Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis – Updated August 2009
The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. Health Canada has recently issued a similar alert to Canadian practitioners. The FDA analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.
Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin’s and non-Hodgkin’s 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); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.
Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.
New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.
The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Health Canada is also working with their respective manufacturers to update the Canadian labeling with this important safety information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.
Additional information can be found at:
Tumor Necrosis Factor-Alpha Blockers Associated with Unrecognized Invasive Fungal Infections – Updated May 28, 2009
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor (anti-TNF) agents adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), and infliximab (Remicade®). The FDA has received reports of pulmonary and disseminated cases of histoplasmosis, coccidioidomycosis, blastomycosis, and other fungal infections associated with use of these agents. In some cases, the symptoms of fungal infection (eg, fever, cough, malaise, dyspnea, fatigue) were unrecognized and precluded prompt antifungal treatment, resulting in 12 deaths. In response, the FDA is requiring manufacturers of these agents to strengthen the boxed warning statement in the labeling to further emphasize the risk of invasive fungal infection. Patients should be monitored closely for signs and symptoms suggestive of fungal infection, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation. Symptomatic patients should be questioned about their residence in or travel from areas of endemic mycoses, which should prompt consideration of empiric antifungal therapy.
Additional information can be found at:
U.S. BRAND NAMES — Humira®
Antirheumatic, Disease Modifying
Gastrointestinal Agent, Miscellaneous
Tumor Necrosis Factor (TNF) Blocking Agent
Rheumatoid 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 over 2 days, then 80 mg 2 weeks later (day 15); Maintenance: 40 mg every other 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
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children ≥ 4 years: SubQ:
15 kg to <30 kg: 20 mg every other week
≥ 30 kg: 40 mg every other week
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL) [contains polysorbate 80]
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]
DOSAGE FORMS: CONCISE
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL)
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — For SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard; rotate injection sites. Needle cap of the prefilled syringe may contain latex.
Treatment 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
DVERSE REACTIONS SIGNIFICANT
Central nervous system: Headache (12%)
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%)
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
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, cutaneous vasculitis, cytopenia, erythema multiforme, fixed drug eruption, Guillain-Barre syndrome, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal perforation, leukemias, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), septic arthritis, thrombocytopenia, transaminases increased, urticaria
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
Canada 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 / PRECAUTIONS
Boxed warnings: Fatal infections: . Tuberculosis evaluation: .
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: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.9/100 patient years), when compared to the control group (0.3/100 patient years). 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. Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy. Tuberculosis evaluation: 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 CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of optic neuritis and demyelinating disease (new onset or exacerbation) have been reported. Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.
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.
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/toxi
c effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. 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
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
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. 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). Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY 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).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It 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 — (data from drugstore.com)
40 mg/0.8 mL (2): $1635.66
Kit (Humira Pen)
40 mg/0.8 mL (2): $1663.63
MONITORING PARAMETERS — Place and read PPD before initiation. Monitor improvement of symptoms and physical function assessments; CBC; signs of infection, bleeding or bruising.
CANADIAN BRAND NAMES — Humira®
INTERNATIONAL BRAND NAMES — Humira (AE, AR, AT, AU, BE, BG, BH, BR, CH, 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 ACTION — Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFalpha 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 / KINETICS
Distribution: 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 antiadalimumab antibodies; decreased in patients 40 years and older
PATIENT INFORMATION — May cause headache, nausea, or stomach pain. Notify prescriber of any signs of infection.