Infliximab

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.

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 a

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. U

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 infecti

7 DRUG INTERACTIONS 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) ] .