Infliximab

1 INDICATIONS AND USAGE 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

12.1 Mechanism of Action Infliximab products neutralize the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibit binding of TNFα with its receptors. Infliximab products do not neutralize TNFβ (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNFα. Biological activities attributed to TNFα include: induction of proinflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNFα bound by infliximab products can be lysed in vitro or in vivo . Infliximab products inhibit the functional activity of TNFα in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes and epithelial cells. The relationship of these biological response markers to the mechanism(s) by which infliximab products exert their clinical effects is unknown. Anti-TNFα antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab products prevent disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allow eroded joints to heal.

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 a

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 se

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

4 CONTRAINDICATIONS 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 )

10 OVERDOSAGE Single doses up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects [see Warnings and Precautions (5) ] and appropriate symptomatic treatment instituted immediately.