Infliximab Warnings Concerning Lymphoma - October 8, 2004

The manufacturers of Remicade® (infliximab) have announced a change to the approved labeling to indicate the possibility of lymphoma in patients treated for rheumatoid arthritis. The revision was prompted by an analysis of clinical trials in which the frequency of lymphoma, although rare, was up to 6 times higher than in the general population. A cause and effect relationship has not been established, and labeling notes the impact of the drug on the development and course of malignancies has not been fully defined. As compared to the general population, an increased risk of lymphoma has been noted with several drugs used in rheumatoid arthritis; however, it is difficult to interpret the relative risk of this reaction since rheumatoid arthritis has been previously associated with an increased rate of lymphoma. The revision will make the labeling of infliximab more consistent with 2 other drugs which modify the levels or activity of tumor necrosis factor in rheumatoid arthritis, etanercept (Enbrel®) and adalimumab (Humira®).

Ankylosing spondylitis: Improving signs and symptoms of disease

Crohn's disease: Induction and maintenance of remission in patients with moderate to severe disease who have an inadequate response to conventional therapy; to reduce the number of draining enterocutaneous and rectovaginal fistulas and to maintain fistula closure

Rheumatoid arthritis: Inhibits the progression of structural damage and improves physical function in patients with moderate to severe disease; used with methotrexate

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.

Severe hepatic reactions have been reported during treatment. Use caution with CHF; if a decision is made to use with CHF, monitor closely and discontinue if exacerbated or new symptoms occur. Use caution with history of hematologic abnormalities; hematologic toxicities (eg, leukopenia, neutropenia, thrombocytopenia, pancytopenia) have been reported; discontinue if significant abnormalities occur. Autoimmune antibodies and a lupus-like syndrome have been reported. If antibodies to double-stranded DNA are confirmed in a patient with lupus-like symptoms, infliximab should be discontinued. Rare cases of demyelinating disease have been reported, use with caution in patients with pre-existing or recent onset CNS demyelinating disorders, or seizures; discontinue if significant CNS adverse reactions develop.

Medications for the treatment of hypersensitivity reactions should be available for immediate use. Safety and efficacy for use in juvenile rheumatoid arthritis and in pediatric patients with Crohn's disease have not been established.

>10%:

Central nervous system: Headache (18%)

Dermatologic: Rash (10%)

Gastrointestinal: Nausea (21%), diarrhea (12%), abdominal pain (12%)

Genitourinary: Urinary tract infection (8%)

Local: Infusion reactions (20%)

Neuromuscular & skeletal: Arthralgia (8%), back pain (8%)

Respiratory: Upper respiratory tract infection (32%), cough (12%), sinusitis (14%), pharyngitis (12%)

Miscellaneous: Development of antinuclear antibodies (~50%), infection (36%), development of antibodies to double-stranded DNA (17%); Crohn's patients with fistulizing disease: Development of new abscess (15%)

5% to 10%:

Cardiovascular: Hypertension (7%)

Central nervous system: Pain (8%), fatigue (9%), fever (7%)

Dermatologic: Pruritus (7%)

Gastrointestinal: Dyspepsia (10%)

Respiratory: Bronchitis (10%), dyspnea (6%), rhinitis (8%)

Miscellaneous: Moniliasis (5%)

<5%: Abscess, adult respiratory distress syndrome, allergic reaction, ALT/AST increased (mild, incidence increased with concomitant methotrexate therapy), anemia, arrhythmia, basal cell carcinoma, biliary pain, bradycardia, brain infarction, breast cancer, cardiac arrest, cellulitis, cholecystitis, cholelithiasis, circulatory failure, confusion, constipation, dehydration, diaphoresis increased, dizziness, edema, gastrointestinal hemorrhage, heart failure, hemolytic anemia, hepatitis, hypersensitivity reactions, hypotension, ileus, intervertebral disk herniation, intestinal obstruction, intestinal perforation, intestinal stenosis, leukopenia, lymphadenopathy, lymphoma, meningitis, menstrual irregularity, MI, neuritis, pancreatitis, pancytopenia, peripheral neuropathy, peritonitis, pleural effusion, pleurisy, proctalgia, pulmonary edema, pulmonary embolism, renal failure, respiratory insufficiency, seizure, sepsis, serum sickness, suicide attempt, symphyseolysis, syncope, tachycardia, tendon disorder, thrombocytopenia, thrombophlebitis (deep), ulceration

Postmarketing and/or case reports: Anaphylactic reactions; demyelinating disorders (eg, multiple sclerosis, optic neuritis); drug-induced lupus-like syndrome, dyspnea, Guillain-Barré syndrome, hepatitis B reactivation, interstitial fibrosis, interstitial pneumonitis, jaundice, latent tuberculosis reactivation, liver failure, liver function tests increased, neuropathy, neutropenia, pericardial effusion, pneumonia, urticaria, vasculitis (systemic and cutaneous), worsening CHF

Anakinra: Infliximab may be associated with increased risk of serious infection when used in combination with anakinra.

Immunosuppressants: When used with infliximab, may decrease the risk of infusion-related reactions, and may decrease development of anti-double-stranded DNA antibodies

Vaccines, live: Concomitant use has not be studied; currently recommended not to administer live vaccines during infliximab therapy

Onset of action: Crohn's disease: ~2 weeks

Half-life elimination: 8-9.5 days

Crohn's disease:

Induction regimen: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter; dose may be increased to 10 mg/kg in patients who respond but then lose their response. If no response by week 14, consider discontinuing therapy.

Rheumatoid arthritis (in combination with methotrexate therapy): 3 mg/kg at 0, 2, and 6 weeks, then every 8 weeks thereafter; doses have ranged from 3-10 mg/kg intravenous infusion repeated at 4- to 8-week intervals

Ankylosing spondylitis: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 6 weeks thereafter

Dosage adjustment with CHF: Weigh risk versus benefits for individual patient:

NYHA Class III or IV: 5 mg/kg

Dosage adjustment in renal impairment: No specific adjustment is recommended

Dosage adjustment in hepatic impairment: No specific adjustment is recommended

Centers for Disease Control, "Testing and Treatment of Latent Tuberculosis Infection,"MMWR Recomm Rep, 2000, 49(RR-6).

Chung ES, Packer M, Lo KH, et al, "Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-Alpha, in Patients With Moderate-to-Severe Heart Failure: Results of the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial,"Circulation, 2003, 107(25):3133-40.

"Diagnostic Standards and Classification of Tuberculosis in Adults and Children. Official Statement of the American Thoracic Society and the Centers for Disease Control and Prevention,"Am J Respir Crit Care Med, 2000, 161:1376-95.