Ixifi Adverse Reactions

Adverse reactions are adverse events that were considered to be reasonably associated with the use of infliximab based on the comprehensive assessment of the available adverse event information. A causal relationship with infliximab cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials for infliximab cannot be directly compared to rates in the clinical trials of other TNF blockers and may not predict the rates observed in clinical practice.
In clinical studies with infliximab, adverse reactions were observed in approximately 60% of infliximab-treated patients and 40% of placebo-treated patients. The adverse reactions listed in Table 11 are based on experience from clinical trials. Within the organ system classes, adverse reactions are listed under the headings of frequency using the following categories: common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000). Infusion-related reactions were the most common adverse reactions reported. Infusion-related reactions (dyspnea, urticaria and headache) were the most common cause for discontinuation. (See Tables 11 and 12.)

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Transient visual loss occurring during or within 2 hours of infliximab infusion have also been reported.
Myocardial ischemia/myocardial infarction and arrhythmia within 24 hours of initiation of infusion have also been reported.
Hemophagocytic lymphohistiocytosis (HLH) has been very rarely reported in patients treated with infliximab.
Infusion-related Reactions: An infusion-related reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion.
In all the clinical studies, approximate 20% of infliximab-treated patients compared with 10% of placebo-treated patients experienced an infusion-related reaction. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period, Week 7 through Week 54. 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 patients discontinued treatment due to infusion-related reactions, and all patients recovered with or without medical therapy.
In a clinical study of patients with rheumatoid arthritis (ASPIRE), study medication was administered to each patient by infusion over 2 hours for the first 3 study infusions. For patients who did not experience a serious infusion reaction with the first 3 study infusions, subsequent infusions could be shortened to not less than 40 minutes. 66% 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 infliximab-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.
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 infliximab monotherapy, 5.0% (9/179) of patients receiving infliximab in combination with azathioprine, and 5.6% (9/161) of patients receiving azathioprine monotherapy. One patient experienced a serious infusion reaction with infliximab monotherapy.
In post-marketing surveillance, anaphylactic-like reactions, including laryngeal/pharyngeal edema, severe bronchospasm, and seizure have been associated with infliximab administration. Transient visual loss occurring during or within 2 hours of infliximab infusion have been reported. Cerebrovascular accidents, myocardial ischemia/myocardial infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported.
Infusion Reactions Following Re-administration of Infliximab: In rheumatoid arthritis, Crohn's disease, and psoriasis clinical trials, re-administration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment.
A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy and safety of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab (maximum of four infusions at 0, 2, 6 and 14 weeks) following disease flare. Patients did not receive any concomitant immunosuppressant therapy. In the re-treatment arm, 4% (8/219) of patients experienced a serious infusion reaction versus < 1% (1/222) on maintenance therapy. The majority of serious infusion reactions occurred during the second infusion at Week 2. The interval between the last maintenance dose and the first re-induction dose ranged from 35-231 days. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed Hypersensitivity: 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 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 infliximab infusions. Infliximab treatment was discontinued and/or other treatment instituted in most cases with improvement or resolution of signs and symptoms.
In a 1-year trial with repeated infusions in patients with Crohn's disease (ACCENT I study), the incidence of serum sickness-like reactions was 2.4%.
Immunogenicity: Patients who developed antibodies to infliximab were more likely (approximately 2-3 fold) to develop infusion-related reactions. Antibodies to infliximab 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 infliximab and infusion-related reactions.
In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies to infliximab were detected in 140 of 980 (14%) patients with any immunosuppressant therapy, and in 92 of 383 (24%) patients without immunosuppressant therapy. In rheumatoid arthritis patients who received the recommended repeated treatment dose regimens with methotrexate, 6 of 77 (8%) patients developed antibodies to infliximab. In Crohn's disease patients who received maintenance treatment, antibodies to infliximab occurred overall in 3.3% of patients receiving immunosuppressants and in 13.3% of patients not receiving immunosuppressants. The antibody incidence was 2-3 folds higher for patients treated episodically. Due to methodological limitations, a negative assay did not exclude the presence of antibodies to infliximab. Some patients who developed high titres of antibodies to infliximab had evidence of reduced efficacy (see Infusion Reactions and Hypersensitivity under Precautions). In psoriasis patients treated with infliximab as a maintenance regimen in the absence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab.
Infections: Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections have been observed in patients receiving infliximab. Some of these infections have been fatal. Opportunistic infections reported in patients on infliximab have included, but are not limited to pneumocystosis, histoplasmosis, cytomegalovirus infection, atypical mycobacterial infections, listeriosis and aspergillosis (see Precautions).
In clinical studies 36% of infliximab-treated patients experienced infections compared with 25% of placebo-treated patients. No increased risk of serious infections was observed with infliximab compared with placebo in Crohn's disease studies and the Phase 3 study of psoriatic arthritis. In RA trials, the incidence of serious infections including pneumonia was higher in infliximab plus methotrexate treated patients compared with methotrexate alone especially at doses of 6 mg/kg or greater (see Precautions). In the psoriasis studies, 1.5% of patients (average of 41.9 weeks of follow-up) receiving infliximab and 0.6% of patients (average of 18.1 weeks of follow-up) receiving placebo developed serious infections.
In post-marketing spontaneous reporting, infections are the most common serious adverse event. Some of the cases have resulted in fatal outcome. Nearly 50% of reported deaths have been associated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extrapulmonary location have been reported (see Precautions). 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 infliximab alone or in combination with immunosuppressive agents.
Malignancies and Lymphoproliferative Disorders: In clinical studies with infliximab in which 5706 patients were treated, representing 4990 patient-years, 5 cases of lymphomas and 24 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1600 placebo-treated patients representing 892 patient-years.
In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6234 patient-years (3210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported.
From August 1998 to August 2005, 1909 cases of suspected malignancies have been reported from post-marketing, clinical trials and registries (321 in Crohn's disease patients, 1302 in rheumatoid arthritis patients and 286 in patients with other or unknown indications). Among those there were 347 lymphoma cases. During this period, the estimated exposure is 1,909, 941 patient-years since first exposure (see Malignancies and Lymphoproliferative Disorders under Precautions).
In an explanatory clinical trial involving patients with moderate to severe COPD who were either current smoker or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in RA and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65%-10.6%]). There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03%-7.0%]). The majority of the malignancies developed in the lung or head and neck.
Post-marketing cases of HSTCL have been reported in patients treated with infliximab with the vast majority of cases occurring in Crohn's disease and ulcerative colitis treated with infliximab, the majority and most of whom were adolescent or young adult males (see Malignancies and Lymphoproliferative Disorders under Precautions).
Heart Failure: In a phase 2 study aimed at evaluating infliximab in congestive heart failure (CHF), higher incidence of mortality due to worsening of heart failure were seen in patients treated with infliximab, especially those treated with the higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this trial 150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction ≤ 35%) were treated with 3 infusions of infliximab 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with infliximab (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one death among the 49 patients on placebo.
There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in infliximab-treated patients. Some of these patients have been under 50 years of age.
Antinuclear Antibodies (ANA)/Anti-double-stranded DNA (dsDNA) Antibodies: In clinical studies, approximately half of infliximab-treated patients who were ANA negative at baseline developed a positive ANA during the trial (compared with approximately one-fifth placebo-treated patients). Anti-dsDNA antibodies developed in approximately 17% of patients treated with infliximab (compared with 0% of placebo-treated patients). At the last evaluation, 57% infliximab-treated patients remained anti-dsDNA positive. Clinical signs consistent with a lupus-like syndrome remained uncommon.
Hepatobiliary Events: In clinical trials, mild or moderate elevations of ALT and aspartate aminotransferase (AST) have been observed in patients receiving infliximab without progression to severe hepatic injury. Elevations of ALT 5 x Upper Limit of Normal (ULN) have been observed (see Table 13). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls, both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. 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 infliximab, or modification of concomitant medications.
In post-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving infliximab (see Precautions). (See Table 13.)

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Special Populations - Pediatrics: Pediatric Crohn's Disease Patients: The following adverse events were reported more commonly in pediatric Crohn's disease patients in the REACH trial (see Pharmacology: Pharmacodynamics under Actions) than in adult Crohn's disease patients; 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%). Other special considerations are discussed as follows.
Infusion-related Reactions: Overall, in REACH, 17.5% of randomized patients experienced 1 or more infusion reactions. There were no serious infusion reactions, and 2 subjects in REACH had non-serious anaphylactic reactions.
Immunogenicity: Antibodies to infliximab were detected in 3 (2.9%) pediatric patients.
Infections: In the REACH trial, infections were reported in 56.3% of randomized subjects treated with infliximab. Infections were reported more frequently for subjects who received every 8-week as opposed to every 12-week infusions (73.6% and 38.0% respectively), while serious infections were reported for 3 subjects in the every 8-week and 4 subjects in 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. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) were reported.
Pediatric Ulcerative Colitis Patients: 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 every 12-week vs. the every 8-week dosing regimen. In the ACT 1 and ACT 2 studies, the most common adverse event was headache. The most common serious adverse event across these three 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 every 8-week as opposed to every 12-week infusions; in Study Peds UC, the overall incidence of infections was similar in the every 8-week (13/22 [59.1%]) and every 12-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 every 8-week and 3 of 23 (13.0%) patients in the every 12-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 every 8-week and 3 of 23 (13.0%) in the every 12-week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.
Antibodies to infliximab 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%] vs. 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.
Post-marketing Experience: Post-marketing spontaneous serious adverse events with infliximab in the pediatric population have included malignancies including hepatosplenic T-cell lymphomas, transient hepatic enzyme abnormalities, lupus-like syndrome, and positive autoantibodies (see Precautions and Malignancies and Lymphoproliferative Disorders as previously mentioned).
Biosimilarity: The biosimilar development program established that IXIFI is biosimilar to Remicade. The clinical program included a single-dose three-arm comparative pharmacokinetic (PK) trial in healthy volunteers and a randomized, double-blind, active-controlled, multi-national efficacy and safety comparative trial in an indication for which Remicade is licensed. The safety results for both studies did not reveal any clinical meaningful differences between IXIFI and Remicade. The safety after transition from Remicade to IXIFI was similar to that with continuous treatment with either IXIFI or Remicade.