INFLECTRA

Infliximab-dyyb, a tumor necrosis factor (TNF) blocker, is a chimeric IgG1κ monoclonal antibody (composed of human constant and murine variable regions). It has a molecular weight of approximately 149.1 kilodaltons. Infliximab-dyyb is produced by a recombinant murine myeloma cell line, SP2/0. INFLECTRA (infliximab-dyyb) for injection is supplied as a sterile, preservative-free, white, lyophilized powder for intravenous infusion after reconstitution and dilution. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the final concentration is 10 mg/mL and the resulting pH is approximately 7.2. Each single-dose vial contains 100 mg infliximab-dyyb, dibasic sodium phosphate, dihydrate (6.1 mg), monobasic sodium phosphate, monohydrate (2.2 mg), polysorbate 80 (0.5 mg), and sucrose (500 mg).

INFLECTRA is a tumor necrosis factor (TNF) blocker indicated for: Crohn's Disease ( 1.1 ): • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease. Pediatric Crohn's Disease ( 1.2 ): • reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active disease who have had an inadequate response to conventional therapy. Ulcerative Colitis ( 1.3 ): • reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. Pediatric Ulcerative Colitis ( 1.4 ): • reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active disease who have had an inadequate response to conventional therapy. Rheumatoid Arthritis ( 1.5 ) in combination with methotrexate: • reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active disease. Ankylosing Spondylitis ( 1.6 ): • reducing signs and symptoms in adult patients with active disease. Psoriatic Arthritis ( 1.7 ): • reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients. Plaque Psoriasis ( 1.8 ): • 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. 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 (CD) who have had an inadequate response to conventional therapy. • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD. 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 CD 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 (UC) who have had an inadequate response to conventional therapy. 1.4 Pediatric Ulcerative Colitis 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 UC 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 adult patients with moderately to severely active rheumatoid arthritis (RA). 1.6 Ankylosing Spondylitis INFLECTRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS). 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 adult patients with psoriatic arthritis (PsA). 1.8 Plaque Psoriasis INFLECTRA is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) 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) ] .

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.

The use of INFLECTRA at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. INFLECTRA is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab products or any of the inactive ingredients of INFLECTRA or any murine proteins [severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness] [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ]. • INFLECTRA doses >5 mg/kg in moderate or severe heart failure. ( 4 ) • Previous severe hypersensitivity reaction to infliximab products or any inactive ingredients of INFLECTRA or to any murine proteins. ( 4 )

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.

Other Biological Products – increased risk of serious infections ( 7.1 ) 7.1 Other Biological Products The combination of INFLECTRA with other biological products used to treat the same conditions as INFLECTRA is not recommended [see Warnings and Precautions (5.10) ]. An increased risk of serious infections was seen in clinical studies of other TNF blockers used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNF blockers. Therefore, the combination of INFLECTRA and anakinra or abatacept is not recommended [see Warnings and Precautions (5.10) ] . The concomitant use of tocilizumab with biological DMARDs such as TNF antagonists, including INFLECTRA, should be avoided because of the possibility of increased immunosuppression and increased risk of infection. 7.2 Methotrexate and Other Concomitant Medications Specific drug interaction studies, including interactions with methotrexate (MTX), have not been conducted. The majority of patients in RA or CD clinical studies received one or more concomitant medications. In RA, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant CD medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In PsA clinical trials, concomitant medications included MTX in approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-drug antibody production and increase infliximab product concentrations. 7.3 Immunosuppressants Patients with CD who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants [see Adverse Reactions (6.1) ] . Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of CD including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates. 7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab products, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of INFLECTRA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. 7.5 Live Vaccines/Therapeutic Infectious Agents It is recommended that live vaccines not be given concurrently with INFLECTRA. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab products for at least 6 months following birth [see Warnings and Precautions (5.13) ] . It is recommended that therapeutic infectious agents not be given concurrently with INFLECTRA [see Warnings and Precautions (5.13) ] .

Storage and Handling Store unopened INFLECTRA ® vials in a refrigerator at 2°C to 8°C (36°F to 46°F). If needed, unopened INFLECTRA vials may be stored at room temperature up to a maximum of 30°C (86°F) for a single period up to 6 months but not exceeding the original expiration date. The new expiration date must be written in the space provided on the carton. Once removed from the refrigerator, INFLECTRA cannot be returned to the refrigerator. Not made with natural rubber latex. For storage condition of the reconstituted and diluted product for administration, see Dosage and Administration (2.11) .