In clinical trials with Remicade, adverse drug reactions (ADRs) reasonably attributable to treatment were observed in 36% of placebo-treated patients and 57% of Remicade-treated patients. Reasonably-related ADRs are listed as follows by system organ class and frequency (common >1/100, <1/10; uncommon >1/1000, <1/100; rare >1/10,000, <1/1000). Frequency is based on the excess incidence of the ADR compared with placebo in pooled data from clinical trials involving 227 patients receiving placebo and 1421 patients receiving Remicade (Crohn's disease and rheumatoid arthritis). Most ADRs were mild to moderate in severity. Infusion-related reactions were the most common ADRs reported. The most common causes for discontinuation of treatment were the infusion-related reactions: Dyspnea, urticaria and headache.
Resistance Mechanism Disorders:
Common: Viral infection (eg, influenza, herpes infections), fever. Uncommon: Abscess, cellulitis, moniliasis, sepsis, impaired healing, bacterial infection, tuberculosis, fungal infection. Rare: Granulomatous lesion.
Common: Serum sickness-like reactions. Uncommon: Autoantibodies, lupus-like syndrome, complement factor abnormality.
Uncommon: Anemia, leukopenia, lymphadenopathy, lymphocytosis, lymphopenia, neutropenia, thrombocytopenia.
Uncommon: Depression, confusion, agitation, amnesia, apathy, nervousness, somnolence, insomnia.
Central and Peripheral Nervous System Disorders:
Common: Headache, vertigo/dizziness. Uncommon: Exacerbation of demyelinating disease suggestive of multiple sclerosis. Rare: Meningitis.
Vision and Hearing Disorders:
Uncommon: Conjunctivitis, endophthalmitis, keratoconjunctivitis.
Common: Flushing. Uncommon: Ecchymosis/hematoma, hypertension, hypotension, syncope, petechia, thrombophlebitis, bradycardia, palpitation, vasospasm, cyanosis, peripheral ischemia, arrhythmia, worsening heart failure*. Rare: Circulatory failure, tachycardia.
Respiratory System Disorders:
Common: Upper respiratory tract infection, lower respiratory tract infection (eg, bronchitis, pneumonia), dyspnea, sinusitis. Uncommon: Epistaxis, bronchospasm, pleurisy, respiratory tract allergic reaction, pulmonary edema. Rare: Pleural effusion.
Gastrointestinal System Disorders:
Common: Nausea, diarrhea, abdominal pain, dyspepsia. Uncommon: Constipation, gastroesophageal reflux, cheilitis, diverticulitis. Rare: Intestinal perforation, intestinal stenosis, gastrointestinal hemorrhage.
Liver and Biliary System Disorders:
Common: Abnormal hepatic function. Uncommon: Cholecystitis. Rare: Hepatitis
Skin and Appendages Disorders:
Common: Rash, pruritus, urticaria, increased sweating, dry skin. Uncommon: Fungal dermatitis/onychomycosis, eczema/seborrhea, hordeolum, bullous eruption, furunculosis, periorbital edema, hyperkeratosis, rosacea, verruca, abnormal skin pigmentation/coloring, alopecia.
Musculoskeletal System Disorders:
Uncommon: Myalgia, arthralgia, back pain.
Urinary System Disorders:
Uncommon: Urinary tract infection, pyelonephritis.
Body as a Whole: General Disorders:
Common: Fatigue, chest pain, infusion-related reactions. Uncommon: Edema, hot flashes, infusion syndrome, pain, chills/rigors, anaphylactic reactions.
Administration/Application Site Disorders:
Uncommon: Injection site reactions.
*Reported in early phase studies evaluating Remicade in patients with congestive heart failure.
In post-marketing spontaneous reporting, infections are the most common serious adverse event. Some of the cases have resulted in fatal outcome. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extrapulmonary location (see Precautions) and other opportunistic infections eg, atypical mycobacteria, pneumocystis carinii pneumonia (PCP), histoplasmosis, coccidiomycosis, cryptococcosis, aspergillosis, listeriosis, candidiasis and salmonellosis have been reported rarely (<1/1000) or very rarely (<1/10,000). In addition, demyelinating disorders (eg, multiple sclerosis and optic neuritis), Guillain-Barre syndrome, neuropathies, numbness, tingling, seizure, transverse myelitis, pancytopenia, hemolytic anemia, idiopathic purpura, thrombotic thrombocytic purpura, hepatocellular damage, anaphylactic shock, interstitial pneumonitis/fibrosis have been reported rarely (<1/1000) or very rarely (<1/10,000).
An infusion-related reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1-2 hrs after an infusion. Approximately twice as many Remicade-treated patients experienced an infusion-related reaction compared to placebo-treated patients. Among all Remicade infusions, approximately 3% of infusions were accompanied by nonspecific symptoms eg, fever or chills; <1% were accompanied by pruritus or urticaria, 1% were accompanied by cardiopulmonary reactions (primary chest pain, hypotension, hypertension or dyspnea), and 0.1% were accompanied by combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Discontinuation of treatment resulted in 2% of patients, and all patients recovered with or without medical therapy. Infusion-related effects in patients were more likely to occur during the 1st (7%) and less likely on subsequent infusions (2nd, 6%; 3rd, 6%; and 4th, 5%; etc).
Patients who became positive for antibodies to infliximab were more likely (approximately 2-3 fold) to have an infusion reaction than those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of infusion-related reactions.
In a clinical trial of 41 patients re-treated with Remicade following a 2- to 4-year period without Remicade treatment, 10 patients experienced undesirable effects manifesting 3-12 days following infusion. In 6 of these patients, the effects were considered serious. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash. Some patients also experienced pruritus, facial, hand or lip edema, dysphagia, urticaria, sore throat and/or headache. The clinical data are not adequate to determine if occurrence of these reactions is due to the different formulations administered to these patients in this study. Patients' signs and symptoms improved substantially or resolved with treatment in all cases. There are insufficient data on the incidence of these events after drug-free intervals of 1-2 years. These events have been observed only infrequently in clinical studies and post-marketing surveillance with re-treatment intervals up to 1 year.
Patients who developed antibodies to infliximab were more likely to develop infusion-related reactions. In clinical trials using single and multiple infliximab doses ranging from 1-20 mg/kg, antibodies to infliximab were detected in approximately 14% of patients with any immunosuppressant therapy, and in approximately 24% of patients without immunosuppressant therapy. In rheumatoid arthritis patients who received the recommended repeated treatment dose regimen with methotrexate, approximately 8% of patients developed antibodies to infliximab. Of Crohn's disease patients who received maintenance treatment, approximately 6-13% developed antibodies to infliximab. The antibody incidence was 2- to 3-fold higher for patients treated episodically. Due to methodological shortcomings, a negative assay did not exclude the presence of antibodies to infliximab. Some patients who developed high titers of antibodies to infliximab had evidence of reduced efficacy.
In clinical trials, 35% of Remicade-treated patients experienced infections compared with 22% of placebo-treated patients. Serious infections eg, pneumonia, were reported in 5% of both Remicade-treated patients and placebo-treated patients (see Precautions).
Malignancies and Lymphoproliferative Disorders:
Cases of lymphoma, myeloma and other malignancies have occurred in Crohn's disease and rheumatoid arthritis patients treated with Remicade, but these were within the expected incidence ranges reported in the literature for these diseases. It is unknown if chronic exposure to Remicade can cause the development of these disorders.
In a phase II study aimed at evaluating Remicade in moderate to severe congestive heart failure (CHF), higher incidence of mortality due to worsening of heart failure was seen in patients treated with Remicade, especially those treated with the higher doses of 10 mg/kg.
Antinuclear Antibodies (ANA)/Double-Stranded DNA (dsDNA) Antibodies:
In clinical studies, approximately 52% (of 1261) infliximab-treated patients who were ANA negative at baseline developed a positive ANA during the trial (compared with approximately 19% of 129 placebo-treated patients). Anti-dsDNA antibodies developed in approximately 17% (261) of patients treated with Remicade (compared with 0% of 162 placebo-treated patients). At the last evaluation, 150 of these 261 infliximab-treated patients (57%) remained anti-dsDNA positive.
Clinical signs consistent with a lupus-like syndrome remain uncommon.