Golimumab

12.1 Mechanism of Action Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF). The clinical relevance of these findings is unknown.

1 INDICATIONS AND USAGE SIMPONI ARIA is a tumor necrosis factor (TNF) blocker indicated for the treatment of: Adult patients with moderately to severely active Rheumatoid Arthritis (RA) in combination with methotrexate ( 1.1 ) Active Psoriatic Arthritis (PsA) in patients 2 years of age and older ( 1.2 ) Adult patients with active Ankylosing Spondylitis (AS) ( 1.3 ) Active polyarticular Juvenile Idiopathic Arthritis (pJIA) in patients 2 years of age and older ( 1.4 ) 1.1 Rheumatoid Arthritis (RA) SIMPONI ARIA, in combination with methotrexate (MTX), is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. 1.2 Psoriatic Arthritis (PsA) SIMPONI ARIA is indicated for the treatment of active psoriatic arthritis in patients 2 years of age and older. 1.3 Ankylosing Spondylitis (AS) SIMPONI ARIA is indicated for the treatment of adult patients with active ankylosing spondylitis. 1.4 Polyarticular Juvenile Idiopathic Arthritis (pJIA) SIMPONI ARIA is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older.

2 DOSAGE AND ADMINISTRATION Adult patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: 2 mg/kg intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter ( 2.1 ) Pediatric patients with polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis: 80 mg/m 2 intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter ( 2.2 ) Dilution of supplied SIMPONI ARIA solution with 0.9% Sodium Chloride Injection, USP is required prior to administration. Alternatively, 0.45% Sodium Chloride Injection, USP can also be used ( 2.4 ) 2.1 Dosage in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The SIMPONI ARIA dosage regimen is 2 mg per kg given as an intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter. Follow the dilution and administration instructions for SIMPONI ARIA [see Dosage and Administration (2.4) ] . For patients with rheumatoid arthritis (RA), SIMPONI ARIA should be given in combination with methotrexate. The efficacy and safety of switching between intravenous and subcutaneous formulations and routes of administration have not been established. 2.2 Dosage in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis The SIMPONI ARIA dosage regimen, based on body surface area (BSA), is 80 mg/m 2 given as an intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter. Follow the dilution and administration instructions for SIMPONI ARIA [see Dosage and Administration (2.4) ] . 2.3 Evaluation for Tuberculosis and Hepatitis B Prior to Dosage Prior to initiating SIMPONI ARIA and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1) ] . Prior to initiating SIMPONI ARIA, test patients for hepatitis B viral infection [see Warnings and Precautions (5.1) ] . 2.4 Important Administration Instructions SIMPONI ARIA solution for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: Calculate the dosage and the number of SIMPONI ARIA vials needed based on the recommended adult dosage of 2 mg/kg and the patient's weight for RA, PsA and AS. Calculate the dosage and number of SIMPONI ARIA vials needed based on the recommended pediatric dosage of 80 mg/m 2 and the patient's body surface area (BSA), for pJIA and pediatric patients with PsA. Each 4 mL vial of SIMPONI ARIA contains 50 mg of golimumab. Check that the solution in each vial is colorless to light yellow. The solution may develop a few fine translucent particles, as golimumab is a protein. Do not use if opaque particles, discoloration, or other foreign particles are present. Dilute the total volume of the SIMPONI ARIA solution with 0.9% Sodium Chloride Injection, USP to a final volume of 100 mL. For example, this can be accomplished by withdrawing a volume of the 0.9% Sodium Chloride Injection, USP from the 100-mL infusion bag or bottle equal to the total volume of SIMPONI ARIA. Slowly add the total volume of SIMPONI ARIA solution to the 100-mL infusion bag or bottle. Gently mix. Discard any unused solution remaining in the vials. Alternatively, SIMPONI ARIA can be diluted using the same method described above with 0.45% Sodium Chloride Injection, USP. Prior to infusion, visually inspect the diluted SIMPONI ARIA solution for particulate matter or discoloration. Do not use if these are present. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.22 micrometer or less). Do not infuse SIMPONI ARIA concomitantly in the same intravenous line with other agents. No physical biochemical compatibility studies have been conducted to evaluate the use of SIMPONI ARIA with other intravenous agents in the same intravenous line. Infuse the diluted solution over 30 minutes. Once diluted, the infusion solution can be stored for up to 4 hours at room temperature.

6 ADVERSE REACTIONS The most serious adverse reactions were: Serious Infections [see Warnings and Precautions (5.1) ] Malignancies [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥ 3%) are: upper respiratory tract infection, alanine aminotransferase increased, viral infection, aspartate aminotransferase increased, neutrophil count decreased, bronchitis, hypertension, and rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (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 clinical practice. The safety data described below are based on one, randomized, double-blind, controlled Phase 3 trial in patients with RA receiving SIMPONI ARIA by intravenous infusion (Trial RA). The protocol included provisions for patients taking placebo to receive treatment with SIMPONI ARIA at Week 16 or Week 24 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Comparisons between placebo and SIMPONI ARIA were based on the first 24 weeks of exposure. Trial RA included 197 control-treated patients and 463 SIMPONI ARIA-treated patients (which includes control-treated patients who switched to SIMPONI ARIA at Week 16). The proportion of patients who discontinued treatment due to adverse reactions in the controlled phase of Trial RA through Week 24 was 3.5% for SIMPONI ARIA-treated patients and 0.5% for placebo-treated patients. Upper respiratory tract infection was the most common adverse reaction reported in the trial through Week 24 occurring in 6.5% of SIMPONI ARIA-treated patients as compared with 7.6% of control-treated patients, respectively. Infections Serious infections observed in SIMPONI ARIA-treated patients included sepsis, pneumonia, cellulitis, abscess, opportunistic infections, tuberculosis (TB), and invasive fungal infections. Cases of TB included pulmonary and extrapulmonary TB. The majority of the TB cases occurred in countries with a high incidence rate of TB [see Warnings and Precautions (5.1) ] . In the controlled phase of Trial RA through Week 24, infections were observed in 27% of SIMPONI ARIA-treated patients compared with 24% of control-treated patients, and serious infections were observed in 0.9% of SIMPONI ARIA-treated patients and 0.0% of control-treated patients. Through Week 24, the incidence of serious infections per 100 patient-years of follow-up was 2.2 (95% CI 0.61, 5.71) for the SIMPONI ARIA group, and 0 (0.00, 3.79) for the placebo group. In the controlled and uncontrolled portions of Trial RA, 958 total patient-years of follow-up with a median follow-up of approximately 92 weeks, the incidence per 100 patient-years of all serious infections was 4.07 (95% CI: 2.90, 5.57) in patients receiving SIMPONI ARIA [see Warnings and Precautions (5.1) ] . In the controlled and uncontrolled portions of Trial RA, in SIMPONI ARIA-treated patients, the incidence of active TB per 100 patient-years was 0.31 (95% CI: 0.06; 0.92) and the incidence of other opportunistic infections per 100 patient-years was 0.42 (95% CI: 0.11, 1.07). Malignancies One case of malignancy other than lymphoma and NMSC with SIMPONI ARIA was reported through Week 24 during the controlled phase of Trial RA. In the controlled and uncontrolled portions through approximately 92 weeks, the incidence of malignancies per 100 patient-years, other than lymphoma and NMSC, in SIMPONI ARIA-treated patients was 0.31 (95% CI: 0.06, 0.92) and the incidence of NMSC was 0.1 (95% CI: 0.00, 0.58). Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In the controlled phase of Trial RA, through Week 24, ALT elevations ≥ 5 × ULN occurred in 0.8% of SIMPONI ARIA-treated patients and 0% of control-treated patients and ALT elevations ≥ 3 × ULN occurred in 2.3% of SIMPONI ARIA-treated patients and 2.5% of control-treated patients. In the controlled phase of Trial PsA, through Week 24, ALT elevations ≥ 5 × ULN occurred in 1.7% of SIMPONI ARIA-treated patients and <1% of placebo-treated patients, and ALT elevations ≥ 3 × ULN to < 5 × ULN occurred in 2.9% of SIMPONI ARIA-treated patients and <1% of placebo-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], MTX, or isoniazid prophylaxis), the relationship between SIMPONI ARIA and liver enzyme elevation is not clear. Autoimmune Disorders and Autoantibodies At Week 20 in Trial RA, 17% of SIMPONI ARIA-treated patien

7 DRUG INTERACTIONS Biologics, including abatacept and anakinra: Increased risk of serious infections ( 5.1 , 5.6 , 5.7 , 5.8 , 7.2 ). Live vaccines should not be given with SIMPONI ARIA ( 5.10 , 7.3 ). 7.1 Methotrexate SIMPONI ARIA should be used with MTX for the treatment of RA [see Clinical Studies (14.1) ] . Following IV administration, concomitant administration of methotrexate decreases the clearance of SIMPONI ARIA by approximately 9% based on population pharmacokinetics (PK) analysis. In addition, concomitant administration of methotrexate decreases the SIMPONI ARIA clearance by reducing the development of antibodies to golimumab. 7.2 Biologic Products for RA, PsA, AS, and pJIA An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI ARIA with other biologic products, including abatacept or anakinra, is not recommended [see Warnings and Precautions (5.6 and 5.7) ] . A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. The concomitant use of SIMPONI ARIA with biologics approved to treat RA, PsA, AS, and pJIA is not recommended because of the possibility of an increased risk of infection. 7.3 Live Vaccines/Therapeutic Infectious Agents Live vaccines should not be given concurrently with SIMPONI ARIA [see Warnings and Precautions (5.10) ] . Therapeutic infectious agents should not be given concurrently with SIMPONI ARIA [see Warnings and Precautions (5.10) ] . Infants born to women treated with SIMPONI ARIA during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI ARIA in utero is not recommended for 6 months following the mother's last SIMPONI ARIA infusion during pregnancy [see Warnings and Precautions (5.10) , Use in Specific Populations (8.1) ] . 7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI ARIA 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.