infliximab

1 INDICATIONS AND USAGE Infliximab is a tumor necrosis factor (TNF) blocker indicated for: Crohn's Disease : 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. ( 1.1 ) reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease. ( 1.1 ) Pediatric Crohn's Disease : 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. ( 1.2 ) Ulcerative Colitis : 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. ( 1.3 ) Pediatric Ulcerative Colitis : 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. ( 1.4 ) Rheumatoid Arthritis 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. ( 1.5 ) Ankylosing Spondylitis : reducing signs and symptoms in adult patients with active disease. ( 1.6 ) Psoriatic Arthritis : reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients. ( 1.7 ) Plaque Psoriasis : 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. ( 1.8 ) 1.1 Crohn's Disease Infliximab 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 Infliximab 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 Infliximab 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 Infliximab 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 Infliximab, 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 Infliximab is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS). 1.7 Psoriatic Arthritis Infliximab 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 Infliximab …

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 ) Infliximab is administered by intravenous infusion for at least 2 hours with an in-line filter ( 2.11 ) Crohn's Disease : 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. ( 2.1 ) Pediatric Crohn's Disease (≥ 6 years old) : 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ( 2.2 ) Ulcerative Colitis : 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ( 2.3 ) Pediatric Ulcerative Colitis (≥ 6 years old) : 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ( 2.4 ) Rheumatoid Arthritis : 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. ( 2.5 ) Ankylosing Spondylitis : 5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks. ( 2.6 ) Psoriatic Arthritis and Plaque Psoriasis : 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ( 2.7 , 2.8 ) 2.1 Dosage in Adult Crohn's Disease The recommended dosage of Infliximab 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 Infliximab in these patients. 2.2 Dosage in Pediatric Crohn's Disease The recommended dosage of Infliximab 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 Infliximab 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 Infliximab 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 Infliximab 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. Infliximab 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 Infliximab 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 Infliximab 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. Infliximab can be used with or without methotrexate. 2.8 Dosage in Plaque Psoriasis The recommended dosage of Infliximab in adult patients is 5 mg/kg …

3 DOSAGE FORMS AND STRENGTHS For injection: 100 mg of infliximab as a white lyophilized powder in a single-dose vial for reconstitution and dilution. For injection: 100 mg of infliximab as a lyophilized powder in a single-dose vial for reconstitution and dilution. ( 2.11 , 3 )

4 CONTRAINDICATIONS The use of Infliximab 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) ] . Infliximab is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab or any of the inactive ingredients of Infliximab 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) ]. Infliximab doses >5 mg/kg in moderate or severe heart failure. ( 4 ) Previous severe hypersensitivity reaction to infliximab or any inactive ingredients of Infliximab or to any murine proteins. ( 4 )

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 Janssen Biotech, Inc. at 1-800-526-7736 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 to 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 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 …

7 DRUG INTERACTIONS Other Biological Products – increased risk of serious infections. ( 7.1 ) 7.1 Other Biological Products The combination of Infliximab with other biological products used to treat the same conditions as Infliximab 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 Infliximab 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 Infliximab, 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-infliximab antibody production and increase infliximab 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, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of Infliximab 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 Infliximab. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab 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 Infliximab [see Warnings and Precautions (5.13) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available observational studies in pregnant women exposed to Infliximab showed no increased risk of major malformations among live births as compared to those exposed to non-biologics. However, findings on other birth and maternal outcomes were not consistent across studies of different study design and conduct (see Data ) . Monoclonal antibodies such as infliximab are transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ) . Because infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with Infliximab. In a developmental study conducted in mice using an analogous antibody, no evidence of maternal toxicity or fetal harm was observed (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that there is an increased risk of adverse pregnancy outcomes in women with inflammatory bowel disease or rheumatoid arthritis associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2.5 kg) and small for gestational age at birth. Fetal/Neonatal Adverse Reactions As with other IgG antibodies, infliximab crosses the placenta. Infliximab has been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants [see Warnings and Precautions (5.13) ] . Cases of agranulocytosis in infants exposed in utero have also been reported [see Adverse Reactions (6.3) ] . Data Human Data Two prospective cohort studies were conducted assessing birth outcomes as well as the health status of infants up to the age of one year in women exposed to Infliximab compared to non-biologic comparators including methotrexate, azathioprine, 6-mercaptopurine and systemic corticosteroids used for the treatment of similar diseases. The first study was conducted in an IBD pregnancy registry in the United States and assessed pregnancy outcomes in 294 women with inflammatory bowel disease exposed to Infliximab during pregnancy compared with 515 women on a non-biologic treatment. Infliximab exposure was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small for gestational age, or infection in the first year of life. The second study among IBD and non-IBD patients in Sweden, Finland, and Denmark compared 97, 7, and 166 women exposed to Infliximab to 2,693, 2,499 and 1,268 women on non-biologic systemic therapy, respectively. In this study, comparing pooled data across the three countries, exposure to Infliximab was not associated with increased rates of congenital anomalies or infant death. Infliximab in combination with immunosuppressants (mainly systemic corticosteroids and azathioprine) was associated with increased rates of preterm birth, small for gestational age, low birth weight, and infant hospitalization for infection compared with non-biologic systemic treatment. Although the study did not show any associations with Infliximab monotherapy, the analyses could have been underpowered to detect an association. Ther …

12.1 Mechanism of Action Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibits binding of TNFα with its receptors. Infliximab does not neutralize TNFβ (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNFα. Biological activities attributed to TNFα include: induction of pro-inflammatory 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 can be lysed in vitro or in vivo . Infliximab inhibits 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 exerts its 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 prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allows eroded joints to heal.

11 DESCRIPTION Infliximab, 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 is produced by a recombinant murine myeloma cell line, SP2/0. Infliximab 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, dibasic sodium phosphate, dihydrate (6.1 mg), monobasic sodium phosphate, monohydrate (2.2 mg), polysorbate 80 (0.5 mg), and sucrose (500 mg).

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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Infliximab for injection is supplied in a carton containing one single-dose vial (NDC 57894-160-01). Each single-dose vial contains 100 mg of infliximab as a sterile, preservative-free, white lyophilized powder for reconstitution and dilution (more than one vial may be needed for a full dose) [see Dosage and Administration (2.11) ]. Storage and Handling Store unopened Infliximab vials in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F). If needed, unopened Infliximab vials may be stored at room temperatures up to a maximum of 30 °C (86 °F) for a single period of 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, Infliximab cannot be returned to the refrigerator. For storage conditions of the reconstituted and diluted product for administration, see Dosage and Administration (2.11) .

How Supplied Infliximab for injection is supplied in a carton containing one single-dose vial (NDC 57894-160-01). Each single-dose vial contains 100 mg of infliximab as a sterile, preservative-free, white lyophilized powder for reconstitution and dilution (more than one vial may be needed for a full dose) [see Dosage and Administration (2.11) ].