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2 DOSAGE AND ADMINISTRATION Prior to treatment, ensure appropriate personnel and medication are available to treat reactions (e.g., hypersensitivity) that occur during infusion and shortly after infusion ( 2.11 ) INFLECTRA is administered by intravenous infusion for at least 2 hours with an in-line filter ( 2.11 ) Crohn's Disease ( 2.1 ) • 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg every 8 weeks if they later lose their response. Pediatric Crohn's Disease (≥ 6 years old) ( 2.2 ) • 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Ulcerative Colitis ( 2.3 ) • 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Pediatric Ulcerative Colitis (≥ 6 years old) ( 2.4 ) • 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Rheumatoid Arthritis ( 2.5 ) • In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg every 8 weeks or treating as often as every 4 weeks. Ankylosing Spondylitis ( 2.6 ) • 5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks. Psoriatic Arthritis ( 2.7 ) and Plaque Psoriasis ( 2.8 ) • 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. 2.1 Dosage in Adult Crohn's Disease The recommended dosage of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active CD or fistulizing CD. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg every 8 weeks. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue INFLECTRA in these patients. 2.2 Dosage in Pediatric Crohn's Disease The recommended dosage of INFLECTRA for pediatric patients 6 years and older with moderately to severely active CD is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks. 2.3 Dosage in Adult Ulcerative Colitis The recommended dosage of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active UC. 2.4 Dosage in Pediatric Ulcerative Colitis The recommended dosage of INFLECTRA for pediatric patients 6 years and older with moderately to severely active UC is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks. 2.5 Dosage in Rheumatoid Arthritis The recommended dosage of INFLECTRA is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active RA. INFLECTRA should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dosage up to 10 mg/kg every 8 weeks or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses per infusion or more frequent dosing [see Adverse Reactions (6.1) ] . 2.6 Dosage in Ankylosing Spondylitis The recommended dosage of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active AS. 2.7 Dosage in Psoriatic Arthritis The recommended dosage of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of PsA. INFLECTRA can be used with or without methotrexate. 2.8 Dosage in Plaque Psoriasis The recommended dosage of INFLECTRA in adult patients is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) Ps. 2.9 Assessment for Latent and Active Tuberculosis Prior to initiating INFLECTRA and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection [see Warnings and Precautions (5.1) ] . 2.10 Administration Instructions Regarding Infusion Reactions Prior to treatment, ensure appropriate personnel and medication are available to treat reactions (e.g., hypersensitivity, other reactions) that occur during infusion and shortly after infusion. Prior to infusion with INFLECTRA, patient may be premedicated with histamine-1 receptor antagonists, histamine-2 receptor antagonists, acetaminophen, and/or corticosteroids [see Warnings and Precautions (5.7) ] . For mild to moderate reactions during the infusion, consider slowing or stopping the infusion. Upon resolution of these reactions, may reinitiate at a lower infusion rate and/or with histamine-1 receptor antagonists, histamine-2 receptor antagonists, acetaminophen, and/or corticosteroids. Discontinue the infusion if the mild to moderate reactions reoccur. Discontinue the infusion if severe hypersensitivity reactions occur during the infusion. 2.11 Reconstitution, Dilution, and Administration Instructions INFLECTRA is intended for use under the guidance and supervision of a healthcare provider. The supplied lyophilized powder must be reconstituted and diluted prior to administration. The infusion solution should be prepared and administered by a trained medical professional using aseptic technique by the following procedure: 1. Calculate the dose, total volume of reconstituted INFLECTRA solution required and the number of INFLECTRA vials needed. More than one vial may be needed for a full dose. 2. Reconstitute each 100 mg INFLECTRA vial with 10 mL of Sterile Water for Injection, USP, to obtain a concentration of 10 mg/mL, using a syringe equipped with a 21-gauge or smaller needle as follows: • Remove the flip-top from the vial and wipe the top with an alcohol swab. • Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder, which has a cake-like appearance. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. • Allow the reconstituted solution to stand for 5 minutes. Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab-dyyb is a protein. Do not use if the lyophilized powder has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present. Do not store unused reconstituted INFLECTRA solution. 3. Dilute the total volume of the reconstituted INFLECTRA solution to 250 mL For volumes greater than 250 mL, either use a larger infusion bag (e.g. 500 mL) or multiple 250 mL infusion bags to ensure that the concentration of the infusion solution does not exceed 4 mg/mL. with sterile 0.9% Sodium Chloride Injection, USP, (do not dilute with any other diluent) as follows: • Withdraw a volume from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag equal to the total volume of reconstituted INFLECTRA required for a dose. Slowly add the total volume of reconstituted INFLECTRA solution from the vial(s) to the 250 mL infusion bottle or bag. • Discard any unused portion of the reconstituted INFLECTRA solution remaining in the vial(s). • Gently invert the bag to mix the solution. The resulting infusion concentration should range between 0.4 mg/mL (minimum recommended concentration) and 4 mg/mL (maximum recommended concentration) of infliximab-dyyb. 4. The INFLECTRA infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered intravenously for at least 2 hours with an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less). 5. Given that the vials do not contain antibacterial preservatives, discard any unused portion of the infusion solution (do not store for reuse). No physical biochemical compatibility studies have been conducted to evaluate the co-administration of INFLECTRA with other agents. INFLECTRA should not be infused concomitantly in the same intravenous line with other agents.
Side Effects Overview
6 ADVERSE REACTIONS Most common adverse reactions (>10%) – infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION, Inc. at 1-800-383-7504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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). Infusion-Related Reactions 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 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 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, treatment with infliximab 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 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. Infections 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 (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 postmarketing. 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 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 CD developed a new fistula-related abscess. In clinical studies with infliximab in patients with UC, 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 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. Autoantibodies/Lupus-like Syndrome 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. Malignancies 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 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 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 products have not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5) ]. Hepatotoxicity Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving infliximab products [see Warnings and Precautions (5.4) ] . Reactivation of hepatitis B virus has occurred in patients receiving TNF blockers, including infliximab products, 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. Table 1 Proportion of Patients with Elevated ALT in Clinical Trials in Adults Proportion of patients with elevated ALT >1 to 3 × ULN ≥3 × ULN ≥5 × ULN Placebo Infliximab Placebo Infliximab Placebo Infliximab Rheumatoid arthritis Placebo patients received methotrexate while patients treated with infliximab received both infliximab and methotrexate. Median follow-up was 58 weeks. 24% 34% 3% 4% <1% <1% Crohn's disease Placebo patients in the 2 Phase 3 trials in CD received an initial dose of 5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to infliximab are included in the infliximab group in ALT analysis. Median follow-up was 54 weeks. 34% 39% 4% 5% 0% 2% Ulcerative colitis Median follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for infliximab. 12% 17% 1% 2% <1% <1% Ankylosing spondylitis Median follow-up was 24 weeks for the placebo group and 102 weeks for infliximab group. 15% 51% 0% 10% 0% 4% Psoriatic arthritis Median follow-up was 39 weeks for infliximab group and 18 weeks for the placebo group. 16% 50% 0% 7% 0% 2% Plaque psoriasis ALT values are obtained in 2 Phase 3 Ps studies with median follow-up of 50 weeks for infliximab and 16 weeks for placebo. 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 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 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. Table 2 Adverse Reactions that Occurred in ≥ 5% of Patients who Received ≥ 4 Infliximab Infusions for RA Placebo Infliximab (n=350) (n=1129) Average weeks of follow-up 59 weeks 66 weeks Upper respiratory tract infection 25% 32% Nausea 20% 21% Headache 14% 18% Sinusitis 8% 14% Diarrhea 12% 12% Abdominal pain 8% 12% Pharyngitis 8% 12% Coughing 8% 12% Bronchitis 9% 10% Rash 5% 10% Dyspepsia 7% 10% Fatigue 7% 9% Urinary tract infection 6% 8% Pain 7% 8% Arthralgia 7% 8% Pruritus 2% 7% Fever 4% 7% Hypertension 5% 7% Moniliasis 3% 5% 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%). 6.2 Immunogenicity 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 UC where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods. Immunogenicity in Adult Patients The incidence of antibodies to infliximab in patients with RA and CD given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of infliximab treatment. A higher incidence of antibodies to infliximab was observed in CD patients receiving infliximab after drug-free intervals >16 weeks. In a PsA study 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. Antibody development was lower among RA and CD patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX. Patients who were antibody-positive were more likely to have higher rates of clearance, have reduced efficacy, and to experience an infusion reaction than were patients who were antibody negative [see Adverse Reactions (6.1) ] . In the Ps 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 Ps 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 Ps patients as compared to patients with other diseases treated with infliximab products over the long term is not known. Immunogenicity in Pediatric Patients with Crohn's Disease 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. Immunogenicity in Pediatric Patients with Ulcerative Colitis 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. 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. 6.3 Postmarketing Experience Adverse reactions, some with fatal outcomes, 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. Postmarketing Adverse Reactions in Adults and Pediatric Patients • Neutropenia [see Warnings and Precautions (5.6) ] , agranulocytosis (including infants exposed in utero to infliximab products), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura. • Interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and rapidly progressive disease). • Pericardial effusion, systemic and cutaneous vasculitis. • Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), worsening psoriasis (all subtypes including pustular, primarily palmoplantar), lichenoid reactions. • Peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy) 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 vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab products [see Warnings and Precautions (5.13) ] . • Malignancies, including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2) ] • Anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products. • 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) ] . • New onset immune disorders (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease). Postmarketing Serious Adverse Reactions in Pediatric Patients The following serious adverse reactions have been reported in the postmarketing experience in pediatric patients: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, hypersensitivity reactions, malignancies, including hepatosplenic T-cell lymphomas [see Boxed Warning and Warnings and Precautions (5.2) ] , transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.
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5 WARNINGS AND PRECAUTIONS • Serious infections – do not give INFLECTRA during an active infection. If an infection develops, monitor carefully and stop INFLECTRA if infection becomes serious. ( 5.1 ) • Invasive fungal infections – for patients who develop a systemic illness on INFLECTRA, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic. ( 5.1 ) • Malignancies – the incidence of malignancies, including invasive cervical cancer and lymphoma, was greater in infliximab-treated patients than in controls. Due to the risk of HSTCL carefully assess the risk/benefit especially if the patient has Crohn's disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. ( 5.2 ) • Hepatitis B virus (HBV) reactivation – test for HBV infection before starting INFLECTRA. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop INFLECTRA and begin anti-viral therapy. ( 5.3 ) • Hepatotoxicity – severe hepatic reactions, some fatal or necessitating liver transplantation. Stop INFLECTRA in cases of jaundice and/or marked liver enzyme elevations. ( 5.4 ) • Heart failure –new onset or worsening symptoms may occur. ( 4 , 5.5 ) • Cytopenias – advise patients to seek immediate medical attention if signs and symptoms develop, and consider stopping INFLECTRA. ( 5.6 ) • Hypersensitivity – serious infusion reactions including anaphylaxis or serum sickness-like reactions may occur. ( 5.7 ) • Cardiovascular and Cerebrovascular Reactions – Cerebrovascular accidents, myocardial infarctions (some fatal), and arrhythmias have been reported during and within 24 hours of initiation of infliximab product infusion. Monitor patients during INFLECTRA infusion and if serious reaction occurs, discontinue infusion. ( 5.8 ) • Demyelinating disease –exacerbation or new onset may occur. ( 5.9 ) • Lupus-like syndrome –stop INFLECTRA if syndrome develops. ( 5.12 ) • Vaccinations and Use of Live vaccines/therapeutic infectious agents – Prior to initiating INFLECTRA bring pediatric and adult patients up to date with all vaccinations. Live vaccines or therapeutic infectious agents should not be given with INFLECTRA. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab products. ( 5.13 ) 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. Tuberculosis 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. Monitoring 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. 5.2 Malignancies 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. Lymphomas 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) ]. Skin Cancer 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. Cervical 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) ] . Other Malignancies 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. 5.4 Hepatotoxicity 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. 5.7 Hypersensitivity 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 Infliximab products and 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. 5.12 Autoimmunity 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 Vaccinations 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.