Simponi

1 INDICATIONS AND USAGE SIMPONI 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 ) adult patients with active psoriatic arthritis (PsA) alone, or in combination with methotrexate ( 1.2 ) adult patients with active ankylosing spondylitis (AS) ( 1.3 ) adult and pediatric patients weighing at least 15 kg with moderately to severely active ulcerative colitis (UC) ( 1.4 ) 1.1 Rheumatoid Arthritis SIMPONI, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. 1.2 Psoriatic Arthritis SIMPONI, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis. 1.3 Ankylosing Spondylitis SIMPONI is indicated for the treatment of adult patients with active ankylosing spondylitis. 1.4 Ulcerative Colitis SIMPONI is indicated for the treatment of adults and pediatric patients weighing at least 15 kg with moderately to severely active ulcerative colitis .

2 DOSAGE AND ADMINISTRATION RA, PsA, and AS : 50 mg administered by subcutaneous injection once a month ( 2.2 ) UC : The recommended dosage and administration by subcutaneous injection in adults and pediatric patients weighing at least 15 kg is shown in the table ( 2.3 ) Recommended Dosage Weight for Patients with UC Week 0 Week 2 Week 6 and every 4 weeks thereafter Adults and pediatric patients 40 kg and greater For pediatric patients weighing 15 kg or greater, administer the appropriate dose using the prefilled syringe (50 mg/0.5 mL or 100 mg/mL). 200 mg 100 mg 100 mg Pediatric patients at least 15 kg to less than 40 kg 100 mg 50 mg 50 mg 2.1 Recommended Evaluations and Immunizations Before Initiating SIMPONI Prior to initiating treatment with SIMPONI: Evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1) ]. Test patients for hepatitis B viral infection. If possible, complete all age-appropriate vaccinations according to current immunization guidelines [see Warnings and Precautions (5.11) ] . 2.2 Recommended Dosage for Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis The recommended SIMPONI dosage in adults is 50 mg administered by subcutaneous injection once a month. For patients with rheumatoid arthritis (RA), SIMPONI should be given in combination with methotrexate and for patients with psoriatic arthritis (PsA) or ankylosing spondylitis (AS), SIMPONI may be given with or without methotrexate or other nonbiologic Disease-Modifying Antirheumatic Drugs (DMARDs). For patients with RA, PsA, or AS, corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with SIMPONI. 2.3 Recommended Dosage for Moderately to Severely Active Ulcerative Colitis in Adults and Pediatric Patients Weighing at least 15 kg The recommended dosage is shown in Table 1. Table 1: Recommended Subcutaneous Dosage for Adults and Pediatric Patients Weighing at least 15 kg with Moderately to Severely Active Ulcerative Colitis Weight for Patients with UC Recommended Dosage of SIMPONI Week 0 Week 2 Week 6 and every 4 weeks thereafter Adults and pediatric patients 40 kg and greater For pediatric patients weighing 15 kg or greater, administer the appropriate dose using the prefilled syringe (50 mg/0.5 mL or 100 mg/mL). 200 mg 100 mg 100 mg Pediatric patients at least 15 kg to less than 40 kg 100 mg 50 mg 50 mg 2.4 Preparation and Administration Instructions SIMPONI is intended for use under the guidance and supervision of a healthcare provider after proper training in subcutaneous injection technique. Patients may self-inject with SIMPONI if a physician determines that it is appropriate. Instruct patients to follow the directions provided in the Instructions for Use. SIMPONI Prefilled Syringe Adult and pediatric patients 12 years of age and older may self-inject with SIMPONI prefilled syringe. SIMPONI SmartJect ® Autoinjector Adult patients may self-inject with SIMPONI SmartJect ® autoinjector. Use of the SmartJect ® autoinjector for pediatric self-administration has not been evaluated. • To ensure proper use, allow the prefilled syringe or autoinjector to sit at room temperature outside the carton for at least 30 minutes prior to subcutaneous injection. Do not warm SIMPONI in any other way. • Prior to administration, visually inspect the solution for particles and discoloration through the viewing window. SIMPONI is clear to slightly opalescent and colorless to light yellow. Do not use SIMPONI, if the solution is discolored, or cloudy, or if foreign particles are present. • Do not use any leftover product remaining in the prefilled syringe or prefilled autoinjector. • Instruct patients sensitive to latex not to handle the needle cover on the prefilled syringe or the needle cover of the prefilled syringe within the autoinjector cap because it contains dry natural rubber (a derivative of latex). • At the time of dosing, if multiple injections are required, administer …

5 WARNINGS AND PRECAUTIONS Serious Infections: Do not start SIMPONI during an active infection. If an infection develops, monitor carefully, and stop SIMPONI if infection becomes serious ( 5.1 ) Invasive Fungal Infections: For patients who develop a systemic illness on SIMPONI, consider empiric antifungal therapy for those who reside in or travel to regions where mycoses are endemic ( 5.1 ) Malignancies: Incidence of lymphoma was greater than in the general U.S. population. Cases of other malignancies have been observed among patients receiving TNF blockers ( 5.2 ) Congestive Heart Failure: Worsening, or new onset, may occur. Stop SIMPONI if new or worsening symptoms occur ( 5.3 ) Demyelinating Disorders: Exacerbation or new onset may occur ( 5.4 ) Hepatitis B Reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop SIMPONI and begin antiviral therapy ( 5.5 ) Lupus-like Syndrome: Discontinue SIMPONI if symptoms develop ( 5.6 ) Hypersensitivity Reactions: Serious systemic hypersensitivity reactions including anaphylaxis may occur ( 5.12 ) 5.1 Serious Infections Patients treated with SIMPONI 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, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI and these biologic products is not recommended [see Warnings and Precautions (5.6 , 5.7) and Drug Interactions (7.2) ] . Treatment with SIMPONI should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating SIMPONI 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. Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI. Discontinue SIMPONI if a patient develops a serious infection, an opportunistic infection, or sepsis. For a patient who develops a new infection during treatment with SIMPONI, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor them. Serious Infection in Clinical Trials In controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, serious infections were observed in 1.4% of SIMPONI-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.7 (95% CI: 3.8, 8.2) for the SIMPONI group and 4.2 (95% CI: 1.8, 8.2) for the placebo group. In the controlled Phase 2/3 trial through Week 6 of SIMPONI induction in UC, the incidence of serious infections in SIMPONI 200/100 mg-treated patients was similar to the incidence of serious infections in placebo-treated patients. Through Week 60, the incidence of serious infections was similar in patients who received SIMPONI in…

4 CONTRAINDICATIONS None. None ( 4 )

7 DRUG INTERACTIONS Abatacept: Increased risk of serious infection ( 5.1 , 5.7 , 7.2 ) Anakinra: Increased risk of serious infection ( 5.1 , 5.8 , 7.2 ) Live vaccines/therapeutic infectious agents: Avoid use with SIMPONI ( 5.11 , 7.3 ). 7.1 Methotrexate For the treatment of RA, SIMPONI should be used with methotrexate (MTX) [see Clinical Studies (14.1) ] . Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of SIMPONI in the treatment of PsA or AS, SIMPONI can be used with or without MTX in the treatment of PsA and AS [see Clinical Studies (14.2 , 14.3) and Clinical Pharmacology (12.3) ] . 7.2 Biological Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA trials of other TNF blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI with abatacept or anakinra is not recommended [see Warnings and Precautions (5.7 , 5.8) ] . 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 with biologics approved to treat RA, PsA, or AS 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 [see Warnings and Precautions (5.11) ] . Therapeutic infectious agents should not be given concurrently with SIMPONI [see Warnings and Precautions (5.11) ] . Infants born to women treated with SIMPONI during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI in utero is not recommended for 6 months following the mother's last SIMPONI injection during pregnancy [see 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 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.

8.1 Pregnancy Risk Summary Available data from postmarketing case reports with golimumab use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. An observational study of northern European births observed similar unadjusted rates of major birth defects in infants exposed in utero to golimumab compared to no treatment or non-biologic systemic therapy. However, this study had important limitations (see Data ) . Monoclonal antibodies, such as golimumab, are transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ) . In an animal reproductive study, golimumab administered by the subcutaneous route to pregnant monkeys, during the period of organogenesis, at doses that produced exposures approximately 360 times the maximum recommended human dose (MRHD) had no adverse fetal effects (see Data ) . In a pre- and post-natal development study with pregnant monkeys, subcutaneous administration of golimumab, during the later gestational and lactation periods, at doses producing maximal maternal blood concentrations approximately 460 times those found with the MRHD had no adverse developmental effects on infants (see Data ) . Data suggest that there are risks to the mother and the fetus associated with rheumatoid arthritis and ulcerative colitis in pregnancy (see Clinical Considerations ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The 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 of miscarriage is 15–20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Golimumab crosses the placenta during pregnancy. Another TNF-blocking monoclonal antibody administered during pregnancy was detected for up to 6 months in the serum of infants. Consequently, these infants may be at increased risk of infection. Administration of live vaccines to infants exposed to SIMPONI in utero is not recommended for 6 months following the mother's last SIMPONI injection during pregnancy [see Warnings and Precautions (5.11) and Drug Interactions (7.3) ] . Data Human Data An observational, exposure-based, cohort study based on data from the Swedish, Danish, and Finnish Medical Birth Registers conducted between 2006–2020 (Sweden and Denmark) and 2006–2019 (Finland) compared the risk of major birth defects in 134 live-born infants exposed to golimumab (116 from women treated for rheumatic conditions, 18 from women treated for ulcerative colitis) to no treatment or non-biologic systemic therapy. The unadjusted rate of major birth defects in infants exposed in utero was similar across all groups. However, this study had important limitations such as a small number of pregnant women exposed to golimumab, a wide exposure ascertainment window, and incomplete risk adjustment for potential confounders. Animal Data In an embryofetal developmental toxicology study in which pregnant cynomolgus monkeys were treated with golimumab during the period organogenesis from gestation days (GD) 20 to 51, exposures up to 360 times greater than the exposure at the MRHD (on an area under the curve (AUC) basis with maternal subcutaneous doses up to 50 mg/kg twice weekly) produced no evidence of fetal malformations or embryotoxicity. There was no eviden…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions (5.1) ] Malignancies [see Warnings and Precautions (5.2) ] Congestive Heart Failure [see Warnings and Precautions (5.3) ] Demyelinating Disorders [see Warnings and Precautions (5.4) ] Hepatitis B Reactivation [see Warnings and Precautions (5.5) ] Autoimmunity [see Warnings and Precautions (5.6) ] Hematologic Cytopenias [see Warnings and Precautions (5.10) ] Hypersensitivity Reactions [see Warnings and Precautions (5.12) ] Most common adverse reactions in adults (incidence > 5%) are upper respiratory tract infection, nasopharyngitis, injection site reactions ( 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: Five pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Trials RA-1, RA-2, RA-3, PsA, and AS) [see Clinical Studies (14.1 , 14.2 , and 14.3) ] . These 5 trials included 639 control-treated patients and 1659 SIMPONI-treated patients including 1089 with RA, 292 with PsA, and 278 with AS. Three pooled, randomized, double-blind, controlled Phase 2/3 in 1233 SIMPONI-treated adult patients with UC (Trials UC-1, UC-2, and UC-3 (NCT03596645)) [see Clinical Studies (14.4) ] . An open-label trial in 69 SIMPONI-treated pediatric patients weighing at least 15 kg with UC (Trial UC-3) (NCT03596645) [see Clinical Studies (14.5) ] . The proportion of adult patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for SIMPONI-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of SIMPONI in the controlled Phase 3 trials in RA, PsA and AS through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most common adverse drug reactions leading to discontinuation through Week 60 of the UC trials in adult patients who received SIMPONI induction and 100 mg during maintenance compared with patients who received SIMPONI induction and placebo during maintenance were tuberculosis (0.3% vs. 0.6%) and anemia (0.3% vs. 0%), respectively. Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials in adults through Week 16, occurring in 7% and 6% of SIMPONI-treated patients as compared with 6% and 5% of control-treated patients, respectively. Infections In adult controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of SIMPONI-treated patients compared to 25% of control-treated patients. For serious infections, see the Warnings and Precautions section [see Warnings and Precautions (5.1) ] . In Trial UC-1, the rates of infections were similar in SIMPONI 200/100 mg-treated patients and placebo-treated patients, or approximately 12%. Through Week 60, the incidence per patient year of infections was similar in patients who received SIMPONI induction and 100 mg during maintenance compared with patients who received SIMPONI induction and placebo during the maintenance period Trial UC-2. Demyelinating Disorders In Trial UC-1 of SIMPONI induction through Week 6, no cases of demyelination were observed in SIMPONI 200/100 mg-treated patients or placebo-treated patients. Through Week 60 in Trial UC-2, there were no cases of demyelination in the SIMPONI 100 mg group during mainten…