only the patient may activate the device (40 mcg dose of fentanyl per activation, delivered over 10 minutes; maximum: 6 doses per hour). Only 1 device may be applied at a time and operates for up to 24 hours or 80 doses, whichever comes first. Reapply every 24 hours, as necessary, with each subsequent device applied to a different skin site; maximum duration: 72 hours. If inadequate analgesia is achieved with 1 device, either provide additional supplemental analgesia or replace with an alternative analgesic. Refer to manufacturer's labeling for activation instructions and application sites.Acute nonoperative severe painAcute nonoperative severe pain:Note: For use in ICU or other closely monitored settings.Intermittent dosing: IV, IM: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (Ref). Note: More frequent administration may be necessary when used by the IV route due to short duration of activity. IM route should only be used if IV administration is not available (eg, loss of IV access).Chronic pain, including chronic cancer painChronic pain, including chronic cancer pain: Note: Opioids, including fentanyl, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred, with the exception of chronic pain from sickle cell disease and end-of-life care. Opioids, including fentanyl, should only be considered in patients with chronic, noncancer pain who are expected to experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref).SUBQ continuous infusion: Note: For progressive illnesses (eg, cancer), a continuous SUBQ infusion, with or without a patient-controlled analgesia option, can be used as pain requirements increase. In general, SUBQ continuous infusion dose is equivalent to IV continuous infusion dose (Ref). Individualize dose based on previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain. Reported dosing varies greatly and is based on practice and patient needs; refer to institutional protocols (Ref).Transdermal patch: Discontinue or taper all other around-the-clock or extended-release opioids when initiating therapy with fentanyl transdermal patch.Initial: To convert patients from oral or parenteral opioids to fentanyl transdermal patch, a 24-hour analgesic requirement should be calculated (based on prior opioid use). Using the table below, the appropriate initial dose can be determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage equivalent and titrated to minimize adverse effects and provide analgesia. While there are useful tables of opioid equivalents available, substantial interpatient variability exists in relative potency of different opioids and products. Therefore, it is safer to underestimate the daily fentanyl requirement and provide breakthrough pain relief with rescue medication (eg, immediate-release opioid) than to overestimate requirements, which could result in adverse reactions. With the initial application, the absorption of transdermal fentanyl requires several hours to reach plateau; therefore, transdermal fentanyl is inappropriate for management of acute pain. Change patch every 72 hours. The majority of patients may be controlled on every-72-hour administration; however, some patients may require every-48-hour administration because of more breakthrough pain in the last 24 hours of each cycle.Conversion from continuous IV infusion of fentanyl: In patients who have adequate pain relief with IV fentanyl infusion, may convert to transdermal dosing at a rate equivalent to the IV rate using a 2-step taper of the infusion to be completed over 12 hours after the patch is applied. Six hours after the application of the first patch, decrease the infusion to 50% of the original rate; discontinue infusion 12 hours after patch application (Ref).Titration: Do not titrate more frequently than every 3 days after the initial application or every 6 days thereafter. Short-acting opioids may be required until analgesic efficacy is established and/or as supplements for breakthrough pain. The number and quantity of supplemental doses should be closely monitored. When increasing the dose, base the new dose on the daily requirement of supplemental opioids required by the patient during the second or third day of initial application. For example, if 24-hour oral morphine requirement for breakthrough pain is 50 mg, then may increase transdermal fentanyl dose by 25 mcg/hour (Ref).Dose conversion guidelines for transdermal fentanyl (see table below):Note: Using the manufacturer's recommended dose conversion guidelines, based upon the daily oral morphine dose, may underestimate the transdermal fentanyl strength required and result in the need for supplemental immediate-release opioid therapy for breakthrough pain or in the patient experiencing withdrawal syndrome (Ref). The manufacturers recommend a ratio of approximately 45 mg/24 hours of oral morphine to a 12 mcg/hour fentanyl dosage (US labeling) or the ratio of 45 to 59 mg/24 hours of oral morphine to a 12 mcg/hour fentanyl dosage (Canadian labeling). Below is a less conservative dosing conversion strategy based on a 2:1 ratio of oral morphine to transdermal fentanyl (Ref). For the more conservative dose conversion strategy, see the manufacturer's labeling. The table is only to be used for the conversion from current opioid therapy to transdermal fentanyl. Do not use this table to convert from transdermal fentanyl to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). This is not a table of equianalgesic doses.Step 1: Determine the patient's 24-hour oral morphine requirement. If patient was not receiving oral morphine, must convert the 24-hour requirement to the oral morphine equivalent using a conversion chart or tool.Step 2: Once the 24-hour oral morphine requirement is determined, use the Dose Conversion Guidelines to determine the appropriate fentanyl transdermal dose (mcg/hour).Dose Conversion Guidelines: Recommended Initial Fentanyl Transdermal Dose Based Upon Daily Oral Morphine Dosea,b,cOral 24-Hour Morphine Dose (mg/day)Fentanyl Transdermal Dose (mcg/hour)a Portenoy 2019a.b The table should not be used to convert from transdermal fentanyl to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.c Suggested doses for conversion to transdermal fentanyl from other opioids are less conservative than recommendations in the US product labeling. The recommendations in this table are based on guidance available at experienced centers.251250251005015075200100250125300150350175400200450225500250550275600300Discontinuation or tapering of therapy: When discontinuing or tapering long-term opioid therapy, the dose should be gradually tapered down. An optimal tapering schedule has not been established (Ref). Proposed schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). When discontinuing transdermal fentanyl and not converting to another opioid, particularly in patients who are physically opioid dependent, use a gradual downward titration (eg, decrease the dose by 25% every 2 to 4 weeks) (Ref). Upon system removal of transdermal fentanyl, ≥17 hours are required for a 50% decrease in fentanyl levels. Individualize discontinuation or taper based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns, as well as the opioid's pharmaco*kinetics. Slower tapers may be appropriate after long-term use (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (Ref). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Ref). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Ref). In patients who continue to take long-term opioid therapy but no longer require fentanyl for breakthrough pain, fentanyl can usually be discontinued without a taper.Chronic cancer pain, management of breakthrough pain episodesChronic cancer pain, management of breakthrough pain episodes: Transmucosal:Note: For patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Dose titration should be done if patient requires more than 1 dose per breakthrough pain episode for several consecutive episodes. Patients experiencing >4 breakthrough pain episodes per day should have the dose of their long-term opioid reevaluated. Patients must remain on around-the-clock opioids during use (Ref).Lozenge (Actiq): Note: Do not convert patients from any other fentanyl product to Actiq on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 200 mcg; individually titrate to provide adequate analgesia while minimizing adverse effects.Initial dose: 200 mcg (consumed over 15 minutes) for all patients; if after 30 minutes from the start of the lozenge (ie, 15 minutes following the completion of the lozenge) pain is unrelieved, a second 200 mcg dose may be given over 15 minutes. A maximum of 1 additional dose can be given per pain episode; must wait at least 4 hours before treating another episode. To limit the number of units in the home during titration, only prescribe an initial titration supply of six 200 mcg lozenges.Dose titration: From the initial dose, closely monitor patients and modify the dose until patient reaches a dose providing adequate analgesia using a single dosage unit per breakthrough cancer pain episode. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses. If adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given for that episode; must wait at least 4 hours before treating another episode.Maintenance dose: Once titrated to an effective dose, patients should generally use a single dosage unit per breakthrough pain episode. During any pain episode, if adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given over 15 minutes for that episode; must wait at least 4 hours before treating another episode. Consumption should be limited to ≤4 units per day (once an effective breakthrough dose is found). If adequate analgesia is not provided after treating several episodes of breakthrough pain using the same dose, increase dose to next highest lozenge strength (initially dispense no more than 6 units of the new strength). Reevaluate the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses.Buccal tablet (Fentora): Note: Do not convert patients from any other fentanyl product to Fentora on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to buccal tablet (Fentora).Initial dose: 100 mcg for all patients unless patient is already using Actiq; see Conversion from lozenge (Actiq) to buccal tablet (Fentora). If after 30 minutes pain is unrelieved, a second 100 mcg dose may be administered (US labeling) or an alternative analgesic rescue medication (other than Fentora) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Must wait at least 4 hours before treating another episode with buccal tablet.Dose titration: If titration required, the 100 mcg dose may be increased to 200 mcg using two 100 mcg tablets (one on each side of mouth) with the next breakthrough pain episode. If 200 mcg dose is not successful, patient can use four 100 mcg tablets (two on each side of mouth) with the next breakthrough pain episode. If titration requires >400 mcg per dose, titrate using 200 mcg tablets; do not use more than 4 tablets simultaneously (maximum single dose: 800 mcg). During any breakthrough pain episode, if adequate relief is not achieved 30 minutes after buccal tablet application, a second dose of same strength for that breakthrough pain episode may be used (US labeling) or an alternative analgesic rescue medication (other than Fentora) may be given (Canadian labeling). Must wait at least 4 hours before treating another episode with buccal tablet. Maintenance dose: Following titration, the effective maintenance dose using 1 tablet of the appropriate strength should be administered once per episode; if after 30 minutes pain is unrelieved, may administer a second dose of the same strength (US labeling) or an alternative analgesic rescue medication (other than Fentora) may be given (Canadian labeling). Must wait at least 4 hours before treating another episode with buccal tablet. Limit to 4 applications per day. Reevaluate the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day. Once an effective maintenance dose has been established, the buccal tablet may be administered sublingually (alternative route). To prevent confusion, patient should only have one strength available at a time. Once maintenance dose is determined, all other unused tablets should be disposed of and that strength (using a single tablet) should be used. Using more than 4 buccal tablets at a time has not been studied.Conversion from lozenge (Actiq) to buccal tablet (Fentora):Lozenge dose 200 or 400 mcg: Initial buccal tablet dose is 100 mcg; may titrate using multiples of 100 mcg.Lozenge dose 600 or 800 mcg: Initial buccal tablet dose is 200 mcg; may titrate using multiples of 200 mcg.Lozenge dose 1,200 or 1,600 mcg: Initial buccal tablet dose is 400 mcg (using two 200 mcg tablets); may titrate using multiples of 200 mcg.Intranasal (Lazanda): Note: Do not convert patients from any other fentanyl product to Lazanda on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects.Initial dose: 100 mcg (one 100 mcg spray in one nostril) for all patients; if after 30 minutes pain is unrelieved, an alternative rescue medication may be used. Must wait at least 2 hours before treating another episode with fentanyl intranasal. However, for the next pain episode, increase to a higher dose using the recommended dose titration steps.Dose titration: If titration required, increase to a higher dose for the next pain episode using the following titration steps (Note: Must wait at least 2 hours before treating another episode with fentanyl intranasal): If no relief with 100 mcg dose, increase to 200 mcg dose per episode (one 100 mcg spray in each nostril); if no relief with 200 mcg dose, increase to 300 mcg dose per episode (alternating one 100 mcg spray in right nostril, one 100 mcg spray in left nostril, and one 100 mcg spray in the right nostril); if no relief with 300 mcg dose, increase to 400 mcg dose per episode (one 400 mcg spray in one nostril or alternating two 100 mcg sprays in each nostril); if no relief with 400 mcg dose, increase to 600 mcg dose per episode (one 300 mcg spray in each nostril); if no relief with 600 mcg dose, increase to 800 mcg dose per episode (one 400 mcg spray in each nostril). Note: Single doses >800 mcg have not been evaluated. Avoid use of a combination of dose strengths to treat an episode, as this may cause confusion and dosing errors.Maintenance dose: Once maintenance dose for breakthrough pain episode has been determined, use that dose for subsequent episodes. For pain that is not relieved 30 minutes after Lazanda administration or if a separate breakthrough pain episode occurs within the 2-hour window before the next Lazanda dose is permitted, a rescue medication may be used. Limit Lazanda use to ≤4 doses per day. If patient is experiencing >4 breakthrough pain episodes per day, consider increasing the around-the-clock, long-acting opioid therapy; if long-acting opioid therapy dose is altered, reevaluate and retitrate Lazanda dose as needed. If response to maintenance dose changes (increase in adverse reactions or alterations in pain relief), dose readjustment may be necessary.Sublingual:Sublingual spray (Subsys): Note: Do not convert patients from any other fentanyl product to Subsys on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to sublingual spray (Subsys).Initial dose: 100 mcg for all patients unless patient is already using Actiq; see Conversion from lozenge (Actiq) to sublingual spray (Subsys). If after 30 minutes pain is unrelieved, 1 additional 100 mcg dose may be given. A maximum of 2 doses can be given per breakthrough pain episode. Must wait at least 4 hours before treating another episode with sublingual spray.Dose titration: If titration required, titrate to a dose that provides adequate analgesia (with tolerable side effects) using the following titration steps: If no relief with 100 mcg dose, increase to 200 mcg dose (using one 200 mcg unit); if no relief with 200 mcg dose, increase to 400 mcg dose (using one 400 mcg unit); if no relief with 400 mcg dose, increase to 600 mcg dose (using one 600 mcg unit); if no relief with 600 mcg dose, increase to 800 mcg dose (using one 800 mcg unit); if no relief with 800 mcg dose, increase to 1,200 mcg dose (using two 600 mcg units); if no relief with 1,200 mcg dose, increase to 1,600 mcg dose (using two 800 mcg units). During dose titration, if breakthrough pain is unrelieved 30 minutes after Subsys administration, 1 additional dose using the same strength may be administered (maximum: 2 doses per breakthrough pain episode); patient must wait 4 hours before treating another breakthrough pain episode with sublingual spray.Maintenance dose: Once maintenance dose for breakthrough pain episode has been determined, use that dose for subsequent episodes. If occasional episodes of unrelieved breakthrough pain occur 30 minutes after Subsys administration, 1 additional dose using the same strength may be administered (maximum: 2 doses per breakthrough pain episode); patient must wait 4 hours before treating another breakthrough pain episode with sublingual spray. Once maintenance dose is determined, limit Subsys use to ≤4 doses per day. If response to maintenance dose changes (increase in adverse reactions or alterations in pain relief), dose readjustment may be necessary. If patient is experiencing >4 breakthrough pain episodes per day, reevaluate the around-the-clock, long-acting opioid therapy.Conversion from lozenge (Actiq) to sublingual spray (Subsys):Lozenge dose 200 or 400 mcg: Initial sublingual spray dose is 100 mcg; may titrate using multiples of 100 mcg.Lozenge dose 600 or 800 mcg: Initial sublingual spray dose is 200 mcg; may titrate using multiples of 200 mcg.Lozenge dose 1,200 or 1,600 mcg: Initial sublingual spray dose is 400 mcg; may titrate using multiples of 400 mcg.Sublingual tablet (Abstral): Note: Do not convert patients from any other fentanyl product to Abstral on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to sublingual tablet (Abstral).Initial dose: 100 mcg for all patients unless patient is already using Actiq; see Conversion from lozenge (Actiq) to sublingual tablet (Abstral). If after 30 minutes pain is unrelieved, a second 100 mcg dose may be given (US labeling) or an alternative rescue medication (other than Abstral) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Must wait at least 2 hours before treating another episode with sublingual tablet.Dose titration: If titration required, increase in 100 mcg increments (up to 400 mcg) over consecutive breakthrough episodes. If titration requires >400 mcg per dose, increase in increments of 200 mcg, starting with a 600 mcg dose and titrating up to 800 mcg. During titration, patients may use multiples of 100 mcg and/or 200 mcg tablets for any single dose; do not exceed 4 tablets at one time; safety and efficacy of doses >800 mcg have not been evaluated. During dose titration, if breakthrough pain is unrelieved 30 minutes after sublingual tablet administration, 1 additional dose using the same strength may be administered (US labeling) or an alternative rescue medication (other than Abstral) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Must wait 2 hours before treating another breakthrough pain episode with sublingual tablet.Maintenance dose: Once maintenance dose for breakthrough pain episode has been determined, use only 1 tablet of the appropriate strength per episode; if pain is unrelieved with maintenance dose, a second dose may be given after 30 minutes (US labeling) or an alternative rescue medication (other than Abstral) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Separate treatment of subsequent episodes by ≥2 hours; limit Abstral use to ≤4 doses per day. Consider reevaluating the around-the-clock, long-acting opioid therapy in patients experiencing >4 breakthrough pain episodes per day; if long-acting opioid therapy dose altered, reevaluate and retitrate Abstral dose as needed.Conversion from lozenge (Actiq) to sublingual tablet (Abstral):Lozenge dose of 200 mcg: Initial sublingual tablet dose is 100 mcg; may titrate using multiples of 100 mcg.Lozenge dose of 400, 600, 800, or 1,200 mcg: Initial sublingual tablet dose is 200 mcg; may titrate using multiples of 200 mcg.Lozenge dose of 1,600 mcg: Initial sublingual tablet dose is 400 mcg; may titrate using multiples of 400 mcg.Critically ill patients in the ICU, pain and sedationCritically ill patients in the ICU, pain and sedation (off-label use):Note: Multimodal approaches (eg, a combination of analgesics and techniques) should typically be employed for pain control in this setting. Pain should be monitored using validated scales (eg, behavioral pain scale, critical-care pain observation tool) in ICU patients who are unable to self-report (Ref).Intermittent dosing: Loading dose: IV: 25 to 100 mcg or 1 to 2 mcg/kg; may repeat dose if severe pain persists and adverse effects are minimal at the time of expected peak effect (eg, ~5 minutes after administration) (Ref). Follow with intermittent maintenance dose or a continuous infusion.Maintenance dose: IV: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (Ref).Continuous infusion: IV: After initial loading dose (see Intermittent dosing: Loading dose), begin continuous infusion at an initial rate of 25 to 50 mcg/hour; titrate every 30 to 60 minutes to clinical effect (ie, pain control and/or sedation). Usual dosing range: 50 to 200 mcg/hour (some patients may require doses as high as 300 mcg/hour); weight-based dosing range: 0.7 to 10 mcg/kg/hour (Ref). Note: Fentanyl can accumulate in lipid stores when used for extended periods of time and may result in prolonged sedation and reduced ability to liberate from mechanical ventilator (Ref). May administer an additional small bolus dose (eg, 25 mcg) prior to increasing the infusion rate (Ref).Procedural sedation and analgesiaProcedural sedation and analgesia: Outside the operating room (alternative agent) (off-label use):IV: 0.5 to 1 mcg/kg every 2 minutes until desired level of sedation and analgesia achieved (Ref); generally, the maximum total dose is 250 mcg. If administered with other sedatives (eg, etomidate, propofol, midazolam), do not exceed single doses of 0.5 mcg/kg (Ref).Intranasal (using parenteral solution [50 mcg/mL]) (off-label route): 1 to 2 mcg/kg as a single dose; administer half the dose in each nostril; maximum total dose: 100 mcg (50 mcg per nostril; based on volume) (Ref). Note: Recommend using a nasal atomizer for delivery (Ref).Analgesia during monitored anesthesia care or regional anesthesia: IV: Usual initial dose range: 0.5 to 2 mcg/kg, administered in incremental boluses of 25 to 50 mcg, titrated to effect. When used in combination with a sedative (eg, midazolam), consider dosage reduction (Ref). Note: Since an IV should be in place with anesthesia, the IM route is rarely used but still maintained as an option in the manufacturer's labeling. If IM route is used, the dose is equivalent to the recommended IV dose.Rapid sequence intubation, pretreatmentRapid sequence intubation, pretreatment (off-label use): IV: Usual dose: 50 to 200 mcg (or 1 to 3 mcg/kg) over 30 to 60 seconds administered ~3 minutes prior to induction. In patients with tenuous hemodynamic status, use lower doses (eg, 1 mcg/kg [or 50 mcg]) or avoid use; in patients with elevated intracranial pressure, use higher doses (eg, 3 mcg/kg [or 200 mcg]) (Ref).General anesthesiaGeneral anesthesia: Preinduction: IV: 25 mcg; may repeat in increments of 25 mcg (typical total dose is ≤100 mcg) to provide pain relief or if patient requires a regional anesthesia procedure prior to surgery (Ref).Induction: IV: 25 to 100 mcg (or 0.5 to 1 mcg/kg) (Ref). Some use a high-dose opioid induction technique (eg, 10 to 25 mcg/kg) for select patients (eg, those with poor myocardial function) who will remain intubated for several hours postoperatively (Ref).Maintenance: Intermittent: IV: 25 to 50 mcg bolus as needed; may be used to provide supplemental analgesia during maintenance of general anesthesia with inhaled agents (Ref).Continuous infusion: IV: 1 to 2 mcg/kg/hour as supplement to total IV anesthesia (TIVA) when controlled postoperative ventilation is planned (Ref).Neuraxial analgesiaNeuraxial analgesia:Epidural: Note: Reserve use for patients with severe acute pain (eg, after major abdominal surgery, cancer pain, during labor and delivery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (Ref). Use a preservative-free formulation intended for neuraxial use (Ref).Single dose: 25 to 100 mcg; may provide adequate relief for up to 8 hours. May repeat with additional 100 mcg boluses on demand (Ref) or alternatively may administer by a continuous infusion (Ref).Continuous infusion: 25 to 100 mcg/hour (fentanyl alone). When combined with a local anesthetic (eg, bupivacaine), fentanyl requirement is less (Ref).Intrathecal: Note: Reserve use for patients with severe acute pain (eg, after major abdominal surgery, cancer pain, during labor and delivery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (Ref). Use a preservative-free formulation intended for neuraxial use (Ref).Single dose: 15 to 25 mcg; may provide adequate relief for up to 6 hours. When combined with a local anesthetic (eg, bupivacaine), fentanyl dose requirement is less (eg, 10 to 15 mcg instead of 15 to 25 mcg) (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: Although limited pharmaco*kinetic data exist in patients with renal insufficiency, <7% to 10% of fentanyl is excreted as unchanged drug and its metabolites are inactive. Fentanyl may be used and is generally considered safe for use in patients with kidney impairment with low initial doses and careful monitoring for accumulation and adverse effects (Ref).Altered Kidney Function:Injection: CrCl <50 mL/minute:No dosage adjustment necessary when single or infrequent bolus doses are used for short interventional procedures (Ref). For more frequent dosing, use small, incremental doses to titrate based on analgesic response and adverse effects (Ref). May need to decrease dose to avoid accumulation (Ref), especially with continuous infusions (Ref).Transdermal (patch):Note: Although the manufacturer recommends to avoid use of transdermal fentanyl in severe impairment, fentanyl can be used safely in these patients with caution and close monitoring with initial and long-term use (Ref). The following dose adjustments have been proposed when initiating transdermal fentanyl:CrCl >50 mL/minute: No dosage adjustment necessary.CrCl 10 to 50 mL/minute: Initial: 75% of normal dose (Ref).CrCl <10 mL/minute: Initial: 50% of normal dose (Ref).Transdermal (device): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); fentanyl pharmaco*kinetics may be altered in kidney disease.Transmucosal (buccal tablet, sublingual spray/tablet, lozenge) and intranasal: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Although fentanyl pharmaco*kinetics may be altered in kidney disease, transmucosal fentanyl can be used successfully in the management of breakthrough cancer pain. Doses should be titrated to reach clinical effect with careful monitoring of patients with severe kidney disease.Dialysis, Intermittent (thrice weekly): Not dialyzable (Ref):Transdermal patch: Initial: 50% of normal dose (Ref).All other formulations/routes: Use lowest effective dose with gradual titration and close monitoring of response and adverse effects (Ref).Peritoneal dialysis:Transdermal patch: Initial: 50% of normal dose (Ref).All other formulations/routes: Use lowest effective dose with gradual titration and close monitoring of response and adverse effects (Ref).CRRT: All formulations/routes: Use lowest effective dose with gradual titration and close monitoring of response and adverse effects (Ref).Dosing: Hepatic Impairment: AdultInjection: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.Transdermal (device): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); fentanyl pharmaco*kinetics may be altered in hepatic disease.Transdermal (patch):Mild to moderate impairment: Initial: Reduce dose by 50%.Severe impairment: Use not recommended.Transmucosal (buccal tablet, sublingual spray/tablet, lozenge) and intranasal: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Although fentanyl pharmaco*kinetics may be altered in hepatic disease, fentanyl can be used successfully in the management of breakthrough cancer pain. Doses should be titrated to reach clinical effect with careful monitoring of patients with severe hepatic disease.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productLiquid, Sublingual, as base: Subsys: 100 mcg (1 ea [DSC], 10 ea); 200 mcg (1 ea [DSC], 30 ea); 400 mcg (1 ea [DSC], 30 ea); 600 mcg (1 ea [DSC], 30 ea); 800 mcg (1 ea, 30 ea); 1200 mcg (2 ea); 1600 mcg (2 ea) [contains alcohol, usp, levomenthol, propylene glycol]Lozenge on a Handle, Buccal, as citrate [strength expressed as base]: Actiq: 200 mcg (1 ea, 30 ea); 400 mcg (1 ea, 30 ea); 600 mcg (1 ea, 30 ea); 800 mcg (1 ea, 30 ea); 1200 mcg (1 ea, 30 ea); 1600 mcg (1 ea, 30 ea) [berry flavor]Generic: 200 mcg (1 ea, 30 ea); 400 mcg (1 ea, 30 ea); 600 mcg (1 ea, 30 ea); 800 mcg (1 ea, 30 ea); 1200 mcg (1 ea, 30 ea); 1600 mcg (1 ea, 30 ea)Patch, Transdermal, as hydrochloride [strength expressed as base]: Ionsys: 40 mcg/actuation (1 ea [DSC], 6 ea [DSC])Patch 72 Hour, Transdermal, as base: Duragesic-12: 12 [delivers 12.5 mcg/hr] (5 ea [DSC])Duragesic-25: 25 [delivers 25 mcg/hr] (5 ea [DSC])Duragesic-50: 50 [delivers 50 mcg/hr] (5 ea [DSC])Duragesic-75: 75 [delivers 75 mcg/hr] (5 ea [DSC])Duragesic-100: 100 [delivers 100 mcg/hr] (5 ea [DSC])Generic: 100 [delivers 100 mcg/hr] (1 ea, 5 ea); 12 [delivers 12.5 mcg/hr] (1 ea, 5 ea); 25 [delivers 25 mcg/hr] (1 ea, 5 ea); 37.5 [delivers 37.5 mcg/hr] (1 ea, 5 ea); 50 [delivers 50 mcg/hr] (1 ea, 5 ea); 62.5 [delivers 62.5 mcg/hr] (1 ea, 5 ea); 75 [delivers 75 mcg/hr] (1 ea, 5 ea); 87.5 [delivers 87.5 mcg/hr] (1 ea, 5 ea)Solution, Injection [preservative free]: Generic: 2500 mcg/50 mL (50 mL)Solution, Injection, as citrate [preservative free]: Generic: 50 mcg/mL (1 mL); 2500 mcg/50 mL (50 mL)Solution, Injection, as citrate [strength expressed as base, preservative free]: Generic: 100 mcg/2 mL (2 mL); 1000 mcg/20 mL (20 mL); 250 mcg/5 mL (5 mL); 500 mcg/10 mL (10 mL)Solution, Intravenous, as citrate [strength expressed as base]: Generic: 2500 mcg/50 mL (50 mL)Solution, Nasal, as citrate [strength expressed as base]: Lazanda: 100 mcg/actuation (1 ea); 400 mcg/actuation (1 ea); 300 mcg/spray (1 ea [DSC]) [contains propylparaben]Solution Cartridge, Injection, as citrate [strength expressed as base, preservative free]: Generic: 100 mcg/2 mL (2 mL)Solution Prefilled Syringe, Injection, as citrate: Generic: 100 mcg/2 mL (2 mL)Solution Prefilled Syringe, Injection, as citrate [preservative free]: Generic: 50 mcg/mL (1 mL)Solution Prefilled Syringe, Intravenous, as citrate: Generic: 100 mcg/10 mL (10 mL); 500 mcg/50 mL (50 mL); 1000 mcg/20 mL (20 mL); 2500 mcg/50 mL (50 mL)Solution Prefilled Syringe, Intravenous, as citrate [strength expressed as base]: Generic: 100 mcg/2 mL (2 mL)Tablet, Buccal, as citrate [strength expressed as base]: Fentora: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcgGeneric: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcgTablet Sublingual, Sublingual, as citrate [strength expressed as base]: Abstral: 100 mcg [DSC], 200 mcg [DSC], 300 mcg [DSC], 400 mcg [DSC], 600 mcg [DSC], 800 mcg [DSC]Generic Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Patch 72 Hour, Transdermal: Generic: 37 mcg/hr (5 ea)Patch 72 Hour, Transdermal, as base: Generic: 100 [delivers 100 mcg/hr] (5 ea); 12 [delivers 12.5 mcg/hr] (5 ea); 25 [delivers 25 mcg/hr] (5 ea); 50 [delivers 50 mcg/hr] (5 ea); 75 [delivers 75 mcg/hr] (5 ea)Solution, Injection, as citrate: Generic: 50 mcg/mL (1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 50 mL)Solution, Injection, as citrate [strength expressed as base]: Generic: 100 mcg/2 mL (2 mL)Tablet, Buccal, as citrate [strength expressed as base]: Fentora: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcgProduct AvailabilityIonsys (transdermal device) and Abstral (sublingual tablets) have been discontinued in the United States for >1 year.Controlled SubstanceC-IIPrescribing and Access RestrictionsAs a requirement of the REMS program, access is restricted.Transmucosal immediate-release fentanyl products (eg, sublingual tablets and spray, oral lozenges, buccal tablets, intranasal) are only available through the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS program. Enrollment in the program is required for outpatients, prescribers for outpatient use, pharmacies (inpatient and outpatient), and distributors. Enrollment is not required for inpatient administration (eg, hospitals, hospices, long-term care facilities), inpatients, and prescribers who prescribe to inpatients. Further information is available at 1-866-822-1483 or at www.TIRFREMSaccess.comNote: Effective December, 2011, individual REMs programs for TIRF products were combined into a single access program (TIRF REMS Access). Prescribers and pharmacies that were enrolled in at least one individual REMS program for these products will automatically be transitioned to the single access program.Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Abstral: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022510s018lbl.pdf#page=29Actiq: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020747s056lbl.pdf#page=43Duragesic: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/019813s081lbl.pdf#page=52Fentora: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021947s038lbl.pdf#page=42Lazanda: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022569s030lbl.pdf#page=35Onsolis: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022266s025lbl.pdf#page=32Subsys: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202788s023lbl.pdf#page=40Administration: PediatricParenteral: IV:Neonates: Administer as a continuous infusion via an infusion pump or by slow IV push over 3 to 5 minutes. Larger bolus doses (>5 mcg/kg) should be administered over 5 to 10 minutes; may also administer intermittent doses via syringe pump over 15 to 30 minutes (Ref). Risk of chest wall rigidity is minimized when doses are administered over at least 1 to 2 minutes (Ref).Infants, Children, and Adolescents: Administer by slow IV push over 3 to 5 minutes or by continuous infusion. Larger bolus doses (>5 mcg/kg) should be given by slow IV push over 5 to 10 minutes.Transdermal patch: Children ≥2 years and Adolescents: Apply to nonhairy, clean, dry, nonirritated, intact skin of the flat area of front or back of upper torso, flank area, or upper arm; apply to upper back in young children or in people with cognitive impairment to decrease the potential of the patient removing the patch. Monitor the adhesion of the system closely in children. Clip hair prior to application, do not shave area; prior to application, skin may be cleaned with clear water (do not use soaps, lotions, alcohol, oils, or other substances which may irritate the skin); allow skin to dry thoroughly prior to application. Apply patch immediately after removing from package; firmly press in place and hold for at least 30 seconds; change patch every 72 hours; remove old patch before applying new patch; do not apply new patch to same place as old patch; wash hands after applying patch. If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape; if difficulty with adhesion persists, an adhesive film dressing (eg, Bioclusive, Tegaderm) may be applied over the system. If patch falls off before 72 hours, a new patch may be applied to a different skin site. Dispose of any used or unused patches by removing patch from protective pouch and liner, fold adhesive ends together and flush patch down toilet immediately. Do not flush pouch or protective liner as such items can be discarded in the trash.Note: Transdermal patch is a membrane-controlled system; do not cut the patch to deliver partial doses; do not use patches that are cut, damaged, or leaking; do not use if seal of package is broken; rate of drug delivery may be significantly increased if patch is cut, damaged, or leaking and result in absorption of a potentially fatal dose; reservoir contents and adhesion may be affected if cut; if partial dose is needed, surface area of patch can be blocked proportionally using adhesive bandage (Ref). Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin as they may increase transdermal absorption; use copious amounts of water. Avoid exposing application site to external heat sources (eg, electric blanket, heating pad, heat lamp, tanning lamp, sauna, heated water bed, hot tub, hot baths, sunbathing). Dispose of properly.Transmucosal products:Intranasal (using parenteral preparation):Solution (parenteral preparation): If congested, suction nostrils prior to administration. Using a 50 mcg/mL solution, administer half of the dose to each nostril using an atomizer such as the MAD Nasal Drug delivery device or drip into the nostril slowly with a syringe; higher concentrations (150 mcg/mL and 300 mcg/mL) have been studied to prevent excess volume administration, but comparative trials have not been performed (Ref).Oral lozenge (eg, Actiq): Adolescents ≥16 years: Oral: Foil overwrap should be removed just prior to administration, patient should place the unit in mouth between cheek and lower gum; occasionally move lozenge from one side of the mouth to the other and allow it to dissolve. Do not bite or chew lozenge; consume lozenge over 15 minutes. Remove handle after lozenge is consumed. Early removal should be considered if the patient has achieved an adequate response and/or shows signs of respiratory depression. After consumption of a complete unit, the handle may be disposed of in a trash container that is out of the reach of children. For a partially consumed unit, or a unit that still has any drug matrix remaining on the handle, the handle should be placed under hot running tap water until the drug matrix has dissolved. Special child-resistant containers are available to temporarily store partially consumed units that cannot be disposed of immediately.Administration: AdultEpidural (Canadian labeling; not in US labeling): For postoperative pain management may administer as bolus dose (diluted in preservative free NS to a final concentration of 10 mcg/mL) or by continuous infusion at a rate of 1 mcg/kg/hour. Use within 24 hours.Parenteral: Administer IM or IV slowly over 1 to 2 minutes; rapid IV infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest. May also administer SubQ, by continuous infusion, or PCA (off-label).Transdermal device (eg, Ionsys): Always wear gloves when handling the device. Avoid contact with synthetic materials (such as carpeted flooring) while assembling and avoid exposing the device to electronic security systems. Prior to administration, clip excessive hair from application site if necessary (do not shave); clean the site with alcohol and let dry; do not use soaps, lotions, or other agents. Apply one device to healthy, unbroken/intact, non-irritated, and non-irradiated skin on the chest or upper outer arm only. Allow only the patient to self-administer doses; each on-demand dose is delivered over a 10-minute period. Each device operates up to 24 hours or 80 doses, whichever comes first. After 24 hours have elapsed, or 80 doses have been delivered, the device will not deliver any additional doses; if the patient tries to initiate a dose, the device will ignore the dose request. Ionsys may be used for a maximum of 72 hours, with each subsequent device applied to a different skin site. Refer to manufacturer's labeling for complete activation, administration, and removal instructions.Transdermal patch (eg, Duragesic): Apply to nonirritated and nonirradiated skin on a flat surface, such as chest, back, flank, or upper arm; apply to the upper back in patients with cognitive impairment. Hair at application site may be clipped (do not shave). If application site must be cleaned prior to application, clean site with clear water and allow to dry completely. Do not use damaged, cut or leaking patches; patch may be less effective. Do not use soaps, oils, lotions, alcohol, or any other agents to cleanse skin before application because they may irritate the skin or alter its characteristics. Immediately after removal from sealed package, firmly press patch in place and hold for 30 seconds. Wash hands immediately with soap and water after applying patch. Change patch every 72 hours; apply new patch to a different skin site. Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl and should be avoided. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, tanning lamps, hot tub, sunbathing, saunas, heated water beds). If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape. If there is continued difficulty with adhesion, an adhesive film dressing (eg, Bioclusive, Tegaderm) may be applied over the system. Dispose of any used or unused patches by removing patch from protective pouch and liner, fold adhesive ends together and flush patch down toilet immediately. Do not flush pouch or protective liner as such items can be discarded in the trash. For used and unused patches, the Canadian labeling recommends folding adhesive ends together and returning to a pharmacy for proper disposal; temporary storage in a biohazard container may be used before returning to pharmacy.Lozenge: Foil overwrap should be removed just prior to administration. Place the unit in mouth between the cheek and gum and allow it to dissolve. Do not chew. Lozenge may be moved from one side of the mouth to the other using the handle. The unit should be consumed over a period of 15 minutes. After consumption of a complete unit, the handle may be disposed of in a trash container that is out of the reach of children. For a unit that still has any drug matrix remaining on the handle, the handle should be placed under hot running tap water until the entire drug matrix has dissolved. Special child-resistant containers are available to temporarily store partially consumed units that cannot be disposed of immediately. Refer to manufacturer's labeling for additional disposal instructions.Buccal tablet: Patient should not open blister until ready to administer. The blister backing should be peeled back to expose the tablet; tablet should not be pushed out through the blister. Immediately use tablet once removed from blister. Place entire tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or under the tongue (US labeling recommends for maintenance dosing only; Canadian labeling does not restrict sublingual use to maintenance dosing only); should dissolve in about 14 to 25 minutes. If remnants remain after 30 minutes, they may be swallowed with water. Tablet should not be split, crushed, sucked, chewed, or swallowed whole. When possible, alternate sides of mouth with each dose.Intranasal:Lazanda: Prior to initial use, prime device by spraying 4 sprays into the provided pouch (the counting window will show a green bar when the bottle is ready for use). Insert nozzle a short distance into the nose (~1/2 inch or 1 cm) and point towards the bridge of the nose (while closing off the other nostril using 1 finger). Press on finger grips until a “click” sound is heard and the number in the counting window advances by one. The “click” sound and dose counter are the only reliable methods for ensuring a dose has been administered (spray is not always felt on the nasal mucosa). Patient should remain seated for at least 1 minute following administration. Do not blow nose for ≥30 minutes after administration. Wash hands before and after use. If not used within 5 days, re-prime by spraying once. There are 8 full therapeutic sprays in each bottle; do not continue to use bottle after “8” sprays have been used. Dispose of bottle and contents if it has been ≥60 days since first use. Before disposal, all unopened or partially used bottles must be completely emptied by spraying the contents into the provided pouch. After “8” therapeutic sprays has been reached on the counter, patients should continue to spray an additional four sprays into the pouch to ensure that any residual fentanyl has been expelled (an audible click will no longer be heard and the counter will not advance beyond “8”). The empty bottle and the sealed pouch must be put into the child-resistant container before placing in the trash. Wash hands with soap and water immediately after handling the pouch. If the pouch is lost, another one can be ordered by the patient or caregiver by calling 1-866-458-6389.Parenteral solution (off-label route): Using 50 mcg/mL parenteral solution, administer half the dose in each nostril using a mucosal atomizer device (preferred) or drip into nostril with a needleless syringe; maximum volume per nostril: 1 mL (Ref).SubQ continuous infusions: Change site every 3 to 7 days or when erythema occurs (Ref). To maintain comfort, the SubQ infusion rate should generally not exceed 5 mL/hour (Ref).Sublingual spray: Open sealed blister unit with scissors immediately prior to administration. Contents of unit should be sprayed into mouth under the tongue. Dispose of each unit dose immediately after use; place used unit into one of the provided white disposal bags. After sealing appropriately, discard in the trash. Dispose of any unused units as soon as no longer needed. Prior to disposal, empty all the medicine into the provided charcoal-lined disposal pouch. The disposal pouch should then be placed into the white disposal bag, sealed appropriately, and discarded in the trash.Sublingual tablet: Remove from the blister unit immediately prior to administration. Place tablet directly under the tongue on the floor of the mouth and allow to completely dissolve; do not chew, suck, or swallow. Do not eat or drink anything until tablet is completely dissolved. In patients with a dry mouth, water may be used to moisten the buccal mucosa just before administration. To dispose of sublingual tablets; remove any unused tablets from the blister cards and dispose by flushing down the toilet. In Canada, it is recommended that unused tablets be disposed of via a pharmacy take back program.Usual Infusion Concentrations: NeonatalIV infusion: 10 mcg/mL Usual Infusion Concentrations: PediatricIV infusion: 10 mcg/mL, 50 mcg/mLStorage/StabilityInjection: Store intact vials in original carton at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.Intranasal: Do not store above 25°C (77°F); do not freeze. Protect from light. Bottle should be stored in the provided child-resistant container when not in use and kept out of the reach of children at all times.Transdermal device, transdermal patch, transmucosal (buccal tablet, lozenge, sublingual spray, sublingual tablet): Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect transmucosal products from freezing and moisture. Keep all products out of the reach of children.UseParenteral: Relief of pain; preoperative medication; adjunct to general or regional anesthesia (FDA approved in ages ≥2 years and adults); has also been used for sedation and intranasally for analgesia.Transdermal patch (eg, Duragesic): Treatment of persistent, moderate-to-severe chronic pain in opioid-tolerant patients who are currently receiving opioids (FDA approved in ages ≥2 years and adults); see Note.Transdermal device (eg, Ionsys): Short-term management of acute postoperative pain requiring opioid analgesia in the hospital (FDA approved in adults).Transmucosal products:Buccal tablet (eg, Fentora): Breakthrough cancer pain in opioid-tolerant patients who are currently receiving around-the-clock opioids for persistent cancer pain (FDA approved in adults); see Note.Nasal spray (eg, Lazanda): Breakthrough cancer pain in opioid-tolerant patients who are currently receiving around-the-clock opioids for persistent cancer pain (FDA approved in adults); see Note.Oral lozenge (eg, Actiq): Breakthrough cancer pain in opioid-tolerant patients who are currently receiving around-the-clock opioids for persistent cancer pain (FDA approved in ages ≥16 years and adults); see Note.Sublingual spray (eg, Subsys): Breakthrough cancer pain in opioid-tolerant patients who are currently receiving around-the-clock opioids for persistent cancer pain (FDA approved in adults); see Note.Sublingual tablet (eg, Abstral): Breakthrough cancer pain in opioid-tolerant patients who are currently receiving around-the-clock opioids for persistent cancer pain (FDA approved in adults); see Note.Note: Patients are considered opioid-tolerant if they are receiving around-the-clock opioids at a dose of at least 60 mg/day of oral morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day of oral oxycodone, 8 mg/day of oral hydromorphone, 25 mg/day of oral oxymorphone or an equivalent dose of another opioid for 1 week or longer.Medication Safety IssuesSound-alike/look-alike issues:FentaNYL may be confused with alfentanil, SUFentanilHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.Administration issues:Fentanyl transdermal system patches: Leakage of fentanyl gel from the patch has been reported; patch may be less effective; do not use. Thoroughly wash any skin surfaces coming into direct contact with gel with water (do not use soap). May contain conducting metal (eg, aluminum); remove patch prior to MRI.Other safety concerns:Fentanyl transdermal system patches:Avoid use of patches in opioid-naive patients and/or acute pain. Patches are only intended for use in opioid-tolerant patients; steps should be taken to verify opioid status and type of pain being treated prior to prescribing to prevent inappropriate use. Serious harm, including fatalities, are associated with use of patches in opioid-naive patients. Dosing of transdermal fentanyl patches may be confusing. Transdermal fentanyl patches should always be prescribed in mcg/hour, not size. Patch dosage form of Duragesic-12 actually delivers 12.5 mcg/hour of fentanyl. Use caution, as orders may be written as “Duragesic 12.5” which can be erroneously interpreted as a 125 mcg dose.Patches should be stored and disposed of with care to avoid accidental exposure to children. The FDA has issued numerous safety advisories to warn users of the possible consequences (including hospitalization and death) of inappropriate storage or disposal of patches. According to the 2020 to 2021 ISMP Targeted Medication Safety Best Practices for Hospitals, patches should not be stored in automated dispensing cabinets or as unit stock in clinical areas where acute pain is primarily treated (eg, emergency departments, operating rooms, postanesthesia care units, procedural areas).Abstral, Actiq, Fentora, and Subsys are not interchangeable; do not substitute doses on a mcg-per-mcg basis.Adverse Reactions (Significant): ConsiderationsOpioid-induced constipationOpioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction (OIBD), which is a broader term that encompasses additional GI opioid-induced adverse reactions including nausea, vomiting, and gastroesophageal reflux. Tolerance does not develop to OIC (Ref). Constipation due to fentanyl may decrease quality of life, contribute to nonadherence, and result in treatment failure (Ref). Transdermal fentanyl may cause less constipation than oral opioids (eg, oxycodone, morphine) (Ref). Fentanyl may cause less constipation than morphine in critically ill children (Ref).Mechanism: Time-related; activity in both the central and enteric nervous systems, predominantly via the mu-opioid receptor, delays gastric emptying, inhibits peristalsis, impairs enzyme release, and produces antisecretory effects (Ref).Onset: Varied; changes in peristalsis may occur 5 to 25 minutes after administration of opioids (Ref). However, OIC is defined based on a 7-day period of change (Ref).Risk factors:• Chronic opioid administration (Ref)Opioid-induced respiratory depressionSerious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of fentanyl (Ref). Fentanyl may be particularly hazardous secondary to potency, faster onset of action, and lower cross tolerance (Ref).Mechanism: Dose-related; mediated predominately via the mu-opioid receptor. Activates specific CNS sites (ie, pre-Bötzinger complex and Kölliker-Fuse nucleus) that control respiratory rhythms (Ref).Onset: Rapid; OIRD reported from 5 minutes to 1.2 hours (Ref).Risk factors:• Overdose (but may also occur at therapeutic doses)• Initiation or dose escalation• Opioid naive (Ref)• Opioid misuse/abuse (Ref)• Respiratory disease (eg, obstructive sleep apnea) (Ref)• Cardiac disease (Ref)• Morbid obesity (Ref)• Older adults• Kidney and/or liver impairment• Cachectic or debilitated• Concurrent benzodiazepines or other CNS depressants• Concurrent use with cytochrome P450 3A4 inhibitorsOpioid-induced withdrawalAbrupt discontinuation or dose reduction in patients who are physically dependent (ie, have opioid dependence) to opioids has been associated with a serious opioid-induced withdrawal syndrome (OIW), uncontrolled pain, attempts to find other opioids (including illicit), and suicide in all ages. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Reversal of analgesia, irritability, nausea, and vomiting, abdominal cramping, tachycardia, restlessness, and sweating are common symptoms. Symptoms typically dissipate over 4 to 7 days and fully resolve within 14 days; may cause significant distress but are rarely life-threatening (Ref).Mechanism: Withdrawal; abrupt discontinuation in patients who are physically dependent on opioids results in noradrenergic hyperactivity. This hyperactivity occurs due to abrupt reversal of adaptive mechanisms related to cAMP, locus coeruleus firing rate, and norepinephrine levels that occur with prolonged exposure to opioids (Ref).Onset: Rapid; symptoms typically occur within 12 hours after discontinuation and peak at 36 to 72 hours; varies based on half-life of opioid (Ref).Risk factors:• Prolonged exposure to opioids (Ref)- Pediatrics: Neonates >1 week, infants, and children <22 months: Duration of ≥9 days or a total dose ≥2.5 mg/kg has been associated with a 100% chance of developing opioid withdrawal; similarly, a duration of 5 days or a total dose of 1.5 mg/kg has a reported 50% chance of developing opioid withdrawal (Ref)• Opioid use disorder (Ref)• Abrupt discontinuation or dose reduction (Ref)• Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics• Discontinuation of concurrent cytochrome P450 3A4 inhibitorsAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Cardiovascular: Peripheral edema (5% to 32%)Dermatologic: Hyperhidrosis (1% to 14%)Endocrine & metabolic: Dehydration (9% to 21%), hypokalemia (2% to 15%), weight loss (3% to 11%)Gastrointestinal: Abdominal pain (3% to 15%), anorexia (5% to 11%), constipation (1% to 26%), diarrhea (6% to 16%), dysgeusia (1% to 14%), nausea (2% to 42%), vomiting (1% to 37%)Hematologic & oncologic: Anemia (3% to 32%), cancer pain (2% to 16%)Local: Application site erythema (transdermal device: 14%)Nervous system: Confusion (1% to 16%), depression (1% to 11%), dizziness (1% to 32%), drowsiness (3% to 20%), fatigue (2% to 20%), headache (1% to 17%), insomnia (1% to 11%)Neuromuscular & skeletal: Asthenia (2% to 30%), back pain (4% to 11%)Respiratory: Dyspnea (2% to 19%), pneumonia (2% to 16%)1% to 10%:Cardiovascular: Bradycardia (≥1%), chest pain (≥1%), chest wall pain (≥1%), deep vein thrombosis (≥1%), edema (≥1%), hypertension (≥1%), hypotension (2%), palpitations (4%), pulmonary embolism (nasal spray: ≥1%), sinus tachycardia (≥1%), tachycardia (≥1%), vascular injury (≥1%), vasodilation (1% to 4%)Dermatologic: Alopecia (≥1%), cellulitis (≥1%), dermal ulcer (≥1%), diaphoresis (1% to 3%), ecchymoses (≥1%), erythema of skin (1%), night sweats (≥1%), pallor (≥1%), pressure ulcer (≥1%), pruritus (1% to 6%), skin lesion (≥1%), skin rash (1% to 8%)Endocrine & metabolic: Cachexia (≥1%), hypercalcemia (≥1%), hyperglycemia (≥1%), hypoalbuminemia (≥1%), hypocalcemia (≥1%), hypomagnesemia (≥1%), hyponatremia (≥1%), lactic acidosis (≥1%)Gastrointestinal: Abdominal distention (≥1%), aphthous stomatitis (sublingual tablet: ≥1%), decreased appetite (≥1%), delayed gastric emptying (≥1%), dyspepsia (≥1%), dysphagia (lozenge, buccal tablet, sublingual spray: ≥1%), eructation (≥1%), flatulence (≥1%), gastritis (≥1%), gastroenteritis (≥1%), gastroesophageal reflux disease (≥1%), gastrointestinal hemorrhage (≥1%), gingival pain (buccal tablet: ≥1%), gingival ulceration (sublingual tablet: ≥1%), gingivitis (lozenge: ≥1%), glossalgia (≥1%), glossitis (lozenge: ≥1%), hematemesis (≥1%), intestinal obstruction (2% to 4%; subileus: <1%), mucosal swelling (buccal tablet: ≥1%), oral candidiasis (lozenge, buccal tablet, sublingual spray: ≥1%), oral herpes simplex infection (≥1%), oral mucosa ulcer (lozenge, buccal and sublingual tablets, nasal spray: ≥1%; including lip ulceration), periodontal abscess (lozenge: (≥1%), rectal disease (≥1%), rectal pain (≥1%), stomach discomfort (≥1%), stomatitis (lozenge, buccal and sublingual tablets, sublingual spray: 1% to 8%), tongue disease (sublingual tablet: ≥1%), upper abdominal pain (3%), xerostomia (1% to 6%)Genitourinary: Difficulty in micturition (≥1%), dysuria (≥1%), erectile dysfunction (≥1%), hematuria (≥1%), mastalgia (≥1%), pelvic pain (≥1%), scrotal edema (≥1%), urinary incontinence (≥1%), urinary retention (1% to 3%), urinary tract infection (≥1%), urinary urgency (≥1%), vagin*l hemorrhage (≥1%), vaginitis (≥1%)Hematologic & oncologic: Breast neoplasm (≥1%), bruise (≥1%), leukopenia (≥1%), lymphadenopathy (≥1%), lymphedema (≥1%), neutropenia (2% to 8%), pancytopenia (≥1%), rectal hemorrhage (≥1%), thrombocytopenia (≥1%)Hepatic: Ascites (≥1%), increased serum alkaline phosphatase (≥1%), increased serum aspartate aminotransferase (≥1%), jaundice (≥1%)Hypersensitivity: Hypersensitivity reaction (≥1%)Infection: Fungal infection (≥1%), infection (≥1%), influenza (≥1%), sepsis (≥1%), tooth abscess (≥1%), viral infection (≥1%)Local: Application site irritation (buccal tablet, sublingual spray: ≤3%), application site pain (buccal tablet, transdermal device: ≤4%), application site reaction (buccal tablet, transdermal patch: ≤10%), application site vesicles (buccal tablet, nasal spray, transdermal patch and device: ≤3%)Nervous system: Abnormal dreams (1%), abnormal gait (1% to 5%), abnormality in thinking (1% to 2%), agitation (≥1%), altered sense of smell (≥1%), amnesia (≥1%), anxiety (2% to 9%), balance impairment (≥1%), chills (≥1%), disorientation (≥1%), disturbance in attention (≥1%), dysphoria (≥1%), emotional lability (≥1%), euphoria (≥1%), falling (≥1%), hallucination (1% to 2%), hypertonia (2%), hypoesthesia (≥1%), irritability (≥1%), lethargy (≥1%), malaise (4%), mental status changes (≥1%), migraine (≥1%), myasthenia (≥1%), myoclonus (4%), nervousness (1% to 4%), neuropathy (≥1%), pain (≥1%), paranoid ideation (≥1%), paresthesia (2%), peripheral neuropathy (≥1%), restlessness (≥1%), sedated state (≥1%), seizure (1% to 2%), sensation of cold (6%), sleep disturbance (≥1%), speech disturbance (≥1%), stupor (1% to 4%), tightness in chest or throat (≥1%), vertigo (1% to 4%), withdrawal syndrome (≥1%)Neuromuscular & skeletal: Arthralgia (3% to 8%), arthropathy (≥1%), bone disease (≥1%), hypokinesia (≥1%), limb pain (≥1%), lower limb cramp (≥1%), muscle spasm (4%), myalgia (≥1%), neck pain (≥1%), ostealgia (≥1%), pathological fracture (≥1%), shoulder pain (≥1%), tremor (1% to 3%)Ophthalmic: Blepharoptosis (nasal spray: ≥1%), blurred vision (≥1%), conjunctivitis (≥1%), dry eye syndrome (nasal spray: ≥1%), strabismus (nasal spray: ≥1%), swelling of eye (nasal spray: ≥1%), visual disturbance (1% to 2%)Otic: Ear disease (≥1%, including pain), tinnitus (≥1%)Renal: Hydronephrosis (≥1%), renal failure syndrome (≥1%)Respiratory: Asthma (≥1%), bradypnea (≥1%), bronchitis (≥1%), cough (3% to 9%; increased cough: ≥1%), dyspnea on exertion (≥1%), epistaxis (≥1%), flu-like symptoms (≥1%), hemoptysis (≥1%), hypoxia (≥1%), increased bronchial secretions (≥1%), laryngitis (sublingual spray: ≥1%), nasal congestion (nasal spray: ≥1%), nasal discomfort (nasal spray: ≥1%), nasopharyngitis (≥1%), oropharyngeal pain (≥1%), pharyngitis (≥1%), pharyngolaryngeal pain (≥1%), pleural effusion (≥1%), post nasal drip (nasal spray: ≥1%), rhinitis (≥1%), rhinorrhea (nasal spray: ≥1%), sinusitis (≥1%), upper respiratory tract infection (≥1%), wheezing (≥1%)Miscellaneous: Fever (5% to 7%), reduced intake of food/fluids (buccal tablet: ≥1%)<1%:Cardiovascular: Angina pectoris, cerebral ischemia, facial edema, orthostatic hypotension, peripheral vascular disease, subdural hematomaDermatologic: Allergic dermatitis, cheilitis, contact dermatitis, contact hypersensitivity (transdermal patch, application site), eczema, exfoliative dermatitis, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash (application site: transdermal device, lozenge)Endocrine & metabolic: Decreased libido, hypoglycemia, increased thirstGastrointestinal: Dental caries, esophagitis, fecal impaction, fecal incontinence, gastrointestinal disease, gingival hemorrhage (lozenge), hiccups, mucous membrane diseaseGenitourinary: Nocturia, oliguria, sexual disorderHematologic & oncologic: Granuloma, hemorrhage, prolonged bleeding timeHepatic: Hepatorenal syndrome, liver tendernessInfection: Bacterial infection, herpes zoster infectionLocal: Application-site dermatitis (transdermal patch), local skin hyperpigmentation (transdermal device, lasting 2 to 3 weeks)Nervous system: Ataxia, delirium, facial nerve paralysis, flank pain, hemiplegia, voice disorderNeuromuscular & skeletal: Amyotrophy, arthritis, foot-drop, muscle twitching, myopathy, neck stiffness, synovitis, tendinopathyOphthalmic: Disease of the lacrimal apparatus, injury to eye region (hemorrhage), miosisOtic: Deafness, reversible hearing lossRenal: Polyuria, pyelonephritis, renal painRespiratory: Cyanosis, hyperventilation, pneumothorax, pulmonary disease, respiratory depression, respiratory failure, respiratory insufficiencyMiscellaneous: CystFrequency not defined:Cardiovascular: Acute myocardial infarction, atrial fibrillation, bigeminy, cardiac arrhythmia, flushing, syncopeDermatologic: Exfoliation of skin (application site, transdermal device), papule of skin (application site, transdermal device), pustules (application site, transdermal device), xeroderma (application site, transdermal device)Infection: AbscessLocal: Application site burning (transdermal device), application site discharge (transdermal device), application site edema (transdermal device), application site itching (transdermal device), application site rash (transdermal device)Nervous system: Drug abuse, hypothermia, neonatal withdrawal, opioid dependenceRespiratory: AtelectasisMiscellaneous: Abnormal healingPostmarketing:Dermatologic: Crusted skin (application site scab, transdermal device), skin erosion (application site, transdermal patch)Gastrointestinal: Gingival recession (lozenge), tooth loss (lozenge)Genitourinary: Hypogonadism (Brennan 2013; Debono 2011)Hematologic & oncologic: Local hemorrhage (application site, transdermal device)Infection: Localized infection (application site, transdermal device)Local: Local tissue necrosis (application site, transdermal device)Nervous system: Hyperesthesia, impaired consciousness, loss of consciousnessNeuromuscular & skeletal: Laryngospasm, muscle rigidity (can be dose related)Respiratory: Apnea, hypoventilation, respiratory distressContraindicationsHypersensitivity (eg, anaphylaxis, hypersensitivity) to fentanyl or any component of the formulation.Additional contraindications for transdermal device (Ionsys): Significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; gastrointestinal obstruction, including paralytic ileus (known or suspected); hypersensitivity to cetylpyridinium chloride (eg, Cepacol).Additional contraindications for transdermal patch (Duragesic): Significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; gastrointestinal obstruction, including paralytic ileus (known or suspected); patients requiring short-term therapy, management of acute or intermittent pain, postoperative or mild pain; patients who are not opioid tolerant.Additional contraindications for transmucosal buccal tablets (Fentora), lozenges (Actiq), sublingual tablets (Abstral), sublingual spray (Subsys), intranasal (Lazanda): Significant respiratory depression (Actiq, Fentora only); acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; gastrointestinal obstruction, including paralytic ileus (known or suspected); acute or postoperative pain (including headache, migraine, or dental pain); patients who are not opioid tolerant; acute pain management in the emergency room.Canadian labeling: Additional contraindication (not in US labeling):Injection: Hypersensitivity to other opioids; known or suspected mechanical GI obstruction (eg, bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis, pancreatitis); mild pain that can be managed with other pain medications; acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of a monoamine oxidase inhibitor (MAOI); septicemia; severe hemorrhage or shock; local infection at proposed injection site; disturbances in blood morphology and/or anticoagulant therapy or other concomitant drug therapy or medical conditions which could contraindicate the technique of epidural administrationSublingual tablets (Abstral): Severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild pain that can be managed with other pain medications; acute pain management other than breakthrough or postoperative pain (including headache or migraine, dental pain or emergency room use); acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of an MAOI; breastfeeding women; during labor and delivery; opioid-nontolerant patients (including patients on intermittent or as needed opioid dosing).Transdermal patch: Hypersensitivity to other opioids; suspected surgical abdomen (eg, acute appendicitis, pancreatitis); known or suspected mechanical GI obstruction (eg, bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use of MAOIs or within 14 days of therapy; perioperative pain; women who are nursing, pregnant, or during labor and deliveryTransmucosal buccal tablets (Fentora): Hypersensitivity to other opioids; acute pain management in the emergency room; known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); acute or severe bronchial asthma, chronic obstructive airway, status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of an MAOIDocumentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.Disease-related concerns:• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).• Allergic rhinitis: Intranasal: Allergic rhinitis is not expected to alter fentanyl absorption following nasal administration; however, use of nasal decongestants (eg, oxymetazoline) during episodes of rhinitis may result in lower peak concentrations and delayed Tmax, therefore, titration of intranasal fentanyl is not recommended during use of nasal decongestants.• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.• Bradycardia: Use with caution in patients with bradycardia or bradyarrhythmias (may produce further bradycardia).• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.• Delirium tremens: Use with caution in patients with delirium tremens.• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.• Hepatic impairment: Use with caution in patients with hepatic impairment. Avoid transdermal (patch) in patients with severe hepatic impairment.• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).• Obesity: Use with caution in patients who are morbidly obese.• Oral mucositis: Sublingual spray (Subsys): Cancer patients with oral mucositis experienced increased fentanyl exposure following sublingual spray administration; avoid use in patients with ≥ grade 2 mucositis; use with caution in patients with grade 1 mucositis, and closely monitor for respiratory and CNS depression.• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.• Psychosis: Use with caution in patients with toxic psychosis.• Renal impairment: Use with caution in patients with renal impairment.• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate seizures.• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.Special populations:• Older adult: Use with caution in elderly patients; may be more sensitive to adverse effects. Decrease initial dose. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.Dosage form specific issues: • Transdermal iontophoretic system (Ionsys):- Accidental exposure to an intact Ionsys device or to the hydrogel component, especially by children, can result in a fatal overdose of fentanyl. Following accidental contact with the device or its components, immediately rinse the affected area thoroughly with water. Do not use soap, alcohol, or other solvent because they may enhance the drug's ability to penetrate the skin; monitor for signs of respiratory or CNS depression. If the device is not handled correctly using gloves, healthcare professionals are at risk of accidental exposure to a fatal overdose of fentanyl.- Ionsys device is considered magnetic resonance unsafe. The device contains metal parts and must be removed and properly disposed of before an MRI procedure to avoid injury to the patient and damage to device. It is unknown if exposure to an MRI procedure increases release of fentanyl from the device. Monitor any patients wearing the device with inadvertent exposure to an MRI for signs of CNS and respiratory depression.- Use of Ionsys device during cardioversion, defibrillation, X-ray, CT, or diathermy can damage the device from the strong electromagnetic fields set up by these procedures. The device contains radio-opaque components and may interfere with an X-ray image or CT scan. Remove and properly dispose of the device prior to cardioversion, defibrillation, X-ray, CT, or diathermy. Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge and damage to the device. Avoid exposing the device to electronic security systems to reduce the possibility of damage. Use near communications equipment (eg, base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast Radio) and Radio Frequency Identification (RFID) transmitters can damage the device. Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between the device and communications equipment or the RFID transmitter ranges between 0.12 and 23 meters. The low-level electrical current provided by the device does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment. If exposure to the procedures listed above, electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs, and if the device does not appear to function normally, remove and replace with a new device.- Topical skin reactions (erythema, sweating, vesicles, papules/pustules) may occur with use and are typically limited to the application site area. If a severe skin reaction is observed, remove device and discontinue further use.• Transdermal patch:- Serum fentanyl concentrations may increase by approximately one-third for patients with a body temperature of 40°C (104°F) secondary to a temperature-dependent increase in fentanyl release from the patch and increased skin permeability.- Avoid unclothed/unwashed application site exposure, inadvertent person-to-person patch transfer (eg, while hugging), incidental exposure (eg, sharing same bed, sitting on patch), intentional exposure (eg, chewing), or accidental exposure by caregivers when applying/removing patch.- May contain conducting metal (eg, aluminum); remove patch prior to MRI.Other warnings/precautions:• Abuse/misuse/diversion:Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age and psychotropic medication use.• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain antiseizure medications and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of) or substance use disorder, have higher opioid dosages (≥50 MME/day orally) (CDC [Dowell 2016]), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.Warnings: Additional Pediatric ConsiderationsDosage form specific:Use transdermal patch in pediatric patients only if they are opioid-tolerant, receiving at least 60 mg oral morphine equivalents per day, and ≥2 years of age.Use of Actiq was evaluated in a clinical trial of 15 opioid-tolerant pediatric patients (age: 5 to 15 years) with breakthrough pain; 12 of the 15 patients received doses of 200 mcg to 600 mcg; no conclusions about safety and efficacy could be drawn due to the small sample size.Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAlmotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAlosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAlvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation.Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modificationAmphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapyAmphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapyAnticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapyAntiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAntiplatelet Agents (P2Y12 Inhibitors): FentaNYL may diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). FentaNYL may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors).Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyCeritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib.Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modificationChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationCYP3A4 Inducers (Moderate): May decrease the serum concentration of FentaNYL. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of FentaNYL. Risk C: Monitor therapyCYP3A4 Inhibitors (Moderate): May increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a moderate CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modificationCYP3A4 Inhibitors (Strong): May increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a strong CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modificationDapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combinationDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDecongestants: May decrease the serum concentration of FentaNYL. Risk C: Monitor therapyDesmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin.Risk C: Monitor therapyDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyDextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDiuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics.Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationEletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyEluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline.Risk X: Avoid combinationErgot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyFexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole.Risk X: Avoid combinationFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod.Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modificationFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).Risk C: Monitor therapyHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationIvabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine.Risk C: Monitor therapyKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide.Risk C: Monitor therapyLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLinezolid: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modificationLisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMeperidine: May enhance the CNS depressant effect of FentaNYL. Meperidine may enhance the serotonergic effect of FentaNYL. This could result in serotonin syndrome. Management: Consider alternatives to this combination. If use is necessary, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modificationMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMethylene Blue: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modificationMetoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMetoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMidodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapyMiFEPRIStone: May increase the serum concentration of FentaNYL. Risk X: Avoid combinationMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMonoamine Oxidase Inhibitors (Antidepressant): FentaNYL may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome.Risk X: Avoid combinationMonoamine Oxidase Inhibitors (Type B): FentaNYL may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome.Risk X: Avoid combinationNalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine.Risk C: Monitor therapyNalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modificationNaltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids.See full drug interaction monograph for detailed recommendations. Risk X: Avoid combinationNefazodone: FentaNYL may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of FentaNYL.Management: Consider reducing fentanyl dose. Monitor for signs and symptoms of respiratory depression, sedation, and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia) when these agents are combined. Risk D: Consider therapy modificationOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOndansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOpioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combinationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOzanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapyOzanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapyParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant.Risk C: Monitor therapyPHENobarbital: May enhance the CNS depressant effect of FentaNYL. PHENobarbital may decrease the serum concentration of FentaNYL. Management: Avoid use of fentanyl and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modificationPiribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil.Risk C: Monitor therapyPonesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod.Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modificationPramipexole: CNS Depressants may enhance the sedative effect of Pramipexole.Risk C: Monitor therapyPrimidone: May enhance the CNS depressant effect of FentaNYL. Primidone may decrease the serum concentration of FentaNYL. Management: Avoid use of fentanyl and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modificationProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPropofol: May enhance the CNS depressant effect of FentaNYL. Management: Consider alternatives to this combination when possible. If the combination is used, monitor more closely for bradycardia, apnea, and excessive CNS depression. Propofol induction dose requirements may be reduced. Pediatric patients may be at greater risk. Risk D: Consider therapy modificationRamosetron: Opioid Agonists may enhance the constipating effect of Ramosetron.Risk C: Monitor therapyRamosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole.Risk C: Monitor therapyRotigotine: CNS Depressants may enhance the sedative effect of Rotigotine.Risk C: Monitor therapyRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySamidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combinationSelective Serotonin Reuptake Inhibitors: Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapySerotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapySerotonergic Non-Opioid CNS Depressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modificationSerotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySerotonin/Norepinephrine Reuptake Inhibitors: FentaNYL may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapySincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide.Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modificationSiponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod.Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modificationSomatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs.Risk C: Monitor therapySt John's Wort: May enhance the serotonergic effect of FentaNYL. This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of FentaNYL. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and reduced fentanyl effects (including withdrawal symptoms) when combined. Monitor for increased fentanyl effects if St. John's wort is discontinued. Risk C: Monitor therapySuccinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapySuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationSyrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationTofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapyTraMADol: Serotonergic Opioids (High Risk) may enhance the CNS depressant effect of TraMADol. Serotonergic Opioids (High Risk) may enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome.Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modificationTricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modificationValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationDietary ConsiderationsTransmucosal lozenge contains 2 g sugar per unit.Reproductive ConsiderationsLong-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013).Pregnancy ConsiderationsFentanyl crosses the placenta (Leuschen 1990). Fentanyl can be detected in neonatal urine 24 hours after maternal epidural administration (Moore 2016).According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 209 2019). Transient muscular rigidity has been observed in the neonate following maternal administration of IV fentanyl; symptoms of respiratory or neurological depression were not different than those observed in infants of untreated mothers following IV or epidural use during labor.[US Boxed Warning]: Prolonged use of fentanyl during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psychophysiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.Fentanyl IM and IV injection are commonly used to treat maternal pain during labor and immediately postpartum; the intranasal route has also been studied (ACOG 209 2019; Jabalameli 2016). Not all formulations are recommended.The ACOG recommends that pregnant women should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).Monitoring ParametersRespiratory rate, blood pressure, heart rate, oxygen saturation, chest wall rigidity (with IV administration), pain relief, level of sedation and mental status; monitor for bowel sounds, abdominal distention, constipation, and urinary retention; signs of misuse, abuse, or addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).Transdermal patch: Monitor patient for at least 24 hours after application of first dose.Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).Mechanism of ActionBinds with stereospecific receptors at many sites within the CNS, increases pain threshold, alters pain reception, inhibits ascending pain pathwaysPharmaco*kinetics (Adult data unless noted)Onset of action:Children 3 to 12 years: Intranasal: 5 to 10 minutes (Borland 2002).Adults: Analgesic: IM: 7 to 8 minutes; IV: Almost immediate (maximal analgesic and respiratory depressant effects may not be seen for several minutes); Transdermal patch (initial placement): 6 hours; Transmucosal: 5 to 15 minutes.Duration: IM: 1 to 2 hours; IV: 0.5 to 1 hour; Transdermal (removal of patch/no replacement): Related to blood level; some effects may last 72 to 96 hours due to extended half-life and absorption from the skin, fentanyl concentrations decrease by ~50% in 20 to 27 hours; Transmucosal: Related to blood level; respiratory depressant effect may last longer than analgesic effect.Absorption:Transdermal, patch: Initial application: Drug is released at a nearly constant rate from the transdermal matrix system into the skin, where it accumulates; this results in a depot of fentanyl in the outer layer of skin. Fentanyl is absorbed into systemic circulation from the depot. This results in a gradual increase in serum concentration over the first 12 to 24 hours, followed by fairly constant concentrations for the remainder of the dosing interval. Absorption is decreased in cachectic patients (compared to normal size patients). Exposure to external heat increases drug absorption from patch.Transdermal, device: At the activation of each dose, an electrical current is activated for 10 minutes, which moves a dose of fentanyl from the drug-containing reservoir through the skin and into the systemic circulation. Fentanyl concentrations increase slowly with device activation and continue to increase for ~5 minutes after the completion of each 10 minute dose. Absorption of fentanyl from the device increases as a function of time and is independent of frequency of dosing.Transmucosal, buccal tablet: Rapid, ~50% from the buccal mucosa; remaining 50% swallowed with saliva and slowly absorbed from GI tract.Transmucosal, lozenge: Rapid, ~25% from the buccal mucosa; 75% swallowed with saliva and slowly absorbed from GI tract.Distribution: Highly lipophilic, redistributes into muscle and fat; Note: IV fentanyl exhibits a 3-compartment distribution model. Changes in blood pH may alter ionization of fentanyl and affect its distribution between plasma and CNS.Vdss:Preterm and term neonates: Note: Volume of distribution is highly variable and significantly influenced by patient weight (Norman 2019; Wu 2022).Bolus dose: 5.1 ± 1 L/kg (Koehntop 1986).Infants, Children, and Adolescents ≤14 years of age (after long-term continuous infusion): ~15 L/kg (range: 5 to 30 L/kg) (Katz 1993).Adults: 4 to 6 L/kg.Protein binding: 79% to 87%, primarily to alpha-1 acid glycoprotein; also binds to albumin and erythrocytes; Note: Free fraction increases with acidosis.Metabolism: Hepatic, primarily via CYP3A4 by N-dealkylation (to norfentanyl) and hydroxylation to other inactive metabolites.Bioavailability: Note: Comparative studies have found the buccal tablet to have a 30% to 50% greater exposure than the transmucosal lozenge.Buccal tablet: 65%.Lozenge: ~50%.Sublingual spray: 76%.Sublingual tablet: 54%.Half-life elimination:IV:Preterm and term neonate (PNA ≤14 days): Bolus dose: 5.28 ± 1.17 hours (Koehntop 1986); Note: Half-life may be prolonged (1.5 to 3 times the population mean) in patients with increased intra-abdominal pressure (Koehntop 1986).Pediatric patients 5 months to 4.5 years: 2.4 hours.Pediatric patients 6 months to 14 years (after long-term continuous infusion): ~21 hours (range: 11 to 36 hours).Adults: 2 to 4 hours; when administered as a continuous infusion, the half-life prolongs with infusion duration due to the large volume of distribution (Sessler 2008).SUBQ bolus injection: 10 hours (Capper 2010).Transdermal device: Terminal: ~16 hours.Transdermal patch: 20 to 27 hours (apparent half-life is influenced by continued fentanyl absorption from skin).Transmucosal products: 3 to 14 hours (dose dependent).Intranasal: 15 to 25 hours (based on a multiple-dose pharmaco*kinetic study when doses are administered in the same nostril and separated by a 1-, 2-, or 4-hour time lapse).Buccal tablet: 100 to 200 mcg: 3 to 4 hours; 400 to 800 mcg: 11 to 12 hours.Time to peak:Buccal tablet: 20 to 240 minutes (median: 47 minutes).Lozenge: 20 to 480 minutes (median: 20 to 40 minutes).Intranasal: Median: 15 to 21 minutes.SubQ bolus injection: 10 to 30 minutes (median: 15 minutes) (Capper 2010).Sublingual spray: 10 to 120 minutes (median: 90 minutes).Sublingual tablet: 15 to 240 minutes (median: 30 to 60 minutes).Transdermal patch: 20 to 72 hours; steady state serum concentrations are reached after two sequential 72-hour applications.Excretion: Urine 75% (primarily as metabolites, <7% to 10% as unchanged drug); feces ~9%.Clearance: Neonates: Clearance rapidly increased based on birthweight and PNA (Wu 2022); one study identified PNA as the most relevant covariate with very low clearance in the first few days after birth and then rapidly increasing until about 10 to 15 days of life (Völler 2019).Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: May alter kinetics because of alterations in clearance and plasma proteins.Hepatic function impairment: May alter kinetics because of alterations in clearance and plasma proteins.Pediatric: Plasma concentrations with transdermal use were approximately twice as high in pediatric patients 1.5 to 5 years of age, who are not opioid-tolerant, compared with adults. Pharmaco*kinetic parameters in older pediatric patients were similar to those seen in adults.Older adult: Reduced clearance and terminal half-life is prolonged (transdermal).Sex: Systemic exposure was higher in women after administration of buccal fentanyl (Fentora); this difference was largely attributed to differences in weight.Race/ethnicity: Systemic exposure was higher in Japanese subjects after administration of buccal fentanyl (Fentora); this difference was largely attributed to differences in weight.Extracorporeal membrane oxygenation (ECMO): Neonates, Infants, Children, and Adolescents: Increases in circulating blood volume and extraction of drug by the ECMO circuit (tubing and/or oxygenator) result in an increased volume of distribution (Vd) of drugs in patients on ECMO (Raffaeli 2019; Zimmerman 2020). As a result, larger doses/infusion rates may be required to achieve adequate pain control and level of sedation.Pricing: USLiquid (Subsys Sublingual)100 mcg (per each): $91.96200 mcg (per each): $121.38400 mcg (per each): $184.01600 mcg (per each): $244.64800 mcg (per each): $305.691200 (600 X 2) mcg (per each): $244.641600 (800 X 2) mcg (per each): $305.69Lozenge (Actiq Buccal)200 mcg (per each): $104.87400 mcg (per each): $132.72600 mcg (per each): $162.66800 mcg (per each): $192.531200 mcg (per each): $250.261600 mcg (per each): $308.72Lozenge (fentaNYL Citrate Buccal)200 mcg (per each): $18.80 - $18.83400 mcg (per each): $23.82 - $23.85600 mcg (per each): $29.18 - $29.21800 mcg (per each): $34.57 - $34.611200 mcg (per each): $44.95 - $45.001600 mcg (per each): $55.44 - $55.50Patch, 72-hour (fentaNYL Transdermal)12 mcg/hr (per each): $20.3025 mcg/hr (per each): $14.42 - $21.2737.5 mcg/hr (per each): $65.3150 mcg/hr (per each): $26.36 - $38.8862.5 mcg/hr (per each): $94.9175 mcg/hr (per each): $40.21 - $59.3187.5 mcg/hr (per each): $129.22100 mcg/hr (per each): $53.36 - $78.71Solution (fentaNYL Citrate (PF) Injection)50 mcg/mL (per mL): $2.34 - $2.65100 mcg/2 mL (per mL): $0.76 - $1.27250 mcg/5 mL (per mL): $0.46 - $0.72500MCG/10ML (per mL): $0.371000 mcg/20 mL (per mL): $0.38 - $0.662500 mcg/50 mL (per mL): $0.43 - $0.60Solution (fentaNYL Citrate Intravenous)2500 mcg/50 mL (per mL): $0.53Solution (Lazanda Nasal)100 mcg/ACT (per each): $1,222.58400 mcg/ACT (per each): $1,949.58Solution Cartridge (fentaNYL Citrate (PF) Injection)100 mcg/2 mL (per mL): $1.26Solution Prefilled Syringe (fentaNYL Citrate Injection)100 mcg/2 mL (per mL): $1.95Solution Prefilled Syringe (fentaNYL Citrate PF Injection)50 mcg/mL (per mL): $2.65Tablets (fentaNYL Citrate Buccal)100 mcg (per each): $58.06200 mcg (per each): $73.35400 mcg (per each): $106.43600 mcg (per each): $138.18800 mcg (per each): $170.23Tablets (Fentora Buccal)100 mcg (per each): $82.24200 mcg (per each): $103.91400 mcg (per each): $150.77600 mcg (per each): $195.73800 mcg (per each): $241.13Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAbstral (BH, BM, EG, ES, GB, HR, IE, LB, NO, PH, QA, TR);Actiq (AU, CH, DE, DK, ES, FR, GB, IE, IL, IT, KR, PT, SE);Adolor (CZ);Breakyl (CZ, GB, LV);Denpax (AU);Dolforin (BG, CZ, LV);Durasic (BD);Durogesic (AE, AU, BH, CN, CO, CY, EG, ES, ID, IN, JO, LB, LK, MX, MY, PH, PK, PY, QA, SA, SG, TH, VN, ZA);Durogesic D Trans (HK, KR, TW);Durogesic D-Trans (BR, CR, DO, GT, HN, NI, PA);Durotep MT (JP);Effentora (CH, EE, ES, FI, GB, HR, IE, MT);Etanyl (ID);Fantamax (SG);Fencino (GB);Fenodid (CR, DO, GT, HN, NI, PA);Fent (LK);Fentaderm Patch (KR);Fentadur Patch (KR);Fentalis (GB, IE);Fentamax Mat Patch (KR);Fentanest (BR, ES, IT, MX, PY, UY);Fentanila (CL);Fentanilo (CU);Fentanyl (SV);Fentanyl Citrate (EC);Fentavera (EG);Fentax (PY);Fentora (HK);Fenvel (IT);Filtaten (MX);Instanyl (AT, CZ, DE, DK, EE, ES, FR, HR, IS, LT, LU, MT, NL, NO, PL, SE, SI, SK);Instanyl Nasal (GB);Ionsys (AT, BE, BG, CH, CZ, DE, DK, EE, FI, FR, GB, GR, IE, MT, NL, PT, RU, SE, SK, TR);Leptanal (NO, SE);Lunaldin (LV);Matrifen (BE, CH, DE, DK, EE, FR, GB);Mezolar Matrix (GB);Oncolis (BM);One Duro (JP);Opifen (BD);Opiodur (GB);Osmanil (GB);PecFent (GB);Pecfent (HK);Pentyl (BD);Recivit (GB);Sublimaze (AR, AU, GB, IE, NZ, PH, ZA);Trofentyl (IN, PH);Vellofent (RO);Verfen (LK);Victanyl (GB)For country code abbreviations (show table)Abstral (fentanyl) [prescribing information]. Solana Beach, CA: Sentynl Therapeutics Inc; October 2019.Abstral (fentanyl) [product monograph]. St-Laurent, Quebec, Canada: Paladin Labs Inc; March 2018.Actiq (fentanyl) [prescribing information]. Parsippany, NJ: Teva Pharmaceuticals USA Inc; March 2021.Alexander JC. Perioperative uses of intravenous opioids in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 21, 2019.Algera MH, Kamp J, van der Schrier R, et al. Opioid-induced respiratory depression in humans: a review of pharmaco*kinetic-pharmacodynamic modelling of reversal. Br J Anaesth. 2019;122(6):e168-e179. doi:10.1016/j.bja.2018.12.023 [PubMed 30915997]American Academy of Pediatrics Committee on Drugs. "Inactive" ingredients in pharmaceutical products: update (subject review). Pediatrics. 1997;99(2):268-278. [PubMed 9024461]American Academy of Pediatrics (AAP) Committee on Fetus and Newborn and Section on Anesthesiology and Pain Medicine. Prevention and management of procedural pain in the neonate: an update. Pediatrics. 2016;137(2):e20154271. doi:10.1542/peds.2015-4271 [PubMed 26810788]American College of Obstetricians and Gynecologists (ACOG). ACOG Committee Opinion No. 775: Nonobstetric surgery during pregnancy. Obstet Gynecol. 2019;133(4):e285-e286. [PubMed 30913200]American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 209: Obstetric analgesia and anesthesia. Obstet Gynecol. 2019;133(3):e208-e225. [PubMed 30801474]American Pain Society (APS). Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 6th ed. Glenview, IL: American Pain Society; 2008.American Society of Health-System Pharmacists (ASHP). Pediatric continuous infusion standards. Available at https://www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/Pediatric-Infusion-Standards.ashx. Updated January 2021. Accessed November 15, 2022.Anand KJ and International Evidence-Based Group for Neonatal Pain. Consensus Statement for the Prevention and Management of Pain in the Newborn. Arch Pediatr Adolesc Med. 2001;155(2):173-180. [PubMed 11177093]Ancora G, Lago P, Garetti E, et al. Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation. J Pediatr. 2013;163(3):645-51.e1. doi:10.1016/j.jpeds.2013.02.039 [PubMed 23582138]Ancora G, Lago P, Garetti E, et al. Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation. Acta Paediatr. 2019;108(2):208-217. doi:10.1111/apa.14606 [PubMed 30290021]Anderson SL, Shreve ST. Continuous subcutaneous infusion of opiates at end-of-life. Ann Pharmacother. 2004;38(6):1015-1023. doi:10.1345/aph.1D395 [PubMed 15122000]Anton-Martin P, Modem V, Taylor D, Potter D, Darnell-Bowens C. A retrospective study of sedation and analgesic requirements of pediatric patients on extracorporeal membrane oxygenation (ECMO) from a single-center experience. Perfusion. 2017;32(3):183-191. doi:10.1177/0267659116670483 [PubMed 27729502]Arnold JH, Truog RD, Scavone JM, et al. Changes in the pharmacodynamics response to fentanyl in neonates during continuous infusion. Journal of Pediatrics. 1991;119:639-643. [PubMed 1919898]Arnold RM, Childers JW. Management of acute pain in the patient chronically using opioids. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 11, 2019.Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. American College of Physicians; 2007.Bahn EL, Holt KR. Procedural sedation and analgesia: a review and new concepts. Emerg Med Clin North Am. 2005;23(2):503-517. doi:10.1016/j.emc.2004.12.013 [PubMed 15829394]Bailey AM, Baum RA, Horn K, et al. Review of intranasally administered medications for use in the emergency department. J Emerg Med. 2017;53(1):38-48. doi:10.1016/j.jemermed.2017.01.020 [PubMed 28259526]Barash PG, Cullen BF, Stoelting RK, et al, eds. Clinical Anesthesia. 6th ed. Lippincott Williams & Wilkins; 2009.Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi:10.1097/CCM.0b013e3182783b72 [PubMed 23269131]Based on expert opinion.Bastani B, Jamal JA. Removal of morphine but not fentanyl during haemodialysis. Nephrol Dial Transplant. 1997;12(12):2802-2804. doi:10.1093/ndt/12.12.2802 [PubMed 9430910]Beathard GA, Urbanes A, Litchfield T, Weinstein A. The risk of sedation/analgesia in hemodialysis patients undergoing interventional procedures. Semin Dial. 2011;24(1):97-103. doi:10.1111/j.1525-139X.2011.00844.x [PubMed 21338400]Bennett MR, Adams AP. Postoperative respiratory complications of opiates. Clin Anaesthesiol. 1983;1:41-56.Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med. 2002;347(14):1094-1103. [PubMed 12362012]Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90(6):828-842. doi:10.1016/j.mayocp.2015.04.003 [PubMed 26046416]Billmire DA, Neale HW, Gregory RO. Use of I.V. Fentanyl in the Outpatient Treatment of Pediatric Facial Trauma. J Trauma. 1985;25(11):1079-1080. [PubMed 4057297]Bluthenthal RN, Simpson K, Ceasar RC, Zhao J, Wenger L, Kral AH. Opioid withdrawal symptoms, frequency, and pain characteristics as correlates of health risk among people who inject drugs. Drug Alcohol Depend. 2020;211:107932. doi:10.1016/j.drugalcdep.2020.107932 [PubMed 32199668]Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A. Non-analgesic effects of opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012;18(37):5994-6004. doi:10.2174/138161212803582469 [PubMed 22747535]Borland M, Jacobs I, King B, et al. A Randomized Controlled Trial Comparing Intranasal Fentanyl to Intravenous Morphine for Managing Acute Pain in Children in the Emergency Department. Ann Emerg Med. 2007;49(3):335-340. [PubMed 17067720]Borland ML, Bergesio R, Pascoe EM, et al. Intranasal Fentanyl Is an Equivalent Analgesic to Oral Morphine in Paediatric Burns Patients for Dressing Changes: A Randomised Double Blind Crossover Study. Burns. 2005;31(7):831-837. [PubMed 16005154]Borland ML, Jacobs I, Geelhoed G. Intranasal fentanyl reduces acute pain in children in the emergency department: a safety and efficacy study. Emerg Med (Fremantle). 2002;14(3):275-280. [PubMed 12487045]Bravenec B. General anesthesia: Intravenous induction agents. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 21, 2019.Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3)(suppl 1):S12-S18. doi:10.1016/j.amjmed.2012.12.001 [PubMed 23414717]Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med. 1998;26(4):676-684. doi:10.1097/00003246-199804000-00015 [PubMed 9559604]Capper SJ, Loo S, Geue JP, et al. Pharmaco*kinetics of fentanyl after subcutaneous administration in volunteers. Eur J Anaesthesiol. 2010;27(3):241-246. doi:10.1097/EJA.0b013e328331a361 [PubMed 19918182]Caraceni A, Hanks G, Kaasa S, et al; European Palliative Care Research Collaborative (EPCRC); European Association for Palliative Care (EAPC). Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13(2):e58-e68. doi:10.1016/S1470-2045(12)70040-2 [PubMed 22300860]Caro D. Pretreatment medications for rapid sequence intubation in adults outside the operating room. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 23, 2020.Centers for Disease Control and Prevention (CDC). Common elements in guidelines for prescribing opioids for chronic pain. https://www.cdc.gov/drugoverdose/pdf/common_elements_in_guidelines_for_prescribing_opioids-a.pdf. Accessed November 22, 2019.Cheng C, Tabbara N, Cheng C, Shah V. Intranasal fentanyl for procedural analgesia in preterm infants. Front Pain Res (Lausanne). 2022;2:815014. doi:10.3389/fpain.2021.815014 [PubMed 35295509]Chou R, Fanciullo GJ, Fine PG, et al. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. J Pain. 2009;10(2):113-130. [PubMed 19187889]Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008 [PubMed 26827847]Chung S, Lim R, Goldman RD. Intranasal Fentanyl Versus Placebo for Pain in Children During Catheterization for Voiding Cystourethrography. Pediatr Radiol. 2010;40(7):1236-1240. [PubMed 20180109]Cloherty JP, Eichenwald EC, Stark AR, eds. Manual of Neonatal Care. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.Cohen RS. Fentanyl transdermal analgesia during pregnancy and lactation. J Hum Lact. 2009;25(3):359-361. [PubMed 19286842]Cole J, Shepherd M, Young P. Intranasal Fentanyl in 1-3-Year-Olds: A Prospective Study of the Effectiveness of Intranasal Fentanyl as Acute Analgesia. Emerg Med Australas. 2009;21(5):395-400. [PubMed 19840089]Cramton RE, Gruchala NE. Managing procedural pain in pediatric patients. Curr Opin Pediatr. 2012;24(4):530-538. [PubMed 22732639]Crellin D, Ling RX, Babl F. Does the Standard Intravenous Solution of Fentanyl (50 microg/mL) Administered Intranasally Have Analgesic Efficacy? Emerg Med Australas. 2010;22(1):62-67. [PubMed 20152004]Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112(1):226-238. doi:10.1097/ALN.0b013e3181c38c25 [PubMed 20010421]d'Arby Toledano R, Leffert L. Neuraxial analgesia for labor and delivery (including instrumented delivery). Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 5, 2019.Davison SN. Clinical pharmacology considerations in pain management in patients with advanced kidney failure. Clin J Am Soc Nephrol. 2019;14(6):917-931. doi:10.2215/CJN.05180418 [PubMed 30833302]Davison SN, Koncicki H, Brennan F. Pain in chronic kidney disease: a scoping review. Semin Dial. 2014;27(2):188-204. doi:10.1111/sdi.12196 [PubMed 24517512]Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497-504. doi:10.1016/j.jpainsymman.2004.02.021 [PubMed 15504625]Debono M, Chan S, Rolfe C, Jones TH. Tramadol-induced adrenal insufficiency. Eur J Clin Pharmacol. 2011;67(8):865-867. doi:10.1007/s00228-011-0992-9 [PubMed 21243342]Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299 [PubMed 30113379]Dionne RA, Yagiela JA, Moore PA, et al. Comparing Efficacy and Safety of Four Intravenous Sedation Regimens in Dental Outpatients. Am Dent Assoc. 2001;132(6):740-751. [PubMed 11433853]Domonoske C. Appendix A: Common neonatal intensive care unit (NICU) medication guidelines. In: Eichenwald EC, Hansen AR, Martin CR, Stark AR. Cloherty and Stark's Manual of Neonatal Care. 8th edition. Lippincott Williams & Wilkins; 2017.Dow K, Ordean A, Murphy-Oikonen J, et al. Neonatal Abstinence Syndrome Clinical Practice Guidelines For Ontario. J Popul Ther Clin Pharmacol. 2012;19(3):e488-e506. [PubMed 23241498]Dowell D. Regarding CDC’s guideline for prescribing opioids for chronic pain [written communication]. Atlanta, GA: Centers for Disease Control and Prevention; February 28, 2019.Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. doi:10.15585/mmwr.rr6501e1 [PubMed 26987082]Duragesic (fentanyl) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; April 2022.Duragesic (fentanyl) [product monograph]. Toronto, Ontario, Canada: Janssen Inc; December 2019.Elliott M, Burnsed J, Heinan K, et al. Effect of dexmedetomidine on heart rate in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia. J Neonatal Perinatal Med. 2022;15(1):47-54. doi:10.3233/NPM-210737 [PubMed 34334427]Erstad BL, Barletta JF. Drug dosing in the critically ill obese patient-a focus on sedation, analgesia, and delirium. Crit Care. 2020;24(1):315. doi:10.1186/s13054-020-03040-z [PubMed 32513237]Farmer AD, Drewes AM, Chiarioni G, et al. Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol J. 2019;7(1):7-20. doi:10.1177/2050640618818305. Erratum in: United European Gastroenterol J. 2019;7(2):178. [PubMed 30788113]Fentanyl citrate injection [prescribing information]. Berkely Heights, NJ: Hikma Pharmaceuticals USA Inc; November 2020.Fentanyl citrate injection preservative free [prescribing information]. Lake Forest, IL: Akorn Inc; October 2019.Fentanyl citrate injection [product monograph]. Boucherville, Quebec, Canada: Jamp Pharma Corporation; October 2020.Fentanyl citrate injection, USP [Canadian product monograph]. Buena, NJ: Telip LLC; September 2021.Fentanyl transdermal patch [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc; November 2019.Fentanyl transdermal system [prescribing information]. Caldwell, NJ: LTS Lohmann Therapy Systems Corp; August 2021.Fentora (fentanyl) [prescribing information]. Parsippany, NJ: Teva Pharmaceuticals USA Inc; March 2021.Fentora (fentanyl) [product monograph]. Toronto, Ontario, Canada: Teva Canada Limited; December 2021.Finn M, Harris D. Intranasal Fentanyl for Analgesia in the Paediatric Emergency Department. Emerg Med J. 2010;27(4):300-301. [PubMed 20385685]Fox LM, Hoffman RS, Vlahov D, Manini AF. Risk factors for severe respiratory depression from prescription opioid overdose. Addiction. 2018;113(1):59-66. doi:10.1111/add.13925 [PubMed 28646524]Frank RL. Procedural sedation in adults outside the operating room. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 11, 2019.Frey TM, Florin TA, Caruso M, Zhang N, Zhang Y, Mittiga MR. Effect of intranasal ketamine vs fentanyl on pain reduction for extremity injuries in children: The PRIME randomized clinical trial. JAMA Pediatr. 2019;173(2):140-146. doi:10.1001/jamapediatrics.2018.4582 [PubMed 30592476]Gallagher R. Killing the symptom without killing the patient. Can Fam Physician. 2010;56(6):544-546, e210-212. [PubMed 20547520]Goma HM, Said RN, El-Ela AM. Study of the newborn feeding behaviors and fentanyl concentration in colostrum after an analgesic dose of epidural and intravenous fentanyl in cesarean section. Saudi Med J. 2008;29(5):678-682. [PubMed 18454213]Grass JA. Patient-controlled analgesia. Anesth Analg. 2005 Nov;101(5)(suppl):S44-S61. [PubMed 16334492]Groth CM, Acquisto NM, Khadem T. Current practices and safety of medication use during rapid sequence intubation. J Crit Care. 2018;45:65-70. doi:10.1016/j.jcrc.2018.01.017 [PubMed 29413725]Gupta K, Prasad A, Nagappa M, Wong J, Abrahamyan L, Chung FF. Risk factors for opioid-induced respiratory depression and failure to rescue: a review. Curr Opin Anaesthesiol. 2018;31(1):110-119. doi:10.1097/ACO.0000000000000541 [PubMed 29120929]Hegenbarth MA. Preparing for pediatric emergencies: drugs to consider. Pediatrics. 2008;121:433-443. [PubMed 18245435]Herd D, Borland M. Intranasal Fentanyl Paediatric Clinical Practice Guidelines. Emerg Med Australas. 2009;21(4):335. [PubMed 19682022]Hill MV, Stucke RS, McMahon ML, Beeman JL, Barth RJ Jr. An educational intervention decreases opioid prescribing after general surgical operations. Ann Surg. 2018;267(3):468-472. doi:10.1097/SLA.0000000000002198 [PubMed 28267689]Hill R, Santhakumar R, Dewey W, Kelly E, Henderson G. Fentanyl depression of respiration: Comparison with heroin and morphine. Br J Pharmacol. 2020;177(2):254-266. doi:10.1111/bph.14860 [PubMed 31499594]Hudak ML, Tan RC, Committee On Drugs, et al. Neonatal Drug Withdrawal. Pediatrics. 2012;129(2):e540-e560. [PubMed 22291123]Imam MZ, Kuo A, Ghassabian S, Smith MT. Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. Neuropharmacology. 2018;131:238-255. doi:10.1016/j.neuropharm.2017.12.032 [PubMed 29273520]Institute for Safe Medication Practice (ISMP). ISMP Targeted Medication Safety Best Practices for Hospitals. https://ismp.org/guidelines/best-practices-hospitals. Published February 21, 2020. Accessed August 4, 2020.Institute for Safe Medication Practice (ISMP); Vermont Oxford Network. Standard Concentrations of Neonatal Drug Infusions. 2011. https://www.ismp.org/Tools/PediatricConcentrations.pdf.Institute for Safe Medication Practices (ISMP). Beware of basal opioid infusions with PCA therapy. https://www.ismp.org/resources/beware-basal-opioid-infusions-pca-therapy. Published March 12, 2009. Accessed December 16, 2019.Intubation sedation guidelines. In: Eichenwald EC, Hansen AR, Martin CR, Stark AR. Cloherty and Stark's Manual of Neonatal Care. 8th edition. Lippincott Williams & Wilkins; 2017.Ionsys (fentanyl transdermal system) [prescribing information]. Parsippany, NJ: The Medicines Company; January 2017.Jabalameli M, Talakoub R, Abedi B, et al. A randomized controlled trial comparing the effect of intravenous, subcutaneous, and intranasal fentanyl for pain management in patients undergoing cesarean section. Adv Biomed Res. 2016;5:198. doi:10.4103/2277-9175.190989 [PubMed 28217636]Jacobi J, Fraser GL, Coursin DB, et al; Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119-141. doi:10.1097/00003246-200201000-00020 [PubMed 11902253]Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmaco*kinet. 2005;44(10):1051-1065. doi:10.2165/00003088-200544100-00004 [PubMed 16176118]Joh J, Sila MK, Bastani B. Nondialyzability of fentanyl with high-efficiency and high-flux membranes. Anesth Analg. 1998;86(2):447. doi:10.1097/00000539-199802000-00049 [PubMed 9459269]Kasirer Y, Shah V, Yoon EW, Bromiker R, Mcnair C, Taddio A. Safety of fentanyl for peripherally inserted central catheter in non-intubated infants in the neonatal intensive care unit. J Perinatol. 2018;38(5):526-529. doi:10.1038/s41372-018-0101-3 [PubMed 29740192]Katz R, Kelly HW. Pharmaco*kinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med. 1993;21(7):995-1000. doi:10.1097/00003246-199307000-00012 [PubMed 8319480]Katz R, Kelly HW, Hsi A. Prospective Study on the Occurrence of Withdrawal in Critically Ill Children Who Receive Fentanyl by Continuous Infusion. Crit Care Med. 1994;22(5):763-767. [PubMed 8181283]Kaushal S, Placencia JL, Maffei SR, Chumpitazi CE. Intranasal fentanyl use in neonates. Hosp Pharm. 2020;55(2):126-129. doi:10.1177/0018578719828335 [PubMed 32214447]Khanna AK, Bergese SD, Jungquist CR, et al; PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) Group Collaborators. Prediction of opioid-induced respiratory depression on inpatient wards using continuous capnography and oximetry: An international prospective, observational trial. Anesth Analg. 2020;131(4):1012-1024. doi:10.1213/ANE.0000000000004788 [PubMed 32925318]Koehntop DE, Rodman JH, Brundage DM, Hegland MG, Buckley JJ. Pharmaco*kinetics of fentanyl in neonates. Anesth Analg. 1986;65(3):227-232. [PubMed 3954090]Koncicki HM, Unruh M, Schell JO. Pain management in CKD: a guide for nephrology providers. Am J Kidney Dis. 2017;69(3):451-460. doi:10.1053/j.ajkd.2016.08.039 [PubMed 27881247]Kornick CA, Santiago-Palma J, Khojainova N, Primavera LH, Payne R, Manfredi PL. A safe and effective method for converting cancer patients from intravenous to transdermal fentanyl. Cancer. 2001;92(12):3056-3061. [PubMed 11753984]Kosten TR, Baxter LE. Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment. Am J Addict. 2019;28(2):55-62. doi:10.1111/ajad.12862 [PubMed 30701615]Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet. 2006;367(9512):766-780. [PubMed 16517277]Ku LC, Simmons C, Smith PB, et al. Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit. J Neonatal Perinatal Med. 2019;12(2):143-148. doi:10.3233/NPM-17149 [PubMed 30562908]Kumar P, Denson SE, Mancuso TJ. Clinical report – premedication for nonemergency endotracheal intubation in the neonate. Pediatrics. 2010;125:608-615. [PubMed 20176672]Lazanda (fentanyl) [prescribing information]. Northbrook, IL: West Therapeutic Development LLC; March 2021.Lee HA, Anderson PO. Giving Partial Doses of Transdermal Patches. Am J Health Syst Pharm. 1997;54(15):1759-1760. [PubMed 9262751]Lemus-Varela ML, Villaseñor-Chávez DA, Gómez-Meda BC, Martínez-Ruezgas ME, Gallegos-Arreola MP, Torres-Mendoza BM. Efficacy and safety of multimodal analgesic therapy to prevent pain during screening for retinopathy of prematurity. J Pediatr Neonatal. 2022;4(2):1-6.Leuschen MP, Willett LD, Hoie EB, et al. Plasma Fentanyl Levels in Infants Undergoing Extracorporeal Membrane Oxygenation. J Thorac Cardiovasc Surg. 1993;105(5):885-891. [PubMed 8487566]Leuschen MP, Wolf LJ, Rayburn WF. Fentanyl excretion in breast milk. Clin Pharm. 1990;9(5):336-337. [PubMed 2350936]Liu LL, Gropper MA. Postoperative Analgesia and Sedation in the Adult Intensive Care Unit. Drugs. 2003;63(8):755-767. [PubMed 12662124]López J, Botrán M, García A, et al. Constipation in the critically ill child: frequency and related factors. J Pediatr. 2015;167(4):857-861.e1. doi:10.1016/j.jpeds.2015.06.046 [PubMed 26254837]Lugli L, Spada C, Garetti E, et al. Fentanyl analgesia in asphyxiated newborns treated with therapeutic hypothermia. J Matern Fetal Neonatal Med. 2022;35(25):7764-7770. doi:10.1080/14767058.2021.1937106 [PubMed 34486466]Mandel L, Carunchio MJ. Rampant caries from oral transmucosal fentanyl citrate lozenge abuse. J Am Dent Assoc. 2011;142(4):406-409.Manion SC, Brennan TJ. Thoracic epidural analgesia and acute pain management. Anesthesiology. 2011;115(1):181-188. doi: 10.1097/ALN.0b013e318220847c. [PubMed 21606825]Mariano ER. Management of acute perioperative pain. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 21, 2019.Martin E, Vickers B, Landau R, Reece-Stremtan S. ABM clinical protocol #28, peripartum analgesia and anesthesia for the breastfeeding mother. Breastfeed Med. 2018;13(3):164-171. [PubMed 29595994]McMillan SC. Assessing and managing opiate-induced constipation in adults with cancer. Cancer Control. 2004;11(3 Suppl):3-9. doi:10.1177/10732748040110S302 [PubMed 15153834]McNair C, Graydon B, Taddio A. A cohort study of intranasal fentanyl for procedural pain management in neonates. Paediatr Child Health. 2018;23(8):e170-e175. doi:10.1093/pch/pxy060 [PubMed 30842699]McPherson ML. Demystifying Conversion Calculations: A Guide for Effective Dosing. 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists; 2016.Miller RD. Miller’s Anesthesia. 7th ed, Philadelphia PA: Churchill Livingstone; 2010.Miller RS, Peterson GM, Abbott F, Maddocks I, Parker D, McLean S. Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients. Br J Clin Pharmacol. 1995;40(6):553-556. [PubMed 8703661]Mitra S, Babadagli ME, Hatfield T, et al. Effect of fentanyl boluses on cerebral oxygenation and hemodynamics in preterm infants: a prospective observational study. Neonatology. 2020;117(4):480-487. doi:10.1159/000508555 [PubMed 32640456]Moore A, el-Bahrawy A, Hatzakorzian R, Li-Pi-Shan W. Maternal epidural fentanyl administered for labor analgesia is found in neonatal urine 24 hours after birth. Breastfeed Med. 2016;11(1):40-41. [PubMed 26701799]Müller-Lissner S, Bassotti G, Coffin B, et al. Opioid-induced constipation and bowel dysfunction: A clinical guideline. Pain Med. 2017;18(10):1837-1863. doi:10.1093/pm/pnw255 [PubMed 28034973]Murtagh FE, Addington-Hall JM, Donohoe P, Higginson IJ. Symptom management in patients with established renal failure managed without dialysis. EDTNA ERCA J. 2006;32(2):93-98. doi:10.1111/j.1755-6686.2006.tb00459.x [PubMed 16898102]Naveed M, Bondi DS, Shah PA. Dexmedetomidine versus fentanyl for neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia. J Pediatr Pharmacol Ther. 2022;27(4):352-357. doi:10.5863/1551-6776-27.4.352 [PubMed 35558346]Nazemian N, Torabi M, Mirzaee M. Atomized intranasal vs intravenous fentanyl in severe renal colic pain management: a randomized single-blinded clinical trial. Am J Emerg Med. 2020;38(8):1635-1640. doi:10.1016/j.ajem.2019.158483 [PubMed 31740092]Nelson AD, Camilleri M. Chronic opioid induced constipation in patients with nonmalignant pain: challenges and opportunities. Therap Adv Gastroenterol. 2015;8(4):206-220. doi:10.1177/1756283X15578608 [PubMed 26136838]Nelson WE, Behrman RE, Kliegman RM, et al, eds. Nelson Textbook of Pediatrics. 15th ed. WB Saunders Company; 1996: 2058-2078.Nemecek BD, Hammond DA. Demystifying drug dosing in renal dysfunction. American Society of Health-System Pharmacists; 2019.Nightingale CE, Margarson MP, Shearer E, et al; Association of Anaesthetists of Great Britain; Ireland Society for Obesity and Bariatric Anaesthesia. Peri-operative management of the obese surgical patient 2015: Association of Anaesthetists of Great Britain and Ireland Society for Obesity and Bariatric Anaesthesia. Anaesthesia. 2015;70(7):859-876. doi:10.1111/anae.13101 [PubMed 25950621]Niscola P, Scaramucci L, Vischini G, et al. The use of major analgesics in patients with renal dysfunction. Curr Drug Targets. 2010;11(6):752-758. doi:10.2174/138945010791170879 [PubMed 20041843]Nitsun M, Szokol JW, Saleh HJ, et al. Pharmaco*kinetics of midazolam, propofol, and fentanyl transfer to human breast milk. Clin Pharmacol Ther. 2006;79(6):549-557. [PubMed 16765143]Norman E, Kindblom JM, Rane A, et al. Individual variations in fentanyl pharmaco*kinetics and pharmacodynamics in preterm infants. Acta Paediatr. 2019;108(8):1441-1446. doi:10.1111/apa.14744 [PubMed 30721546]O'Mara K, Weiss MD. Dexmedetomidine for sedation of neonates with HIE undergoing therapeutic hypothermia: a single-center experience. AJP Rep. 2018;8(3):e168-e173. [PubMed 30186671]Oosten AW, Abrantes JA, Jönsson S, et al. Treatment with subcutaneous and transdermal fentanyl: results from a population pharmaco*kinetic study in cancer patients. Eur J Clin Pharmacol. 2016;72(4):459-467. doi: 10.1007/s00228-015-2005-x. [PubMed 26762381]Paix A, Coleman A, Lees J, et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain. 1995;63(2):263-269. doi: 10.1016/0304-3959(95)00084-6. [PubMed 8628593]Pandharipande P, McGrane S. Pain control in the critically ill adult patient. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 11, 2019.Pang WW, Huang S, Chung YT, et al. Comparison of Intravenous Retention of Fentanyl and Lidocaine on Local Analgesia in Propofol Injection Pain. Acta Anaesthesiol Sin. 1997;35(4):217-221. [PubMed 9553237]Peng PW, Sandler AN. A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology. 1999;90(2):576-599. [PubMed 9952166]Portenoy RK, Broglio K. Approximate dose conversions for commonly used opioids. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 15, 2019a.Portenoy RK, Mehta Z, Ahmed E. Cancer pain management with opioids: Optimizing analgesia. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 21, 2020b.Prielipp RC, Fulesdi B, Brull SJ. Postoperative opioid-induced respiratory depression: 3 steps forward. Anesth Analg. 2020;131(4):1007-1011. doi:10.1213/ANE.0000000000005098 [PubMed 32925317]Quinn K, Kriss S, Drapkin J, et al. Analgesic efficacy of intranasal ketamine versus intranasal fentanyl for moderate to severe pain in children: a prospective, randomized, double-blind study. Pediatr Emerg Care. 2021;37(5):250-254. doi:10.1097/PEC.0000000000001556 [PubMed 30045355]Raffaeli G, Pokorna P, Allegaert K, et al. Drug disposition and pharmacotherapy in neonatal ECMO: from fragmented data to integrated knowledge. Front Pediatr. 2019;7:360. doi:10.3389/fped.2019.00360 [PubMed 31552205]Reece-Stremtan S, Campos M, Kokajko L; Academy of Breastfeeding Medicine. ABM clinical protocol #15: analgesia and anesthesia for the breastfeeding mother, revised 2017. Breastfeed Med. 2017;12(9):500-506. [PubMed 29624435]Refer to US manufacturer's labeling.Refer to Canadian manufacturer's labeling.Reynolds SL, Bryant KK, Studnek JR, et al. Randomized controlled feasibility trial of intranasal ketamine compared to intranasal fentanyl for analgesia in children with suspected extremity fractures. Acad Emerg Med. 2017;24(12):1430-1440. doi:10.1111/acem.13313 [PubMed 28926159]Roberts JR, ed. Roberts and Hedges' Clinical Procedures in Emergency Medicine and Acute Care. 7th ed. Elsevier; 2019.Rosero EB. Monitored anesthesia care in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 21, 2020.Rossi M, Casale G, Badiali D, et al. Opioid-induced bowel dysfunction: suggestions from a multidisciplinary expert Board. Support Care Cancer. 2019;27(11):4083-4090. doi:10.1007/s00520-019-04688-2 [PubMed 30778756]Roth B, Schlunder C, Houben F, et al. Analgesia and Sedation in Neonatal Intensive Care Using Fentanyl by Continuous Infusion. Dev Pharmacol Ther. 1991;17(3-4):121-127. [PubMed 1841826]Sachs HC, Committee On Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796-e809. [PubMed 23979084]Salomäki TE, Laitinen JO, Nuutinen LS. A randomized double-blind comparison of epidural versus intravenous fentanyl infusion for analgesia after thoracotomy. Anesthesiology. 1991;75(5):790-795. [PubMed 1952204]Saunders M, Adelgais K, Nelson D. Use of Intranasal Fentanyl for the Relief of Pediatric Orthopedic Trauma Pain. Acad Emerg Med. 2010;17(11):1155-1161. [PubMed 21175512]Schechter NL, Weisman SJ, Rosenblum M, et al. The Use of Oral Transmucosal Fentanyl Citrate for Painful Procedures in Children. Pediatrics. 1995;95(3):335-339. [PubMed 7862469]Sessler CN, Varney K. Patient-Focused Sedation and Analgesia in the ICU. Chest. 2008;133(2):552-565. [PubMed 18252923]Sevarino KA. Opioid withdrawal in adults: clinical manifestations, course, assessment, and diagnosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 16, 2019.Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med. 2009;10(2):256-259. [PubMed 19188870]Shibutani K, Inchiosa MA Jr, Sawada K, Bairamian M. Accuracy of pharmaco*kinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight ("pharmaco*kinetic mass"). Anesthesiology. 2004;101(3):603-613. doi:10.1097/00000542-200409000-00008 [PubMed 15329584]Shibutani K, Inchiosa MA Jr, Sawada K, Bairamian M. Pharmaco*kinetic mass of fentanyl for postoperative analgesia in lean and obese patients. Br J Anaesth. 2005;95(3):377-383. doi:10.1093/bja/aei195 [PubMed 16024584]Sindhur M, Balasubramanian H, Srinivasan L, Kabra NS, Agashe P, Doshi A. Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial. J Perinatol. 2020;40(6):881-887. doi:10.1038/s41372-020-0608-2 [PubMed 32054982]Skaer TL. Practice guidelines for transdermal opioids in malignant pain. Drugs. 2004;64(23):2629-2638. [PubMed 15537367]Smith HAB, Besunder JB, Betters KA, et al. 2022 Society of Critical Care Medicine clinical practice guidelines on prevention and management of pain, agitation, neuromuscular blockade, and delirium in critically ill pediatric patients with consideration of the ICU environment and early mobility. Pediatr Crit Care Med. 2022;23(2):e74-e110. doi:10.1097/PCC.0000000000002873 [PubMed 35119438]Snyers D, Tribolet S, Rigo V. Intranasal analgosedation for infants in the neonatal intensive care unit: a systematic review. Neonatology. 2022;119(3):273-284. doi:10.1159/000521949 [PubMed 35231912]Spigset O, Hagg S. Analgesics and Breast-feeding: Safety Considerations. Paediatr Drugs. 2000;2(3):223-238. [PubMed 10937472]Steer PL, Biddle CJ, Marley WS, Lantz RK, Sulik PL. Concentration of fentanyl in colostrum after an analgesic dose. Can J Anaesth. 1992;39(3):231-235. [PubMed 1551153]Stollings JL, Diedrich DA, Oyen LJ, Brown DR. Rapid-sequence intubation: a review of the process and considerations when choosing medications. Ann Pharmacother. 2014;48(1):62-76. doi:10.1177/1060028013510488 [PubMed 24259635]Sublimaze [package insert]. Lake Forest, IL; Akorn: January 2012.Subsys (fentanyl) [prescribing information]. Lakewood, NJ: Renaissance Lakewood LLC; April 2021.Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347-1354. [PubMed 17087429]Tucker C, Tucker L, Brown K. The intranasal route as an alternative method of medication administration. Crit Care Nurse. 2018;38(5):26-31. doi:10.4037/ccn2018836 [PubMed 30275061]Van Nimmen NF, Poels KL, Menten JJ, et al. Fentanyl transdermal absorption linked to pharmaco*kinetic characteristics in patients undergoing palliative care. J Clin Pharmacol. 2010;50(6):667-678. doi:10.1177/0091270009347872 [PubMed 20097932]Varga AG, Reid BT, Kieffer BL, Levitt ES. Differential impact of two critical respiratory centres in opioid-induced respiratory depression in awake mice. J Physiol. 2020;598(1):189-205. doi:10.1113/JP278612 [PubMed 31589332]Velázquez Rivera I, Velázquez Clavarana L, García Velasco P, Melero Ramos C. Opioid-induced constipation in chronic pain: Experience with 180 patients. J Opioid Manag. 2019;15(1):69-76. doi:10.5055/jom.2019.0487 [PubMed 30855724]Völler S, Flint RB, Andriessen P, et al. Rapidly maturing fentanyl clearance in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2019;104(6):F598-F603. doi:10.1136/archdischild-2018-315920 [PubMed 31498775]Wang PP, Huang E, Feng X, et al. Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study. Ann Intensive Care. 2017;7(1):88. doi:10.1186/s13613-017-0310-5 [PubMed 28866754]World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the Eleventh WHO Model List of Essential Drugs. 2002. http://apps.who.int/medicinedocs/pdf/s5406e/s5406e.pdf.World Health Organization (WHO). WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. 2012. [PubMed 23720867]Wu Y, Völler S, Flint RB, et al. Pre- and postnatal maturation are important for fentanyl exposure in preterm and term newborns: a pooled population pharmaco*kinetic study. Clin Pharmaco*kinet. 2022;61(3):401-412. doi:10.1007/s40262-021-01076-0 [PubMed 34773609]Wynn RL The sugar-loaded fentanyl lollipop (Actiq) and the risk of tooth decay. Gen Den. 2011;59(3):168-170. [PubMed 21903538]Zeltzer LK, Altman A, Cohen D, et al. Report of the Subcommittee on the Management of Pain Associated With Procedures in Children With Cancer. Pediatrics. 1990;86(5, pt 2):826-831. [PubMed 2216645]Zimmerman KO, Dallefeld SH, Hornik CP, Watt KM. Sedative and analgesic pharmaco*kinetics during pediatric ECMO. J Pediatr Pharmacol Ther. 2020;25(8):675-688. doi:10.5863/1551-6776-25.8.675 [PubMed 33214778]Topic 13298 Version 523.0