Safety data from clinical trials are available from 5561 REMICADE-treated patients including 1304 with rheumatoid arthritis, 117 with juvenile rheumatoid arthritis, 1566 with Crohn's disease (1427 adults and 139 children), 347 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis, 544 with ulcerative colitis (484 adults and 60 children) and 17 with other conditions. Adverse reactions in clinical trials are summarized in Table 1. Infusion-related reactions (e.g., dyspnea, flushing, headache and rash) were among the most common causes for discontinuation, except in ulcerative colitis, pediatric Crohn's disease and psoriatic arthritis. (See Table 1).
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In Phase 3 clinical studies, 18% of REMICADE-treated patients compared with 5% of placebo-treated patients experienced an infusion-related reaction during infusion or within 1 hour post infusion. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.
Approximately 3% of REMICADE infusions were accompanied by nonspecific symptoms such as fever or chills, <1% were accompanied by pruritus or urticaria, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension, or dyspnea), 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 treatment due to infusion reactions and all patients recovered with or without medical therapy.
In a clinical study of patients with rheumatoid arthritis (ASPIRE), sixty six percent of the patients (686 out of 1040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1040) received at least one shortened infusion of 60 minutes or less. Of the REMICADE-treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% (74/494) of patients and serious infusion reactions occurred in 0.4% (2/494) of patients. Shortened infusions at doses >6 mg/kg have not been studied (see Pharmacology under Actions).
In Phase 3 clinical studies, in patients receiving infliximab with or without concomitant immunomodulator therapy, 13-19% of patients receiving infliximab at a low infusion rate (≤6 mg/kg/2-hr) experienced an infusion-related reaction, compared to 15-16% of patients receiving infliximab at a high infusion rate (>6 mg/kg/2-hr or equivalent to >3 mg/kg/1-hr). Of patients receiving infliximab at a low infusion rate, 0.4%-0.7% experienced a serious infusion-related reaction, compared to 0.4%-0.5% of patients receiving infliximab at a high infusion rate.
In a clinical study of patients with Crohn's disease (SONIC), infusion-related reactions occurred in 16.6% (27/163) of patients receiving REMICADE monotherapy, 5.0% (9/179) of patients receiving REMICADE in combination with azathioprine, and 5.6% (9/161) of patients receiving azathioprine monotherapy. One patient experienced a serious infusion reaction with REMICADE monotherapy.
In post-marketing surveillance, reports of anaphylactic-like reactions including laryngeal edema, pharyngeal edema, severe bronchospasm, and seizure have been associated with REMICADE administration. Cases of transient visual loss occurring during or within 2 hours of REMICADE infusion have been reported. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported.
Infusion Reactions Following Re-Administration of REMICADE:
In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, re-administration of REMICADE after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment.
In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction cycle of REMICADE, 4% (8/219) of patients in the intermittent therapy arm experienced serious infusion reactions versus <1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. Intermittent therapy in this trial was defined as the re-administration of an induction cycle (maximum of 4 infusions at 0, 2, 6 and 14 weeks) of REMICADE upon disease flare after a period of no treatment. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, REMICADE treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed Hypersensitivity/Reactions Following Re-Administration:
In a study where 37 of 41 patients with Crohn's disease were retreated with REMICADE following a 2 to 4 year period without REMICADE 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 REMICADE 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 re-treatment intervals up to 1 year. In the 3 psoriasis studies, 1% (15/1373) of patients experienced symptoms of arthralgia, serum sickness, myalgia, fever and rash. When these occurred, they were often early in the treatment course following REMICADE infusions.
REMICADE treatment was discontinued and/or other treatment instituted in most cases with improvement or resolution of signs and symptoms.
Patients who developed antibodies to REMICADE were more likely (approximately 2- to 3-fold) to develop infusion-related reactions. Antibodies to REMICADE occurred in approximately 10% of patients given a 3-dose induction regimen followed by maintenance dosing. Use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to REMICADE and infusion reactions. In a Phase III study of Crohn's disease in patients who were immunomodulator-naive, antibodies occurred at Week 30 in 14% of patients receiving REMICADE monotherapy and 1% of patients receiving REMICADE in combination with azathioprine. A higher incidence of antibodies to REMICADE was observed in Crohn’s disease patients receiving REMICADE after drug free intervals >16 weeks. In the Phase III study of psoriatic arthritis, where patients received 5 mg/kg with and without concomitant methotrexate, antibodies occurred in 15% of patients. In the 2 Phase III studies of psoriasis, REMICADE was administered with induction followed by maintenance therapy without concomitant immunosuppressants. In these studies, antibodies occurred in approximately 25%-30% of patients, who received 5 mg/kg every 8 week maintenance for 1 year, and at higher rates (up to 1.6-fold) with other dosage regimens (3 mg/kg every 8 weeks, 3 mg/kg dosed as needed and 5 mg/kg dosed as needed). Despite the increase in antibody formation, the infusion reaction rates in the two psoriasis phase III studies in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year (14.1%-23%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations.
In clinical studies, 36% of REMICADE-treated patients were treated for infections compared with 28% of placebo-treated patients. No increased risk of serious infections was observed with REMICADE compared with placebo in Crohn's disease studies and the phase III study of psoriatic arthritis. In RA trials, the incidence of serious infections, including pneumonia, was higher in REMICADE plus MTX treated patients compared with methotrexate alone, especially at doses of 6 mg/kg or greater. In the psoriasis studies, 1.5% of patients (average of 41.9 weeks of follow-up) receiving REMICADE and 0.6% of patients (average of 18.1 weeks of follow-up) receiving placebo developed serious infections.
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.
In post-marketing surveillance, very rare cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving REMICADE (see Precautions).
In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving REMICADE without progression to severe hepatic injury. Elevations of ALT >5 x ULN have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving REMICADE than in controls, both when REMICADE was given as monotherapy and when it was used in combination with other immunosuppressive agents (see Table 2).
Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of REMICADE, or modification of concomitant medications.
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During clinical trials of REMICADE, new or recurrent malignancies have been reported in REMICADE-treated patients. The incidence of lymphoma in REMICADE-treated patients was higher than expected in the general populations. The observed incidences of non-lymphoma malignancies were similar to what would be expected in the general population whereas the rate among control patients was lower than expected. In an exploratory clinical trial involving patients with moderate to severe COPD who were either current smokers or ex-smokers, more malignancies were reported in REMICADE-treated patients compared with control patients (see Precautions). A population-based retrospective cohort study found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age (see Precautions).
The potential role of TNF-blocking therapy in the development of malignancies is not known.
Antinuclear Antibodies (ANA)/Double-Stranded DNA (dsDNA) Antibodies:
Approximately half of REMICADE-treated patients in clinical trials who were ANA negative at baseline developed a positive ANA during the trial compared with approximately
one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% of REMICADE-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndrome remain uncommon.
Congestive Heart Failure:
In a phase II study evaluating REMICADE in moderate to severe heart failure (NYHA Class III/IV with a 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.
Higher incidences of mortality and hospitalization due to worsening heart failure were seen in patients receiving the 10 mg/kg REMICADE dose. At 28 weeks, 3 patients in the 10 mg/kg REMICADE group died compared with 1 death in the 5 mg/kg REMICADE group, and no deaths in the placebo group. At the same time point, 11 of 51 patients in the 10 mg/kg REMICADE group were hospitalized for worsening heart failure compared with 3 of 50 patients in the 5 mg/kg Remicade group and 5 of 49 in the placebo group. In follow-up, at 1 year, 8 patients in the 10 mg/kg REMICADE group died compared with 4 deaths each in the 5 mg/kg REMICADE and the placebo groups. REMICADE has not been studied in patients with mild heart failure (NYHA Class I/II) (see Contraindications and Precautions). There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking REMICADE.
There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.
Adverse Reactions in JRA:
The safety and efficacy of REMICADE were assessed 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. A total of 122 patients with active JRA between the ages of 4 and 17 years who had been treated with methotrexate for at least 3 months were enrolled; 120 subjects received study drug. Concurrent use of folic acid, oral corticosteroids (≤10 mg/day), non-steroidal anti-inflammatory drugs and/or MTX was permitted.
Doses of 3 mg/kg REMICADE or placebo were administered intravenously at weeks 0, 2, 6, 14, 20 and then every 8 weeks through week 44. To maintain the treatment blind, the 3 mg/kg treatment group also received a single placebo infusion at week 16 while subjects 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.
The safety and efficacy of REMICADE in the treatment of children with JRA have not been established. Forty-one of 60 children (68.3%) with JRA receiving REMICADE 3 mg/kg in combination with methotrexate experienced an infection over 52 weeks of observation compared with 37 of 57 (64.9%) children with JRA receiving REMICADE 6 mg/kg in combination with methotrexate over 38 weeks of observation and 28 of 60 (46.7%) receiving placebo in combination with methotrexate over 14 weeks of observation. 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.
The incidence of infusion reactions in pediatric patients with JRA receiving 3 mg/kg REMICADE was 35% compared with 17.5% in patients receiving 6 mg/kg. 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 three 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 time less than 2 hours).
Antibodies to REMICADE developed in 37.7% of patients with JRA receiving 3 mg/kg of REMICADE compared with 12.2% of patients receiving 6 mg/kg. The antibody titers were notably higher for the 3 mg/kg compared to the 6 mg/kg group.
Adverse Reactions in Pediatric Crohn's Disease:
In general, the adverse events in pediatric patients who received REMICADE were similar in frequency and type to those seen in adult Crohn's disease patients. Differences from adults and other special consideration are discussed as follows.
The following adverse events were reported more commonly in 103 randomized pediatric Crohn's disease patients administered REMICADE 5 mg/kg through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: Anemia (10.7%), blood in stool (9.7%), leukopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%) and respiratory tract allergic reaction (5.8%).
Infections were reported in 56.3% of randomized subjects in REACH and in 50.3% of subjects receiving REMICADE 5 mg/kg in ACCENT 1. Within REACH, infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38%, respectively) while serious infections were reported for 3 subjects in the q8 week and 4 subjects in the q12 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 in 3 patients, 2 in the q8 week and 1 in the q12 week maintenance treatment groups. Herpes zoster was reported in 2 patients in the q8 week maintenance treatment group.
Overall, in REACH, 17.5% of randomized patients experienced 1 or more infusion reactions, with 17.0% and 18.0% of patients in the q8 week and q12 week maintenance treatment groups, respectively. There were no serious infusion reactions and 2 subjects in REACH had non-serious anaphylactic reactions.
Antibodies to REMICADE developed in 3 (2.9%) pediatric patients.
Adverse Reactions in Pediatric Ulcerative Colitis:
Overall proportions of patients with adverse events and serious adverse events were generally consistent in the pediatric ulcerative colitis and adult ulcerative colitis (ACT 1 and ACT 2) studies. In the pediatric ulcerative colitis study (Study Peds UC), the most common adverse event was worsening of ulcerative colitis which was greater in patients on the q12 week vs the q8 week dosing regimen. In the ACT1 and ACT 2 studies, the most common adverse event was headache. The most common serious adverse event across these 3 studies was worsening of the disease under study.
Infections were reported in 31 (51.7%) of 60 treated patients in Study Peds UC and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in Study Peds UC was similar to that in the pediatric Crohn's disease study (REACH) but higher than the proportion in the adults ulcerative colitis studies (ACT 1 and ACT 2). Unlike REACH, in which infections were reported more frequently for patients who received q8 week as opposed to q12 week infusions; in Study Peds UC, the overall incidence of infections was similar in the q8 week [13/22 (59.1%)] and q12 week [14/23 (60.9%)] maintenance treatment groups. In Study Peds UC, serious infections were reported for 3 of 22 (13.6%) patients in the q8 week and 3 of 23 (13.0%) patients in the q12 week maintenance treatment group. Upper respiratory tract infection [7/60 (11.7%)] and pharyngitis [5/60 (8.3%)] were the most frequently reported respiratory system infections among all treated patients. The infections occurring in more than one patient in a treatment group that required antimicrobial treatment were pharyngitis [4/60 (6.7%)], urinary tract infection [4/60 (6.7%)], and bronchitis [2/60 (3.3%)].
Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.
Antibodies to REMICADE were detected in 4 (7.7%) patients through week 54.
In Study Peds UC, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group [45/60 (75.0%)] versus 15/60 (25.0%)]. While the numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events, there were higher proportions of patients with serious adverse events and discontinuation due to adverse events in the younger age group than in the older age group.
While the proportion of patients with infections was also higher in the younger age group, for serious infections, the proportions were similar in the two age groups. Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups.
Additional adverse events, some with fatal outcome, reported from worldwide post-marketing experience with REMICADE are included in Table 3. 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. (See Table 3).
The most common serious adverse events reported in the postmarketing experience in children were infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions and hypersensitivity reactions. Spontaneous serious adverse events in the postmarketing experience with REMICADE in the pediatric population have included malignancies, transient hepatic enzyme abnormalities, lupus-like syndromes, and positive autoantibodies.
Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with REMICADE with the vast majority of cases occurring in Crohn's disease and ulcerative colitis and most of whom were adolescent or young adult males (see Precautions).
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Inform the physician of all undesirable effects upon drug administration.