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.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
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 blockers 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-Guérin (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 blockers (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 blockers, 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 RA 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 RA, CD, PsA, AS, UC, and Ps, 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 CD, RA or Ps, 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 blockers. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in RA and other diseases. Even in the absence of TNF blocker therapy, patients with RA 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 CD or UC 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) and 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 (6.3)]. 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 RA 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 (6.3)].
In the controlled portions of clinical trials of some TNF blockers, 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 RA, CD, PsA, AS, UC and Ps, 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.
Ps patients should be monitored for nonmelanoma skin cancers (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 blockers 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 antiviral 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 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 products; 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 Heart Failure
The use of INFLECTRA 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 postmarketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in patients treated with infliximab products. Some of these patients have been under 50 years of age.
If a decision is made to administer INFLECTRA (≤ 5 mg/kg) to patients with moderate or severe heart failure or to administer INFLECTRA (any approved dose) to patients with mild 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) and 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 (including anaphylaxis, urticaria, dyspnea, and/or hypotension), have occurred during or within 2 hours of infliximab product 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 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 readministration of INFLECTRA 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 INFLECTRA maintenance therapy for Ps 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 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 Concurrent Administration with Other Biological Products
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 INFLECTRA 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 INFLECTRA and abatacept is not recommended [see Drug Interactions (7.1)].
There is insufficient information regarding the concurrent use of infliximab products with other biological products used to treat the same conditions as INFLECTRA. The concurrent use of INFLECTRA with these biological products is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.1)].
5.11 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 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)].
5.13 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents
Prior to initiating INFLECTRA 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 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.