Biotechnology Healthcare - November/December 2008 - (Page 11) ULN were observed in 3% of patients who received REMICADE compared to none in patients treated with placebo. Adverse Reactions in Pediatric Crohn’s Disease There were some differences observed in the adverse reactions observed in the pediatric patients receiving REMICADE compared to those observed in adults with CD. The following adverse events were reported more commonly in 103 randomized pediatric CD patients administered 5 mg/kg REMICADE through 54 weeks than in 385 adult CD patients receiving a similar treatment regimen: anemia (11%), blood in stool (10%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%). Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn’s and in 50% of adult patients in Study Crohn’s I. In Study Peds Crohn’s, infections were reported more frequently for patients who received every 8 week as opposed to every 12 week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8 week and 4 patients in the every 12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, (2 in the every 8 week and 1 in the every 12 week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8 week maintenance treatment group. In Study Peds Crohn’s, 18% of randomized patients experienced one or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn’s, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions. Antibodies to REMICADE developed in 3% of pediatric patients in Study Peds Crohn’s. Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in CD clinical trials; 4% had ALT elevations ≥3 x ULN, and 1% had elevations ≥5 x ULN. (Median follow-up was 53 weeks.) Adverse Reactions in Psoriasis Studies During the placebo-controlled portion across the three clinical trials up to Week 16, the proportion of patients who experienced at least 1 SAE (defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 1.7% in the 3 mg/kg REMICADE group, 3.2% in the placebo group, and 3.9% in the 5 mg/kg REMICADE group. Among patients in the 2 Phase 3 studies, 12.4% of patients receiving REMICADE 5 mg/kg every 8 weeks through one year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving REMICADE 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through one year of maintenance treatment experienced at least 1 SAE. One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg REMICADE. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving REMICADE 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving REMICADE 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infections (requiring hospitalization) were abscesses (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg REMICADE group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting REMICADE. In placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received REMICADE at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo. In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility. Other Adverse Reactions Safety data are available from 4779 REMICADE-treated adult patients, including 1304 with RA, 1106 with CD, 484 with UC, 202 with AS, 293 with PsA, 1373 with plaque PsO and 17 with other conditions. (For information on other adverse reactions in pediatric patients, see ADVERSE REACTIONS, Adverse Reactions in Pediatric Crohn’s Disease.) Adverse events reported in ≥5% of all patients with RA receiving 4 or more infusions are listed below. The types and frequencies of adverse reactions observed were similar in REMICADE-treated RA, AS, PsA, plaque PsO and CD patients except for abdominal pain, which occurred in 26% of REMICADE-treated patients with CD. In the CD studies, there were insufficient numbers and duration of follow-up for patients who never received REMICADE to provide meaningful comparisons. The percentages of adverse events for placebo-treated patients (n=350; average weeks of follow-up 59) and REMICADE-treated patients (n=1129; average weeks of follow-up 66), respectively, are: Gastrointestinal: Nausea: 20, 21; Abdominal pain: 8, 12; Diarrhea: 12, 12; Dyspepsia: 7, 10; Respiratory: Upper respiratory tract infection: 25, 32; Sinusitis: 8, 14; Pharyngitis: 8, 12; Coughing: 8, 12; Bronchitis: 9, 10; Rhinitis: 5, 8; Skin and appendages disorders: Rash: 5, 10; Pruritis: 2, 7; Body as a whole—general disorders: Fatigue: 7, 9; Pain: 7, 8; Resistance mechanism disorders: Fever: 4, 7; Moniliasis: 3, 5; Central and peripheral nervous system disorders: Headache: 14, 18; Musculoskeletal system disorders: Back pain: 5, 8; Arthralgia: 7, 8; Urinary system disorders: Urinary tract infection: 6, 8; Cardiovascular disorders, general: Hypertension: 5, 7. 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 (including pneumonia), 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. Post-marketing Adverse Events The following adverse events, some with fatal outcome, have been reported during post-approval use of REMICADE: neutropenia (see WARNINGS, Hematologic Events), interstitial lung disease (including pulmonary fibrosis/ interstitial pneumonitis and very rare rapidly progressive disease), idiop athic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), psoriasis (including new onset and pustular, primarily palmar/plantar), transverse myelitis, and neuropathies (additional neurologic events have also been observed, see WARNINGS, Neurologic Events) and acute liver failure, jaundice, hepatitis, and cholestasis (see WARNINGS, Hepatotoxicity). 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. The following serious adverse events have been reported in the post-marketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions. Serious adverse events in the post-marketing experience with REMICADE in the pediatric population have also included malignancies, including hepatosplenic T-cell lymphomas (see Boxed WARNINGS and WARNINGS), transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies. OVERDOSAGE: Single doses up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. Administration Instructions Regarding Infusion Reactions Adverse effects during administration of REMICADE have included flu-like symptoms, headache, dyspnea,
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