Managed Care - December 2008 - (Page 38)

to produce no adverse effects in animal reproduction studies. It is not known whether REMICADE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. REMICADE should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether REMICADE is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from REMICADE, women should not breast-feed their infants while taking REMICADE. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active CD who have had an inadequate response to conventional therapy (see Boxed WARNINGS, WARNINGS, INDICATIONS AND USAGE, PRECAUTIONS, Vaccinations, DOSAGE AND ADMINISTRATION, CLINICAL STUDIES, Active Crohn’s Disease in Pediatric Patients and ADVERSE REACTIONS, Adverse Reactions in Pediatric Crohn’s Disease). REMICADE has not been studied in children with CD <6 years of age. The longer term (greater than one year) safety and effectiveness of REMICADE in pediatric CD patients have not been established in clinical trials. Safety and effectiveness of REMICADE in pediatric patients with UC and plaque psoriasis have not been established. The safety and efficacy of REMICADE in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or DMARDS was permitted. Doses of 3 mg/kg REMICADE or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg REMICADE at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with REMICADE for up to 2 years in a companion extension study. The study failed to establish the efficacy of REMICADE in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults (see CLINICAL PHARMACOLOGY, Pharmacokinetics). A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg REMICADE was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg REMICADE group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg REMICADE group, 2 patients had a serious infusion reaction, one of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received REMICADE by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg REMICADE compared with 12% (6/49) of patients who received 6 mg/kg. A total of 68% (41/60) of patients who received 3 mg/kg REMICADE in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg REMICADE in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient. Geriatric Use In RA and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with RA and 75 patients with PsO, aged 65 or older who received REMICADE, compared to younger patients although the incidence of serious adverse events in patients aged 65 or older was higher in both REMICADE and control groups compared to younger patients. In CD, UC, AS, and PsA studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly (see ADVERSE REACTIONS, Infections). ADVERSE REACTIONS: The data described herein reflect exposure to REMICADE in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn’s disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond one year. (For information on adverse reactions in pediatric patients see ADVERSE REACTIONS, Adverse Reactions in Pediatric Crohn’s Disease.) One of the most common reasons 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 RA 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 CD. Infusion-related Reactions 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 16 weeks. In a study of PsA, where 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction (see ADVERSE REACTIONS, Infusion-related Reactions) than were patients who were antibody negative. Antibody development was lower among RA and CD patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX. In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (Weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for one year and in Study III in patients treated with 5 mg/kg induction (14.1%-23.0%) and serious infusion reaction rates ( 1 to <3 times the upper limit of normal (ULN) compared to 24% of patients treated with placebo + MTX. ALT elevations ≥3 times ULN were observed in 4% of patients who received REMICADE + MTX compared with 3% of patients who received MTX alone. ALT elevations ≥5 times ULN were observed in 1 to 1 to <3 times the ULN compared to 12% of patients treated with placebo. ALT elevations ≥3 times the ULN were observed in 2% of patients who received REMICADE compared with 1% of patients who received placebo. ALT elevations ≥5 times ULN were observed in 1 to 1 to 1 to <3 times the ULN compared to 24% of patients treated with placebo. ALT ≥3 x ULN were observed in 8% of patients who received REMICADE compared to <1% who received placebo. ALT elevations ≥5 x

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Managed Care - December 2008

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