Remicade (Infliximab) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

The data described herein reflect exposure to REMICADE in 1678 patients, including 842 patients exposed beyond 30 weeks and 295 exposed beyond one year. The most common reason for discontinuation of treatment was infusion-related reactions (e.g. dyspnea, flushing, headache and rash). Adverse events have been reported in a higher proportion of rheumatoid arthritis patients receiving the 10 mg/kg dose than the 3 mg/kg dose, however, no differences were observed in the frequency of adverse events between the 5 mg/kg dose and 10 mg/kg dose in patients with Crohn's disease.

INFUSION-RELATED REACTIONS

Acute infusion reactions

An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 to 2 hours after an infusion. Approximately 20% of REMICADE-treated patients in all clinical studies experienced an infusion reaction compared to approximately 10% of placebo-treated patients. Among all REMICADE infusions, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued REMICADE because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. REMICADE infusions beyond the initial infusion were not associated with a higher incidence of reactions.

Patients who became positive for antibodies to infliximab were more likely (approximately 2- to 3-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and infusion reactions (see ADVERSE REACTIONS, Immunogenicity and PRECAUTIONS, Drug Interactions).

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with REMICADE administration.

Reactions following readministration

In a study where 37 of 41 patients with Crohn's disease were retreated with infliximab following a 2 to 4 year period without infliximab treatment, 10 patients experienced adverse events manifesting 3 to 12 days following infusion of which 6 were considered serious. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash, with some patients also experiencing pruritus, facial, hand or lip edema, dysphagia, urticaria, sore throat, and headache. Patients experiencing these adverse events had not experienced infusion-related adverse events associated with their initial infliximab therapy. These adverse events occurred in 39% (9/23) of patients who had received liquid formulation which is no longer in use and 7% (1/14) of patients who received lyophilized formulation. The clinical data are not adequate to determine if occurrence of these reactions is due to differences in formulation. 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 to 2 years. These events have been observed only infrequently in clinical studies and post-marketing surveillance with retreatment intervals up to 1 year.

INFECTIONS

In REMICADE clinical studies, treated infections were reported in 35% of REMICADE-treated patients (average of 53 weeks of follow-up) and in 26% of placebo-treated patients (average of 41 weeks of follow-up). When longer observation of patients on REMICADE was accounted for, the event rate was similar for both groups. The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. No increased risk of serious infections or sepsis was observed with REMICADE compared with placebo in clinical studies. Among REMICADE-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. Three opportunistic infections were reported; coccidioidomycosis (which resulted in death), nocardiosis and cytomegalovirus. Tuberculosis was reported in two patients, one of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of the cases of tuberculosis occurred within the first two months after initiation of therapy with infliximab and may reflect recrudescence of latent disease (see WARNINGS, RISK OF INFECTIONS). During the 54 week ACCENT II trial, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess.

In post-marketing experience, infections have been observed with various pathogens including viral, bacterial, fungal, and protozoal organisms. Infections have been noted in all organ systems and have been reported in patients receiving REMICADE alone or in combination with immunosuppressive agents.

AUTOANTIBODIES/LUPUS-LIKE SYNDROME

Approximately 52% of 1261 infliximab-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately 19% of 129 placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% of 1507 infliximab-treated patients compared with 0% of 162 placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

MALIGNANCIES/LYMPHOPROLIFERATIVE DISEASE

In completed clinical studies of REMICADE for up to 102 weeks, 18 of 1678 patients developed 19 new or recurrent malignancies of various types, such as non-Hodgkin's B-cell lymphoma, breast, melanoma, squamous, rectal and basal cell. There are insufficient data to determine whether REMICADE contributed to the development of these malignancies. The observed rates and incidences were similar to those expected for the populations studied^11,12(see PRECAUTIONS, Malignancy).

PATIENTS WITH HEART FAILURE

In a randomized study evaluating REMICADE in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction </=35%), 150 patients were randomized to receive treatment with 3 infusions of REMICADE 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg REMICADE dose. At 1 year, 8 patients in the 10 mg/kg REMICADE group had died compared with 4 deaths each in the 5 mg/kg REMICADE and the placebo groups. There were trends towards increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg REMICADE treatment groups, versus placebo. REMICADE has not been studied in patients with mild heart failure (NYHA Class I/II). (See CONTRAINDICATIONS and WARNINGS, Patients with Heart Failure.)

IMMUNOGENICITY

Treatment with REMICADE can be associated with the development of antibodies to infliximab. The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through one to two years of REMICADE treatment. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving REMICADE after drug free intervals >16 weeks. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to experience an infusion reaction (see ADVERSE REACTIONS, Infusion-related Reactions). Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX.

The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.

OTHER ADVERSE REACTIONS

Safety data are available from 1678 REMICADE-treated patients, including 555 with rheumatoid arthritis, and 1106 with Crohn's disease and 17 with conditions other than rheumatoid arthritis or Crohn's disease. Adverse events reported in >/=5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 5. The types and frequencies of adverse reactions observed were similar in REMICADE-treated rheumatoid arthritis and Crohn's disease patients except for abdominal pain which occurred in 26% of REMICADE-treated patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received REMICADE to provide meaningful comparisons.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not predict the rates observed in broader patient populations in clinical practice.

The most common serious adverse events observed in clinical trials were infections (see ADVERSE REACTIONS, Infections). Other serious, medically relevant adverse events >/=0.2% or clinically significant adverse events by body system were as follows:

Body as a whole:    allergic reaction, diaphragmatic hernia, edema, surgical/procedural sequela

Blood:    pancytopenia

Cardiovascular:    circulatory failure, hypotension, syncope

Gastrointestinal:    constipation, gastrointestinal hemorrhage, ileus, intestinal obstruction, intestinal perforation, intestinal stenosis, pancreatitis, peritonitis, proctalgia

Central & Peripheral Nervous:    meningitis, neuritis, peripheral neuropathy, dizziness

Heart Rate and Rhythm:    arrhythmia, bradycardia, cardiac arrest, tachycardia

Liver and Biliary:    biliary pain, cholecystitis, cholelithiasis, hepatitis

Metabolic and Nutritional:    dehydration

Musculoskeletal:    intervertebral disk herniation, tendon disorder

Myo-, Endo-, Pericardial and Coronary Valve:    myocardial infarction

Platelet, Bleeding and Clotting:    thrombocytopenia

Neoplasms:    basal cell, breast, lymphoma

Psychiatric:    confusion, suicide attempt

Red Blood Cell:    anemia, hemolytic anemia

Reproductive:    menstrual irregularity

Resistance Mechanism:    cellulitis, sepsis, serum sickness

Respiratory:    adult respiratory distress syndrome, lower respiratory tract infection, pleural effusion, pleurisy, pulmonary edema, respiratory insufficiency

Skin and Appendages:    increased sweating, ulceration

Urinary:    renal calculus, renal failure

Vascular (Extracardiac):    brain infarction, pulmonary embolism, thrombophlebitis

White Cell and Reticuloendothelial:    leukopenia, lymphadenopathy

A greater proportion of patients enrolled into the ATTRACT study who received REMICADE + MTX experienced transient mild (<2 times the upper limit of normal) or moderate (>/=2 but <3 times the upper limit of normal) elevations in AST or ALT (49% and 47%, respectively) compared to patients treated with placebo + MTX (27% and 35%, respectively). Six (1.8%) patients treated with REMICADE + MTX experienced more prolonged elevations in their ALT.

The following adverse events have been reported during post-approval use of REMICADE: neutropenia (see WARNINGS, Hematologic Events), interstitial pneumonitis/fibrosis, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, Guillain-Barré syndrome, transverse myelitis, and neuropathies (additional neurologic events have also been observed, see WARNINGS, Neurologic Events). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to REMICADE exposure.