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Infliximab


Special Alerts

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®).


Pronunciation

 (in FLIKS e mab)


U.S. Brand Names

 Remicade®


Synonyms

 Infliximab, Recombinant


Generic Available

 No


Canadian Brand Names

 Remicade®


Use

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


Pregnancy Risk Factor

 B (manufacturer)


Pregnancy Implications

 Reproduction studies have not been conducted. Use during pregnancy only if clearly needed. A Rheumatoid Arthritis and Pregnancy Registry has been established for women exposed to infliximab during pregnancy (Organization of Teratology Information Services, 877-311-8972).


Lactation

 Excretion in breast milk unknown/not recommended


Contraindications

 Hypersensitivity to murine proteins or any component of the formulation; doses >5 mg/kg in patients with moderate or severe congestive heart failure (NYHA Class III/IV)


Warnings/Precautions

 Serious infections (including sepsis, pneumonia, and fatal infections) have been reported in patients receiving TNF-blocking agents. Many of the serious infections in patients treated with infliximab have occurred in patients on concomitant immunosuppressive therapy. Caution should be exercised when considering the use of infliximab in patients with a chronic infection or history of recurrent infection. Infliximab should not be given to patients with a clinically important, active infection. Patients who develop a new infection while undergoing treatment with infliximab should be monitored closely. If a patient develops a serious infection or sepsis, infliximab should be discontinued. Reactivation of hepatitis B has occurred in chronic virus carriers; evaluate prior to initiation and during treatment. Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to infliximab therapy. Treatment of latent tuberculosis should be initiated before infliximab is used. Tuberculosis (may be disseminated or extrapulmonary) has been reactivated in patients previously exposed to TB while on infliximab. Most cases have been reported within the first 3-6 months of treatment. Other opportunistic infections (eg, invasive fungal infections, listeriosis, Pneumocystis ) have occurred during therapy. The risk/benefit ratio should be weighed in patients who have resided in regions where histoplasmosis is endemic.

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.


Adverse Reactions

 Note: Although profile is similar, frequency of effects may be different in specific populations (Crohn's disease vs rheumatoid arthritis). Percentages reported with rheumatoid arthritis:

>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


Overdosage/Toxicology

 Doses of up to 20 mg/kg have been given without toxic effects. In case of overdose, treatment should be symptom-directed and supportive.


Drug Interactions

 Specific drug interaction studies have not been conducted

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


Stability

 Store vials at 2°C to 8°C (36°F to 46°F); do not freeze. Reconstitute vials with 10 mL sterile water for injection; swirl vial gently to dissolve powder, do not shake, allow solution to stand for 5 minutes; total dose of reconstituted product should be further diluted to 250 mL of 0.9% sodium chloride injection; infusion of dose should begin within 3 hours of preparation


Compatibility

 Do not infuse with other agents.


Mechanism of Action

 Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha (TNF ), thereby interfering with endogenous TNF activity. Biological activities of TNF include the induction of pro-inflammatory cytokines (interleukins), enhancement of leukocyte migration, activation of neutrophils and eosinophils, and the induction of acute phase reactants and tissue degrading enzymes. Animal models have shown TNF expression causes polyarthritis, and infliximab can prevent disease as well as allow diseased joints to heal.


Pharmacodynamics/Kinetics

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

Half-life elimination: 8-9.5 days


Dosage

 I.V.: Adults:

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


Administration

 Infuse over at least 2 hours; do not infuse with other agents; use an in-line filter; pH ~7.2


Monitoring Parameters

 Improvement of symptoms; signs of infection; LFTs (discontinue if >5 times ULN); place and read PPD before initiation.


Patient Education

 This drug can only be administered by infusion. Avoid receiving immunizations unless approved by prescriber. Report headache or unusual fatigue; increased nausea or abdominal pain; cough, runny nose, respiratory difficulty; chest pain or persistent dizziness; fatigue, muscle pain or weakness, back pain; fever or chills; mouth sores; vaginal itching or discharge; sore throat; unhealed sores; or frequent infections. Breast-feeding precaution: Breast-feeding is not recommended.


Nursing Implications

 Medications for the treatment of hypersensitivity reactions should be readily available.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 Fatigue is common; may cause dizziness


Mental Health: Effects on Psychiatric Treatment

 None reported


Dosage Forms

 Injection, powder for reconstitution [preservative free]: 100 mg


References

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.


International Brand Names

 Remicade® (AT, AU, BE, CA, CH, CO, CZ, DE, DK, EC, ES, FI, FR, GB, HR, HU, IE, IL, IT, NL, NO, NZ, PL, RO, SE, SI, TR, YU); Revellex® (ZA)


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