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.
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.
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 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 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, 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 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.
Plaque 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 arthritis:
Note: May continue methotrexate, other nonbiologic DMARDs, corticosteroids, NSAIDs, and/or analgesics.
SUBQ: 40 mg every other week.
Rheumatoid 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, 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 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, 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.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(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 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 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 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 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.
Uveitis (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.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Pen-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]
No
The 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Auto-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]
Abrilada (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.
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=44
Amjevita (adalimumab-atto): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761024s010lbl.pdf#page=46
Cyltezo (adalimumab-adbm): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761058s008lbl.pdf#page=33
Hadlima (adalimumab-bwwd): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761059s004lbl.pdf#page=40
Hulio (adalimumab-fkjp): https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761154s000lbl.pdf#page=41
Humira: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125057s417lbl.pdf#page=60
Hyrimoz (adalimumab-adaz): https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761071s010s012lbl.pdf#page=41
Yusimry (adalimumab-aqvh): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761216s000lbl.pdf#page=38
SUBQ: 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.
SubQ: 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.
Crohn 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.
Sarcoidosis, refractory
Adalimumab may be confused with sarilumab.
Humira may be confused with Humulin, Humalog
Humira Pen may be confused with HumaPen Memoir (used with HumaLOG)
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.
Antibody 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)
New-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 disease
Various 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)
New-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)
Reactivation 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)
Adalimumab 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).
Tumor 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)
Adalimumab 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)
Lymphoma 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).
Patients 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)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Skin rash (12%) (table 1)
|
Drug (Adalimumab) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Adalimumab) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
12% |
6% |
Adults |
40 mg every other week |
Rheumatoid Arthritis |
705 |
690 |
Hematologic & oncologic: Positive ANA titer (12%)
Immunologic: Antibody development (3% to 26%)
Infection: Infection
Local: 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)
|
Drug (Adalimumab) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Adalimumab) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
16% |
N/A |
Children and adolescents |
Either 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 study |
Juvenile idiopathic arthritis |
171 |
N/A |
|
5% |
N/A |
Children and adolescents |
High 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 disease |
192 |
N/A |
|
8% |
1% |
Adults |
40 mg every other week |
Rheumatoid Arthritis |
705 |
690 |
|
20% |
14% |
N/A |
N/A |
Pooled placebo-controlled clinical trials |
N/A |
N/A |
Nervous 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: Appendicitis
Genitourinary: Uterine hemorrhage
Hematologic & oncologic: Carcinoma (including breast, gastrointestinal, lung, skin, urogenital), malignant lymphoma, neutropenia (children and adolescents)
Hepatic: Increased serum transaminases
Infection: 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 infection
Neuromuscular & skeletal: Myositis (children and adolescents), septic arthritis
Renal: Pyelonephritis
Respiratory: 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 failure
Dermatologic: 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, pancreatitis
Hematologic & oncologic: Aplastic anemia, hepatosplenic T-cell lymphomas (children, adolescents, and young adults), leukopenia, pancytopenia, thrombocytopenia
Hepatic: 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 anaphylaxis
Immunologic: Sarcoidosis
Infection: 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 neuritis
Respiratory: Interstitial lung disease (including pulmonary fibrosis)
Miscellaneous: Fever (Choi 2021)
There 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)
Concerns 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.
Postmarketing 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])
None known.
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 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 combination
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Anakinra: 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 combination
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG 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 combination
Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Canakinumab: 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 combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides 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 modification
COVID-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 modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-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 modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
CycloSPORINE (Systemic): Adalimumab may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Dengue 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 combination
Denosumab: 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 modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza 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 modification
Leflunomide: 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 modification
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus 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 combination
Polymethylmethacrylate: 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 modification
Rabies 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 modification
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Rubella- 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 combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-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 modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene 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 combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Theophylline Derivatives: Adalimumab may decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thiopurine 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 therapy
Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Risk X: Avoid combination
Tofacitinib: 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 combination
Typhoid 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 combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (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 modification
Vaccines (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 combination
Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Risk X: Avoid combination
Warfarin: Adalimumab may decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Yellow 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 combination
The 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).
Adalimumab 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.
Adalimumab is present in breast milk
Based 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).
CBC 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).
Inflammatory 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 dose
Therapeutic reference range: ≥7.5 mcg/mL (Feuerstein 2017)
Adalimumab 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.
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 serum
Bioavailability: Absolute: 64%
Half-life elimination: Terminal: ~2 weeks (range: 10 to 20 days)
Time to peak, serum: SubQ: 131 ± 56 hours
Older 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.
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