The use of Infliximab at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. A randomized, double-blind, placebo-controlled study evaluated the use of Infliximab (5 mg/kg or 10 mg/kg at Weeks 0, 2, and 6) in patients with moderate or severe heart failure [New York Heart Association (NYHA) Functional Class III/IV]. Compared to patients who received placebo, there was a higher rate of mortality and a higher risk of hospitalization at Week 28 due to heart failure in patients who received the 10 mg/kg Infliximab dose, and higher rates of cardiovascular adverse events in patients who received Infliximab doses of 5 mg/kg and 10 mg/kg.
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.
If a decision is made to administer Infliximab (≤ 5 mg/kg) to patients with moderate or severe heart failure or to administer Infliximab (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and Infliximab should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1)].
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving Infliximab. The causal relationship to Infliximab therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with Infliximab who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on Infliximab. Discontinuation of Infliximab therapy should be considered in patients who develop significant hematologic abnormalities.
Infliximab has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions (including anaphylaxis, urticaria, dyspnea, and/or hypotension), have occurred during or within 2 hours of Infliximab infusion.
However, in some cases, serum sickness-like reactions have been observed in patients after initial Infliximab therapy (i.e., as early as after the second dose), and when Infliximab therapy was reinstituted following an extended period without Infliximab treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.
Infliximab should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction [see Dosage and Administration (2.10) and Adverse Reactions (6.1)].
In RA, CD and Ps 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 [see Adverse Reactions (6.1)]. In general, the benefit-risk of re-administration of Infliximab after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where Infliximab maintenance therapy for Ps is interrupted, Infliximab should be reinitiated as a single dose followed by maintenance therapy.
Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of Infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of Infliximab. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms [see Adverse Reactions (6)].
Infliximab and other agents that inhibit TNF have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of Infliximab in patients with these neurologic disorders and should consider discontinuation of Infliximab if these disorders develop.
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF blocker, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the concurrent use of etanercept and anakinra therapy, similar toxicities may also result from the concurrent use of anakinra and other TNF blockers. Therefore, the concurrent use of Infliximab and anakinra is not recommended.
In clinical studies, concurrent administration of TNF blockers and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blockers alone, without increased clinical benefit. Therefore, the concurrent use of Infliximab and abatacept is not recommended [see Drug Interactions (7.1)].
There is insufficient information regarding the concurrent use of Infliximab with other biological products used to treat the same conditions as Infliximab. The concurrent use of Infliximab with these biological products is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.1)].
Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.
Treatment with Infliximab may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Infliximab, treatment should be discontinued [see Adverse Reactions (6.1)].
Prior to initiating Infliximab in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines.
Live Vaccines and Therapeutic Infectious Agents
In patients receiving TNF blockers, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with Infliximab is not recommended.
Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab. Infliximab is known to cross the placenta and has been detected up to 6 months following birth. At least a six month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab.
Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Infliximab.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions in Adults
The data described herein reflect exposure to Infliximab in 4779 adult patients (1304 patients with RA, 1106 patients with CD, 202 with AS, 293 with PsA, 484 with UC, 1373 with Ps, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Adverse Reactions (6.1)]. One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).
Adverse Reactions During or Shortly After Infusion
An infusion 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, approximately 20% of Infliximab-treated patients experienced an infusion reaction compared with 10% of placebo-treated patients. 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.
Among all Infliximab 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 Infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. Infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in Ps through 1 year in Ps Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 Ps studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.
Patients who became positive for antibodies to infliximab were more likely (approximately two-to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.2) and Drug Interactions (7.3)].
Infusion Reactions Following Re-administration
In a clinical trial of patients with moderate to severe Ps designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of Infliximab following disease flare, 4% (8/219) of patients in the re-treatment induction 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. 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, Infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed Reactions/Reactions Following Re-administration
In Ps studies, approximately 1% of Infliximab-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.
In Infliximab clinical studies, treated infections were reported in 36% of Infliximab-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among Infliximab-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis (TB) was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of TB, including disseminated TB, also have been reported post-marketing. Most of these cases of TB occurred within the first 2 months after initiation of therapy with Infliximab and may reflect recrudescence of latent disease [see Warnings and Precautions (5.1)]. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving Infliximab every 8 weeks with MTX developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving Infliximab, 1.7% developed pneumonia and 0.4% developed TB, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg Infliximab infusions at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg Infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn’s II Study, 15% of patients with fistulizing CD developed a new fistula-related abscess.
In Infliximab clinical studies in patients with UC, infections treated with antimicrobials were reported in 27% of Infliximab-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with UC were similar to those reported in other clinical studies.
The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.
Approximately half of Infliximab-treated patients in clinical trials who were antinuclear antibody (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 one-fifth of Infliximab-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
In controlled trials, more Infliximab-treated patients developed malignancies than placebo-treated patients [see Warnings and Precautions (5.2)].
In a randomized controlled clinical trial exploring the use of Infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with Infliximab at doses similar to those used in RA and CD. Of these Infliximab-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck [see Warnings and Precautions (5.2)].
Adverse Reactions in Patients with NYHA Class III/IV Heart Failure
In a randomized, double-blind study evaluating Infliximab in moderate or severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of Infliximab 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 Infliximab dose. At 1 year, 8 patients in the 10 mg/kg Infliximab group had died compared with 4 deaths each in the 5 mg/kg Infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg Infliximab treatment groups, versus placebo. Infliximab has not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5)].
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving Infliximab [see Warnings and Precautions (5.4)]. Reactivation of hepatitis B virus has occurred in patients receiving TNF blockers, including Infliximab, who are chronic carriers of this virus [see Warnings and Precautions (5.3)].
In clinical trials in RA, CD, UC, AS, Ps, and PsA, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving Infliximab than in controls (Table 1), both when Infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. 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.
|Proportion of patients with elevated ALT|
|>1 to <3 × ULN||≥3 × ULN||≥5 × ULN|
|Rheumatoid arthritis *||24%||34%||3%||4%||<1%||<1%|
|Crohn’s disease †||34%||39%||4%||5%||0%||2%|
|Ulcerative colitis ‡||12%||17%||1%||2%||<1%||<1%|
|Ankylosing spondylitis §||15%||51%||0%||10%||0%||4%|
|Psoriatic arthritis ¶||16%||50%||0%||7%||0%||2%|
|Plaque psoriasis #||24%||49%||<1%||8%||0%||3%|
Adverse Reactions in Psoriasis Studies
During the placebo-controlled portion across the 3 clinical trials up to Week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg Infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg Infliximab group.
Among patients in the 2 Phase 3 studies, 12.4% of patients receiving Infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving Infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 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 Infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving Infliximab 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 Infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg Infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting Infliximab.
In the placebo-controlled portion of the Ps studies, 7 of 1123 patients who received Infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.
In the Ps 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 in Adults
Safety data are available from 4779 Infliximab-treated adult patients, including 1304 with RA, 1106 with CD, 484 with UC, 202 with AS, 293 with PsA, 1373 with Ps and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1) ]. Adverse reactions reported in ≥5% of all patients with RA receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in Infliximab-treated RA, AS, PsA, Ps, and CD patients except for abdominal pain, which occurred in 26% of Infliximab-treated patients with CD. In the CD studies, there were insufficient numbers and duration of follow-up for patients who never received Infliximab to provide meaningful comparisons.
|Average weeks of follow-up||59 weeks||66 weeks|
|Upper respiratory tract infection||25%||32%|
|Urinary tract infection||6%||8%|
The most common serious adverse reactions observed in clinical trials were infections [see Adverse Reactions (6.1)]. Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows:
- Body as a whole: allergic reaction, edema
- Blood: pancytopenia
- Cardiovascular: hypotension
- Gastrointestinal: constipation, intestinal obstruction
- Central and Peripheral Nervous: dizziness
- Heart Rate and Rhythm: bradycardia
- Liver and Biliary: hepatitis
- Metabolic and Nutritional: dehydration
- Platelet, Bleeding and Clotting: thrombocytopenia
- Neoplasms: lymphoma
- Red Blood Cell: anemia, hemolytic anemia
- Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis
- Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
- Skin and Appendages: increased sweating
- Vascular (Extracardiac): thrombophlebitis
- White Cell and Reticuloendothelial: leukopenia, lymphadenopathy
Adverse Reactions in Pediatric Patients
Adverse Reactions in Pediatric Patients with Crohn’s Disease
There were some differences in the adverse reactions observed in the pediatric patients receiving Infliximab compared to those observed in adults with CD. These differences are discussed in the following paragraphs.
The following adverse reactions were reported more commonly in 103 randomized pediatric CD patients administered 5 mg/kg Infliximab through 54 weeks than in 385 adult CD patients receiving a similar treatment regimen: anemia (11%), 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 1 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.
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 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks).
Adverse Reactions in Pediatric Patients with Ulcerative Colitis
Overall, the adverse reactions reported in the pediatric UC trial and adult UC (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.
Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric CD study (Study Peds Crohn’s) but higher than the proportion in the adults’ UC studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 × ULN, and 2% (1/60) had elevations ≥5 × ULN (median follow-up was 49 weeks).
Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.
In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. 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 (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) 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 (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).
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