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Adalimumab

Adalimumab
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Special Alerts

Tumor Necrosis Factor-alpha (TNFα) Blockers: Risk of Infection from Legionella and Listeria September 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of an update to the Boxed Warning for the entire class of tumor necrosis factor-alpha (TNFα) blockers including Remicade® (infliximab), Enbrel® (etanercept), Humira® (adalimumab), Cimzia® (certolizumab pegol), and Simponi® (golimumab). The Boxed Warning will include the risk of infection from two bacterial pathogens, Legionella and Listeria.

Tumor Necrosis Factor (TNF) Blockers, Azathioprine, and/or Mercaptopurine: Reports of Hepatosplenic T-Cell Lymphoma (HSTCL) April 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals and the public of continued reports of a rare malignancy, Hepatosplenic T-Cell Lymphoma (HSTCL), occurring in patients receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. HSTCL is an aggressive form of a rare white blood cell cancer that is usually fatal. These reports have occurred predominately in adolescents and young adults being treated with these agents for Crohn’s disease or ulcerative colitis; however, some case reports occurred in patients treated for psoriasis (one report) or rheumatoid arthritis (two reports). In addition, most of the reported cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents (including TNF blockers, azathioprine, mercaptopurine), although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy.

The FDA is recommending prescribers discuss with patients the increased risk of HSTCL development, particularly in adolescents and young adults, when prescribing these and other immunosuppressant therapies. Healthcare professionals should monitor for the emergence of malignancies during therapy with TNF blockers, azathioprine, and/or mercaptopurine. Patients should be educated on the signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss) during use. The FDA is also reminding healthcare professionals that patients with rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis may be more likely to develop lymphoma compared to the general U.S. population, which can make assessing the additional risk of immunosuppressant use difficult to determine.

Brand Names: U.S.

  • Humira®;
  • Humira® Pen
Brand Names: Canada

  • Humira®
Pharmacologic Category

  • Antirheumatic, Disease Modifying;
  • Gastrointestinal Agent, Miscellaneous;
  • Monoclonal Antibody;
  • Tumor Necrosis Factor (TNF) Blocking Agent
Dosing: AdultRheumatoid arthritis: SubQ: 40 mg every other week; may be administered with other DMARDs; patients not taking methotrexate may increase dose to 40 mg every week

Ankylosing spondylitis, psoriatic arthritis: SubQ: 40 mg every other week

Crohn’s disease: SubQ: Initial: 160 mg (given as 4 injections on day 1 or as 2 injections/day 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, 2009).

Plaque psoriasis: SubQ: Initial: 80 mg as a single dose; maintenance: 40 mg every other week beginning 1 week after initial dose

Dosing: PediatricJuvenile idiopathic arthritis (JIA): Children ≥4 years: SubQ:

15 kg to <30 kg: 20 mg every other week

≥30 kg: 40 mg every other week

Dosing: GeriatricRefer to adult dosing.

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [preservative free]:

Humira®: 40 mg/0.8 mL (0.8 mL) [contains natural rubber/natural latex in packaging, polysorbate 80; prefilled syringe]

Humira® Pen: 40 mg/0.8 mL (0.8 mL) [contains natural rubber/natural latex in packaging, polysorbate 80]

Injection, solution [pediatric, preservative free]:

Humira®: 20 mg/0.4 mL (0.4 mL) [contains natural rubber/natural latex in packaging, polysorbate 80; prefilled syringe]

Generic Equivalent Available: U.S.No

AdministrationFor SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard. Needle cap of the prefilled syringe may contain latex.

UseTreatment of active rheumatoid arthritis (moderate-to-severe) and active psoriatic arthritis; may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs); treatment of ankylosing spondylitis

Treatment of moderately- to severely-active Crohn’s disease in patients with inadequate response to conventional treatment, or patients who have lost response to or are intolerant of infliximab

Treatment of moderate-to-severe plaque psoriasis

Treatment of moderately- to severely-active juvenile idiopathic arthritis

Medication Safety Issues

Sound-alike/look-alike issues:

Humira® may be confused with Humulin®, Humalog®

Humira® Pen may be confused with HumaPen® Memoir®

Adverse Reactions Significant>10%:

Central nervous system: Headache (12%)

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Dermatologic: Rash (6% to 12%)

Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)

Neuromuscular & skeletal: CPK increased (15%)

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

Miscellaneous: Antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)

5% to 10%:

Cardiovascular: Hypertension (5%)

Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)

Gastrointestinal: Nausea (9%), abdominal pain (7%)

Genitourinary: Urinary tract infection (8%)

Hepatic: Alkaline phosphatase increased (5%)

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

Neuromuscular & skeletal: Back pain (6%)

Renal: Hematuria (5%)

Miscellaneous: Accidental injury (10%), flu-like syndrome (7%)

<5%:

Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, thrombosis (leg), vascular disorder

Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma

Dermatologic: Cellulitis, erysipelas

Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder

Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting

Genitourinary: Cystitis, pelvic pain

Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia

Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis

Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor

Ocular: Cataract

Renal: Kidney calculus, pyelonephritis

Respiratory: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion, pneumonia

Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)

Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, angioneurotic edema, aplastic anemia, appendicitis, cutaneous vasculitis, cytopenia, erythema multiforme, fixed drug eruption, Guillain-Barré syndrome, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal perforation, leukemias, pancreatitis, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), septic arthritis, Stevens-Johnson syndrome, systemic vasculitis, thrombocytopenia, transaminases increased, urticaria

ContraindicationsThere are no contraindications listed within the FDA-approved labeling.

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection)

Warnings/PrecautionsBoxed warnings:

• Fatal infections: See “Concerns related to adverse effects” below.

• Malignancy: See “Concerns related to adverse effects” below.

• Tuberculosis: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioedema; 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.

• Fatal infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (including tuberculosis, invasive fungal and other opportunistic infections) have been reported in patients receiving TNF-blocking agents, including adalimumab. Cases of unrecognized invasive fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis) have also been reported with anti-TNF agent use. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Other opportunistic infections included Aspergillus and Nocardia. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (eg, diabetes or residence/travel from areas of endemic mycoses). Do not give to patients with an active chronic or localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued.

• Hepatitis B: Rare reactivation of hepatitis B virus (HBV) has occurred in chronic virus carriers; evaluate prior to initiation, during, and for several months after treatment. Evaluate patients at risk for HBV infection prior to therapy to determine HBV status.

• Malignancy: [U.S. Boxed Warning]: Lymphoma and other malignancies have been reported in children and adolescent patients receiving other TNF-blocking agents. Half the cases are lymphomas (Hodgkin’s and non-Hodgkin’s) and the other cases are varied, but include malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants. [U.S. Boxed Warning]: Hepatosplenic T-cell lymphoma (HSTCL), a rare T-cell lymphoma, has also been reported primarily in patients with Crohn’s disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males. Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. 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. 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).

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• Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy.

• Tuberculosis: Tuberculosis (disseminated or extrapulmonary) has been reactivated while on adalimumab; most cases have been reported within the first 8 months of treatment. Doses higher than recommended are associated with an increased risk for tuberculosis reactivation. [U.S. Boxed Warnings]: Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic

Disease-related concerns:

• Demyelinating disease: Use with caution in patients with pre-existing or recent onset central or peripheral nervous system demyelinating disorders; rare cases of new-onset or exacerbation of demyelinating disorders (eg, multiple sclerosis, Guillain-Barré syndrome) have been reported. Consider discontinuing use in patients who develop peripheral or central nervous system demyelinating disorders during treatment.

• Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.

Concurrent drug therapy issues:

• Abatacept: Serious infections were reported when abatacept was used with TNF-blocking agents; therefore, concurrent use of adalimumab and abatacept is not recommended.

• Anakinra: Serious infections were reported when anakinra was used with TNF-blocking agents; therefore, concurrent use of adalimumab and anakinra is not recommended.

Special populations:

• Elderly: Infection and malignancy has been reported at a higher incidence in elderly patients compared to younger adults; use caution in elderly patients.

• Pediatrics: Malignancies have been reported among children and adolescents receiving TNF-blocking agents.

Dosage form specific issues:

• Latex: The packaging (needle cover of prefilled syringe) may contain latex.

• Polysorbate 80: Product may contain polysorbate 80.

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 is no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.

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. Risk X: Avoid combination

Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy

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

BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination

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

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

Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy

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

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

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. Risk D: Consider therapy modification

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

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

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

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

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

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

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

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. 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. Risk X: Avoid combination

Ethanol/Nutrition/Herb InteractionsHerb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.

Pregnancy Risk FactorPregnancy Implications

Teratogenic effects were not observed in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to adalimumab during pregnancy (877-311-8972).

LactationExcretion in breast milk unknown/not recommended

Breast-Feeding ConsiderationsIt is not known whether adalimumab is secreted in human milk. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pricing: U.S. (www.drugstore.com)Kit (Humira)

20 mg/0.4 mL (2): $2029.90

40 mg/0.8 mL (2): $1947.08

Kit (Humira Pen)

40 mg/0.8 mL (2): $1946.00

Monitoring ParametersPlace and read PPD before initiation. Monitor improvement of symptoms and physical function assessments; CBC; signs of infection, bleeding, or bruising; signs of HBV reactivation in patients who are carriers (during therapy and several months following discontinuation)

International Brand Names

  • Humira (AE, AR, AT, AU, BE, BG, BH, BR, CH, CL, CN, CO, CY, CZ, DE, DK, EC, EG, FI, FR, GB, GR, HK, HN, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MX, MY, NL, NO, OM, PE, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE);
  • Trudexa (AT, BE, BG, CH, CZ, DE, DK, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
Mechanism of ActionAdalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFα receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn’s disease; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.

Pharmacodynamics/KineticsDistribution: Vd: 4.7-6 L; Synovial fluid concentrations: 31% to 96% of serum

Bioavailability: Absolute: 64%

Half-life elimination: Terminal: ~2 weeks (range: 10-20 days)

Time to peak, serum: SubQ: 131 ± 56 hours

Excretion: Clearance increased in the presence of anti-adalimumab antibodies; decreased in patients ≥40 years of age

REFERENCES
  1. Dommasch E and Gelfand JM, “Is There Truly a Risk of Lymphoma From Biologic Therapies?” Dermatol Ther, 2009, 22 (5):418-30.
  2. Gordon KB, Langley RG, Leonardi C, et al, “Clinical Response to Adalimumab Treatment in Patients With Moderate to Severe Psoriasis: Double-Blind, Randomized Controlled Trial and Open-Label Extension Study,” J Am Acad Dermatol, 2006, 55(4):598-606. [PubMed 17010738]
  3. Keystone EC, Kavanaugh AF, Sharp JYT, et al, “Radiographic, Clinical, and Functional Outcomes of Treatment With Adalimumab (A Human Anti-Tumor Necrosis Factor Monoclonal Antibody) in Patients With Active Rheumatoid Arthritis Receiving Concomitant Methotrexate Therapy: A Randomized, Placebo-Controlled, 52-Week Trial,” Arthritis Rheum, 2004, 50(5):1400-11. [PubMed 15146409]
  4. Lichtenstein GR, Hanauer SB, and Sandborn WJ, “Management of Crohn’s Disease in Adults,” Am J Gastroenterol, 2009, 104(2):465-83. [PubMed 19174807]
  5. Sandborn WJ, Rutgeerts P, Enns R, et al, “Adalimumab Induction Therapy for Crohn Disease Previously Treated With Infliximab: A Randomized Trial.,” Ann Intern Med, 2007, 146(12):829-38. [PubMed 17470824]
  6. van der Heijde D, Kivitz A, Schiff MH, et al, “Efficacy and Safety of Adalimumab in Patients With Ankylosing Spondylitis: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial,” Arthritis Rheum, 2006, 54(7):2136-46. [PubMed 16802350]