WARNING: SERIOUS INFECTIONS and MALIGNANCY
Patients treated with infliximab products are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
INFLECTRA should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before INFLECTRA use and during therapy.1,2 Treatment for latent infection should be initiated prior to INFLECTRA use.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with INFLECTRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with INFLECTRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including infliximab products [see Warnings and Precautions (5.2)].
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males.
INFLECTRA at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating infliximab in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), infliximab treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].
INFLECTRA should not be readministered to patients who have experienced a severe hypersensitivity reaction to infliximab products. Additionally, INFLECTRA should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.
5 WARNINGS AND PRECAUTIONS
5.1 Serious Infections
Patients treated with infliximab products are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Treatment with INFLECTRA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with comorbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
- with chronic or recurrent infection;
- who have been exposed to tuberculosis;
- with a history of an opportunistic infection;
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
- with underlying conditions that may predispose them to infection.
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab products, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with infliximab products during treatment for latent tuberculosis.
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating INFLECTRA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating INFLECTRA, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of INFLECTRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during INFLECTRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with INFLECTRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with INFLECTRA.
INFLECTRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with INFLECTRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Invasive Fungal Infections
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.
Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF blocking agents (initiation of therapy ≤18 years of age), including infliximab products. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.
In the controlled portions of clinical trials of all the TNF blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5707 patients treated with infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
Hepatosplenic T-cell Lymphoma (HSTCL)
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use INFLECTRA alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab product monotherapy from the clinical trial data from studies with infliximab [see Warnings and Precautions (5.7), Adverse Reactions (6.1)].
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products [see Adverse Reactions (6.2)]. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3 fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between infliximab products and cervical cancer cannot be excluded. Periodic screening should continue in women treated with INFLECTRA [see Adverse Reactions (6.2)].
In the controlled portions of clinical trials of some TNF blocking agents, including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF blockers compared with control patients. During the controlled portions of trials with infliximab, in patients with moderately to severely active rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.
In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking [see Adverse Reactions (6.1)]. Prescribers should exercise caution when considering the use of INFLECTRA in patients with moderate to severe COPD.
Psoriasis patients should be monitored for NMSCs, particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, NMSCs were more common in patients with previous phototherapy [see Adverse Reactions (6.1)].
The potential role of TNF blocking therapy in the development of malignancies is not known [see Adverse Reactions (6.1)]. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering INFLECTRA treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving INFLECTRA.
5.3 Hepatitis B Virus Reactivation
Use of TNF blockers, including infliximab products, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including INFLECTRA. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab products. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, INFLECTRA should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab products without progression to severe hepatic injury [see Adverse Reactions (6.1)].
5.5 Patients with Heart Failure
Infliximab products have been associated with adverse outcomes in patients with heart failure, and INFLECTRA should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare postmarketing 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. If a decision is made to administer INFLECTRA to patients with heart failure, they should be closely monitored during therapy, and INFLECTRA should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4), Adverse Reactions (6.1)].
5.6 Hematologic Reactions
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab products. The causal relationship to infliximab product therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with INFLECTRA 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 INFLECTRA. Discontinuation of INFLECTRA therapy should be considered in patients who develop significant hematologic abnormalities.
Infliximab products have been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include anaphylaxis, urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of infusion. However, in some cases, serum sickness-like reactions have been observed in patients after initial therapy with infliximab products (i.e., as early as after the second dose), and when therapy with infliximab products was reinstituted following an extended period without 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 products, loss of detectable serum concentrations of infliximab products, and possible loss of drug efficacy.
INFLECTRA 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 Adverse Reactions (6.1)].
In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, readministration 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 readministration of INFLECTRA after a period of no-treatment, especially as a reinduction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where INFLECTRA maintenance therapy for psoriasis is interrupted, INFLECTRA should be reinitiated as a single dose followed by maintenance therapy.
5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion
Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab product infusion. Cases of transient visual loss have been reported during or within 2 hours of infliximab product infusion. 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)].
5.9 Neurologic Reactions
Agents that inhibit TNF have been associated in rare cases 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 INFLECTRA in patients with these neurologic disorders and should consider discontinuation of INFLECTRA if these disorders develop.
5.10 Use with Anakinra
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα blocking agents. Therefore, the combination of INFLECTRA and anakinra is not recommended.
5.11 Use with Abatacept
In clinical studies, concurrent administration of TNF blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blocking agents alone, without increased clinical benefit. Therefore, the combination of INFLECTRA and abatacept is not recommended [see Drug Interactions (7.1)].
5.12 Concurrent Administration with other Biological Therapeutics
There is insufficient information regarding the concomitant use of infliximab products with other biological therapeutics used to treat the same conditions as INFLECTRA. The concomitant use of INFLECTRA with these biologics is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.3)].
5.13 Switching between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)
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 products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with INFLECTRA, treatment should be discontinued [see Adverse Reactions (6.1)].
5.15 Live Vaccines/Therapeutic Infectious Agents
In patients receiving anti-TNF therapy, 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 could result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with INFLECTRA 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 products. Infliximab products are known to cross the placenta and have 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 products.
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 INFLECTRA.
It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating INFLECTRA therapy. The interval between vaccination and initiation of INFLECTRA therapy should be in accordance with current vaccination guidelines.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
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.
Adverse Reactions in Adults
The data described herein reflect exposure to infliximab 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 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).
An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase 3 clinical studies, 18% of patients treated with infliximab experienced an infusion reaction compared to 5% of placebo-treated patients. Of these 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 infusions with infliximab, 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 treatment with 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 psoriasis through 1 year in psoriasis 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 psoriasis 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 (6.1), Drug Interactions (7.4)].
Infusion reactions following re-administration
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 regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment 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, treatment with infliximab was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed Reactions/Reactions Following Readministration
In psoriasis studies, approximately 1% of patients treated with infliximab 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 patients treated with infliximab (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 patients treated with infliximab, 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 was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported postmarketing. Most of these cases of tuberculosis 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 methotrexate (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 tuberculosis, 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 infusions with infliximab 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 Crohn's disease developed a new fistula-related abscess.
In clinical studies with infliximab in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of patients treated with infliximab (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 ulcerative colitis 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 patients treated with infliximab 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 patients treated with infliximab compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
In controlled trials, more patients treated with infliximab 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 rheumatoid arthritis and Crohn's disease. Of these patients treated with infliximab, 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% confidence interval [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.
Patients with Heart Failure
In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab at 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), Warnings and Precautions (5.5)].
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other infliximab products may be misleading.
Treatment with infliximab products can be associated with the development of antibodies to infliximab products. An enzyme immunoassay (EIA) method was originally used to measure anti-infliximab antibodies in clinical studies of infliximab. The EIA method is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. A separate, drug-tolerant electrochemiluminescence immunoassay (ECLIA) method for detecting antibodies to infliximab was subsequently developed and validated. This method is 60-fold more sensitive than the original EIA. With the ECLIA method, all clinical samples can be classified as either positive or negative for antibodies to infliximab without the need for the inconclusive category.
The incidence of antibodies to infliximab was based on the original EIA method in all clinical studies of infliximab except for the Phase 3 study in pediatric patients with ulcerative colitis where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods [see Adverse Reactions, Pediatric Ulcerative Colitis (6.1)].
The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of treatment with infliximab. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 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 (6.1)] than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-mercaptopurine /azathioprine (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 1 year and in Study III in patients treated with 5 mg/kg induction (14.1% – 23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab products over the long term is not known.
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving infliximab products [see Warnings and Precautions (5.4)]. Reactivation of HBV has occurred in patients receiving TNF blocking agents, including infliximab products, who are chronic carriers of this virus [see Warnings and Precautions (5.3)].
In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, 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|
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 of 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 psoriasis 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 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 adult patients treated with infliximab, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis 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 rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients treated with infliximab except for abdominal pain, which occurred in 26% of patients with Crohn's disease. In the Crohn's disease 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||66|
|Upper respiratory tract infection||25%||32%|
|Skin and appendages disorders|
|Body as a whole-general disorder|
|Resistance mechanism disorders|
|Central and peripheral nervous system disorders|
|Musculoskeletal system disorders|
|Urinary system disorders|
|Urinary tract infection||6%||8%|
|Cardiovascular disorders, general|
The most common serious adverse reactions observed in clinical trials of infliximab 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
Pediatric 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 Crohn's disease. These differences are discussed in the following paragraphs.
The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease 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. In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks.)
Pediatric Ulcerative Colitis
Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (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 Crohn's disease study (Study Peds Crohn's) but higher than the proportion in the adults' ulcerative colitis 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.
In the pediatric UC trial, 58 patients were evaluated for antibodies to infliximab using the EIA as well as the drug-tolerant ECLIA. With the EIA, 4 of 58 (7%) patients had antibodies to infliximab. With the ECLIA, 30 of 58 (52%) patients had antibodies to infliximab [see Adverse Reactions, Immunogenicity (6.1)]. The higher incidence of antibodies to infliximab by the ECLIA method was due to the 60-fold higher sensitivity compared to the EIA method. While EIA-positive patients generally had undetectable trough infliximab concentrations, ECLIA-positive patients could have detectable trough concentrations of infliximab because the ECLIA assay is more sensitive and drug-tolerant.
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%).
6.2 Postmarketing Experience
Adverse reactions have been identified during post approval use of infliximab products in adult and pediatric patients. Because these reactions 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 drug exposure.
The following adverse reactions, some with fatal outcome, have been reported during post-approval use of infliximab products: neutropenia [see Warnings and Precautions (5.6)], agranulocytosis (including infants exposed in utero to infliximab products), interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and very rare rapidly progressive disease), idiopathic 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), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) [see Warnings and Precautions (5.9)], acute liver failure, jaundice, hepatitis, and cholestasis [see Warnings and Precautions (5.4)], serious infections [see Warnings and Precautions (5.1)] and malignancies, including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2)] and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab products [see Warnings and Precautions (5.15)].
In postmarketing experience, cases of anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products.
Cases of transient visual loss have been reported in association with infliximab products during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported [see Warnings and Precautions (5.8)].
Adverse Reactions in Pediatric Patients
The following serious adverse reactions have been reported in the postmarketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.
Serious adverse reactions in the postmarketing experience with infliximab products in the pediatric population have also included malignancies, including HSTCL [see Boxed Warning and Warnings and Precautions (5.2)], transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.
1 INDICATIONS AND USAGE
1.1 Crohn's Disease
INFLECTRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.
INFLECTRA is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.
1.2 Pediatric Crohn's Disease
INFLECTRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.
1.3 Ulcerative Colitis
INFLECTRA is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
1.5 Rheumatoid Arthritis
INFLECTRA, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
1.6 Ankylosing Spondylitis
INFLECTRA is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
1.7 Psoriatic Arthritis
INFLECTRA is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
1.8 Plaque Psoriasis
INFLECTRA is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. INFLECTRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning, Warnings and Precautions (5)].