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Adalimumab

Medically reviewed on Sep 10, 2018

Pronunciation

See also: Stelara

(a da LIM yoo mab)

Index Terms

  • Adalimumab-adbm
  • Adalimumab-atto
  • Amjevita
  • Antitumor Necrosis Factor Alpha (Human)
  • Cyltezo
  • D2E7
  • Human Antitumor Necrosis Factor Alpha

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Pen-injector Kit, Subcutaneous [preservative free]:

Humira Pen: 40 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-Ps/UV Starter: 40 mg/0.8 mL (1 ea); 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); 20 mg/0.4 mL (1 ea); 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); 80 mg/0.8 mL (1 ea); 80 MG/0.8ML & 40MG/0.4ML (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Humira
  • Humira Pediatric Crohns Start
  • Humira Pen
  • Humira Pen-CD/UC/HS Starter
  • Humira Pen-Ps/UV Starter

Pharmacologic Category

  • Antirheumatic, Disease Modifying
  • Gastrointestinal Agent, Miscellaneous
  • Monoclonal Antibody
  • Tumor Necrosis Factor (TNF) Blocking Agent

Pharmacology

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.

Distribution

Vd: 4.7 to 6 L; Synovial fluid concentrations: 31% to 96% of serum

Time to Peak

Serum: SubQ: 131 ± 56 hours

Half-Life Elimination

Terminal: ~2 weeks (range: 10 to 20 days)

Special Populations: Elderly

In patients with rheumatoid arthritis (RA), there was a trend toward lower clearance with increasing age in patients 40 to >75 years of age.

Use: Labeled Indications

Ankylosing spondylitis: Treatment (to reduce signs/symptoms) of active ankylosing spondylitis in adults

Crohn disease: Treatment (to reduce signs/symptoms and to induce and maintain clinical remission) of active Crohn disease (moderate to severe) in adults and pediatric patients ≥6 years (Humira only) with an inadequate response to conventional therapy or who have lost response to or are intolerant to infliximab.

Hidradenitis suppurativa (Humira only): Treatment of moderate to severe hidradenitis suppurativa

Juvenile idiopathic arthritis: Treatment (to reduce signs/symptoms) of active polyarticular juvenile idiopathic arthritis (moderate to severe) in pediatric patients ≥2 years (Humira) or ≥4 years (Amjevita; Cyltezo); may be used alone or in combination with methotrexate

Plaque psoriasis: 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)

Psoriatic arthritis: Treatment (to reduce signs/symptoms, inhibit progression of structural damage, and improve physical function) of active psoriatic arthritis in adults; may be used alone or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs)

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 DMARDs

Ulcerative colitis: Treatment (to induce and sustain clinical remission) of active ulcerative colitis (moderate to severe) in adults who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine. (Note: Efficacy in patients that are intolerant to or no longer responsive to other TNF blockers has not been established.)

Uveitis (Humira only): Treatment of non-infectious intermediate, posterior, and panuveitis in adults

Off Label Uses

Crohn disease (management after surgical resection)

Data from a small prospective, randomized, controlled trial and a meta-analysis support the use of adalimumab in the management of Crohn disease after surgical resection and has demonstrated adalimumab lowers endoscopic and clinical recurrence rates [Savarino 2013], [Singh 2015].

Based on the American Gastroenterological Association Institute Guideline on the Management of Crohn’s Disease after Surgical Resection and American College of Gastroenterology Guidelines on the Management of Crohn’s Disease in Adults, adalimumab is an effective first-line agent for prophylactic therapy in patients who are at higher risk for clinical recurrence following surgical resection.

Crohn disease (perianal/fistulizing disease)

Data from a randomized, placebo-controlled phase III trial support the use of adalimumab in the treatment and maintenance of long-term healing of draining fistulas in patients with Crohn disease [Colombel 2009].

Based on the American College of Gastroenterology Guideline for the Management of Crohn’s Disease in Adults, adalimumab may be effective and should be considered in the management of perianal fistulas in patients with Crohn disease [ACG [Lichtenstein 2018]].

Pyoderma gangrenosum

Preliminary data suggest that adalimumab could be successful as an adjunct therapy or monotherapy for the treatment of severe pyoderma gangrenosum. Adalimumab has been shown to be beneficial in refractory pyoderma gangrenosum in cases in which infliximab and etanercept have failed. Controlled studies are needed to evaluate the efficacy and safety of adalimumab in order to fully determine its place in the treatment of pyoderma gangrenosum.

Uveitis (children/adolescents)

Results from noncontrolled data show that adalimumab is effective in treating uveitis in children and adolescents. However, no prospective controlled clinical trials have been performed. Adalimumab has several safety concerns, including a black box warning regarding serious infections and lymphomas. Further data are needed to establish the efficacy, safety, optimal dosage, and length of adalimumab therapy in the treatment of uveitis in children. An expert review panel recommends adalimumab as a third-line treatment option in children with noninfectious uveitis.

Contraindications

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)

Dosing: Adult

Note: Amjevita (adalimumab-atto) and Cyltezo (adalimumab-adbm) are approved as biosimilar agents to Humira. Approved uses may vary (consult product labeling).

Ankylosing spondylitis: SubQ: 40 mg every other week (may continue methotrexate, other nonbiologic DMARDS, corticosteroids, NSAIDs and/or analgesics)

Crohn disease: SubQ (may continue aminosalicylates and/or corticosteroids; if necessary, azathioprine, mercaptopurine, or methotrexate may also be continued):

Initial: 160 mg (given on day 1 or split and given over 2 consecutive days), then 80 mg 2 weeks later (day 15).

Maintenance: 40 mg every other week beginning day 29. Note: Some patients may require 40 mg every week as maintenance therapy (Lichtenstein 2018).

Crohn disease management after surgical resection (off-label use): SubQ:

Initial: 160 mg (given on day 1), then 80 mg 2 weeks later (day 15) (Savarino 2013; Singh 2015). Note: Administer first infusion within 4 weeks after surgery in high-risk patients (Lichtenstein 2018).

Maintenance: 40 mg every 2 weeks (beginning day 29) (Savarino 2013; Singh 2015).

Crohn disease (perianal/fistulizing disease) (off-label use; Colombel 2009): SubQ:

Initial: 80 mg (given on day 1), then 40 mg 2 weeks later (day 15).

Maintenance: 40 mg every week or 40 mg every other week beginning day 29.

Hidradenitis suppurativa (Humira only): SubQ:

Initial: 160 mg (given on day 1 or split and given over 2 consecutive days), then 80 mg 2 weeks later (day 15)

Maintenance: 40 mg every week beginning day 29

Plaque psoriasis: SubQ:

Initial: 80 mg as a single dose

Maintenance: 40 mg every other week beginning 1 week after initial dose

Psoriatic arthritis: SubQ: 40 mg every other week (may continue methotrexate, other nonbiologic DMARDS, corticosteroids, NSAIDs and/or analgesics)

Pyoderma gangrenosum (off-label use): SubQ: 40 to 80 mg every week or every other week (Fonder 2006; Heffernan 2007; Hubbard 2005; Jacob 2008). Additional data may be necessary to further define the role of adalimumab in the treatment of this condition.

Rheumatoid arthritis: SubQ: 40 mg every other week (may continue methotrexate, other nonbiologic DMARDS, corticosteroids, NSAIDs, and/or analgesics); patients not taking concomitant methotrexate may increase dose to 40 mg every week

Ulcerative colitis: SubQ (may continue aminosalicylates and/or corticosteroids; if necessary, azathioprine, or mercaptopurine may also be continued):

Initial: 160 mg (given on day 1 or split and given over 2 consecutive days), then 80 mg 2 weeks later (day 15).

Maintenance: 40 mg every other week beginning day 29. Note: Only continue maintenance dose in patients demonstrating clinical remission by 8 weeks (day 57) of therapy.

Uveitis (Humira only): SubQ:

Initial: 80 mg as a single dose

Maintenance: 40 mg every other week beginning 1 week after initial dose

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Amjevita (adalimumab-atto) and Cyltezo (adalimumab-adbm) are approved as biosimilar agents to Humira. Approved uses may vary (consult product labeling).

Crohn disease (Humira only): SubQ:

Children ≥6 years and Adolescents:

17 kg to <40 kg:

Initial: 80 mg (given on day 1), then 40 mg 2 weeks later (day 15).

Maintenance: 20 mg every other week beginning week 4 (day 29).

≥40 kg:

Initial: 160 mg (given on day 1 or split and given over 2 consecutive days), then 80 mg 2 weeks later (day 15; given as two 40 mg injections on the same day).

Maintenance: 40 mg every other week beginning week 4 (day 29).

Juvenile idiopathic arthritis (JIA): SubQ:

Children ≥2 years (Humira) or ≥4 years (Amjevita; Cyltezo) and Adolescents:

May continue methotrexate, corticosteroids, NSAIDs and/or analgesics.

Humira (only): 10 to <15 kg: 10 mg every other week

Amjevita and Humira: 15 kg to <30 kg: 20 mg every other week

Amjevita, Cyltezo, and Humira: ≥30 kg: 40 mg every other week

BSA-based dosing (off-label):

2 to <4 years or ≥4 years and <15 kg: 24 mg/m2/dose (maximum: 20 mg/dose) every other week (Kingsbury 2014)

4 to 17 years: 24 mg/m2/dose (maximum: 40 mg/dose) every other week (Lovell 2008)

Uveitis (Humira only): Limited data available; dosing regimens variable; SubQ:

Body surface area-directed dosing: Children ≥4 years and Adolescents: 24 or 40 mg/m2 every 2 weeks; maximum dose 40 mg/dose (Gallagher 2007; Simonini 2011). 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 five patients who received adalimumab at 40 mg/m2/dose every 2 weeks.

Weight-directed dosing: Children ≥2 years and Adolescents (Biester 2007; Sens 2012; Tynjala 2008):

<30 kg: 20 mg every other week

>30 kg: 40 mg every other week

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administration

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.

Storage

Store 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.

Drug Interactions

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. 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. Avoid combination

Baricitinib: May enhance the adverse/toxic effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Avoid combination

Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CycloSPORINE (Systemic): Adalimumab may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

InFLIXimab: Adalimumab may enhance the immunosuppressive effect of InFLIXimab. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Theophylline Derivatives: Adalimumab may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. 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. Monitor therapy

Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

Tofacitinib: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Warfarin: Adalimumab may decrease the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (12%)

Dermatologic: Skin rash (6% to 12%)

Hematologic & oncologic: Positive ANA titer (12%)

Immunologic: Antibody development (3% to 26%; significance unknown)

Infection: Infection (children and adolescents: 45%)

Local: Injection site reaction (5% to 20%; includes erythema, itching, hemorrhage, pain, swelling)

Neuromuscular & skeletal: Increased creatine phosphokinase (15%)

Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)

1% to 10%:

Cardiovascular: Hypertension (5%), atrial fibrillation (<5%), cardiac arrest (<5%), cardiac arrhythmia (<5%), chest pain (<5%), coronary artery disease (<5%), deep vein thrombosis (<5%), hypertensive encephalopathy (<5%), myocardial infarction (<5%), palpitations (<5%), pericardial effusion (<5%), pericarditis (<5%), peripheral edema (<5%), subdural hematoma (<5%), syncope (<5%), tachycardia (<5%)

Central nervous system: Confusion (<5%), myasthenia (<5%), paresthesia (<5%), torso pain (<5%)

Dermatologic: Cellulitis, erysipelas

Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%), dehydration (<5%), ketosis (<5%), menstrual disease (<5%), parathyroid disease (<5%)

Gastrointestinal: Nausea (9%), abdominal pain (7%), cholecystitis (<5%), cholelithiasis (<5%), esophagitis (<5%), gastrointestinal hemorrhage (<5%), vomiting (<5%), diverticulitis

Genitourinary: Urinary tract infection (≤8%), hematuria (5%), cystitis (<5%), pelvic pain (<5%)

Hematologic & oncologic: Adenoma (<5%), agranulocytosis (<5%), paraproteinemia (<5%), polycythemia (<5%), carcinoma (including breast, gastrointestinal, skin, urogenital), malignant lymphoma, malignant melanoma

Hepatic: Increased serum alkaline phosphatase (5%), hepatic necrosis (<5%)

Hypersensitivity: Hypersensitivity reaction (children 5% to 6%; adults 1%)

Infection: Serious infection (4%; including dental caries, gastroenteritis, rotavirus, varicella), herpes simplex infection (≤4%), herpes zoster (≤4%), sepsis

Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)

Neuromuscular & skeletal: Back pain (6%), arthritis (<5%), arthropathy (<5%), bone disease (<5%), bone fracture (<5%), limb pain (<5%), muscle cramps (<5%), myasthenia (<5%), osteonecrosis (<5%), septic arthritis (<5%), synovitis (<5%), tendon disease (<5%), tremor (<5%), arthralgia (3%; plaque psoriasis)

Ophthalmic: Cataract (<5%)

Renal: Nephrolithiasis (<5%), pyelonephritis

Respiratory: Flu-like symptoms (7%), asthma (<5%), bronchospasm (<5%), dyspnea (<5%), pleural effusion (<5%), respiratory depression (<5%), pharyngitis (juvenile idiopathic arthritis: ≤4%), pneumonia (≤4%), tuberculosis (including reactivation of latent infection; disseminated, miliary, lymphatic, peritoneal, and pulmonary)

Miscellaneous: Accidental injury (10%), abnormal healing (<5%), postoperative complication (infection)

<1%, postmarketing, and/or case reports: Abscess (limb, perianal), alopecia, anal fissure, anaphylactoid reaction, anaphylaxis, anemia, angioedema, aplastic anemia, appendicitis, bacterial infection, basal cell carcinoma, blepharitis, bronchitis, cardiac failure, cerebrovascular accident, cervical dysplasia, circulatory shock, clonus, cytopenia, dermal ulcer, diarrhea, diplopia, endometrial hyperplasia, eosinophilia, erythema multiforme, fever, fixed drug eruption, fulminant necrotizing fasciitis, fungal infection, Guillain-Barré syndrome, hepatic failure, hepatitis B (reactivation), hepatosplenic T-cell lymphomas (children, adolescents, and young adults), hepatotoxicity (idiosyncratic) (Chalasani 2014), histoplasmosis, hyperreflexia, hypersensitivity angiitis, increased serum transaminases, interstitial pulmonary disease (eg, pulmonary fibrosis), intestinal obstruction, intestinal perforation, leukemia, leukopenia, liver metastases, lupus-like syndrome, lymphadenopathy, lymphocytosis, malignant neoplasm of ovary, meningitis (viral), Merkel cell carcinoma, multiple sclerosis, musculoskeletal chest pain, mycobacterium avium complex, myositis (children and adolescents), neutropenia, nocturia, optic neuritis, pancreatitis, pancytopenia, protozoal infection, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pulmonary embolism, respiratory failure, sarcoidosis, septic shock, skin granuloma (annulare; children and adolescents), Stevens-Johnson syndrome, streptococcal pharyngitis (children and adolescents), supraventricular cardiac arrhythmia, swelling of eye, systemic lupus erythematosus, testicular neoplasm, thrombocytopenia, urticaria, vascular disease, vasculitis (systemic), viral infection, weakness

ALERT: U.S. Boxed Warning

Serious 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.

Warnings/Precautions

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.

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: 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.

Monitoring Parameters

Monitor improvement of symptoms and physical function assessments. Latent TB screening prior to initiating and during therapy; signs/symptoms of active infection, including tuberculosis (prior to, during, and following therapy); CBC with differential; signs/symptoms/worsening of heart failure; 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. The American Gastroenterological Association suggests reactive therapeutic drug monitoring to guide treatment changes in adult patients treated with adalimumab for active inflammatory bowel disease (Feuerstein 2017).

Pregnancy Considerations

Adalimumab crosses the placenta and can be detected in cord blood. Placental transfer significantly begins in the second trimester and increases as pregnancy progresses (Julsgaard 2016; Nguyen 2016).

Following administration to pregnant patients with inflammatory bowel disease, cord blood and newborn 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 (Julsgaard 2016).

Outcome data from a pregnancy registry are available. Included were women with rheumatoid arthritis treated with adalimumab at least during the first trimester (n=74), women with RA not treated with adalimumab (n=80), and healthy pregnant women without RA (n=219). The incidence of major birth defects was not significantly different between the treatment groups. No pattern of specific defects was noted. There were no adverse pregnancy outcomes associated with therapy (Burmester 2017).

Administration of live vaccines should be postponed until after 6 months of age to an infant exposed to antitumor necrosis factor therapy in utero (Nguyen 2016; van der Woude 2015).

Inflammatory bowel disease is associated with adverse pregnancy outcomes; management of maternal disease should be optimized prior to pregnancy (Nguyen 2016; van der Woude 2015). Maternal adalimumab serum concentrations were found to remain stable during pregnancy in a study of 9 women with Crohn disease (Seow 2017). Recommendations for use of antitumor necrosis factor agents in pregnant women vary by guideline. Some guidelines recommend avoiding use of adalimumab in the third trimester (Flint 2016). Other guidelines recommend discontinuing as early as 20 weeks' gestation (Götestam Skorpen 2016). However, women on antitumor necrosis factor maintenance may continue treatment during pregnancy when needed and treatment may be initiated during pregnancy in some cases (Nguyen 2016; van der Woude 2015).

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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience common cold symptoms, abdominal pain, nausea, or back pain. Have patient report immediately to prescriber signs of infection, signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, angina or shortness of breath, or swelling in the arms or legs), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of aplastic anemia (fever, pharyngitis, mouth sores, infections, bruising, or purple skin splotches), angina, severe headache, burning or numbness feeling, severe dizziness, passing out, seizures, vision changes, extremity weakness, excessive weight loss, night sweats, persistent fever, swollen glands, skin growth, hematuria, pale skin, skin eczema, severe injection site irritation, or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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