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.

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 patients and 13% of control patients were newly antinuclear antibody (ANA)-positive.

Of these patients, one SIMPONI ARIA-treated patient and no control-treated patients had newly positive anti-dsDNA antibodies [see Warnings and Precautions (5.5) ] .

Administration Reactions In the controlled phase of Trial RA through Week 24, 1.1% of SIMPONI ARIA infusions were associated with an infusion reaction compared with 0.2% of infusions in the control group.

The most common infusion reaction in SIMPONI ARIA-treated patients was rash.

No serious infusion reactions were reported.

Other Adverse Reactions Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the SIMPONI ARIA + MTX group with a higher incidence than in the placebo + MTX group during the controlled period of Trial RA through Week 24.

Table 1: Adverse Drug Reactions Reported by ≥ 1% of SIMPONI ARIA-Treated Patients and with a Higher Incidence than Placebo-Treated Patients in Trial RA through Week 24 Placebo + MTX SIMPONI ARIA + MTX Patients treated 197 463 Adverse Reaction Infections and infestations Upper respiratory tract infection (such as upper respiratory tract infection, nasopharyngitis, pharyngitis, laryngitis, and rhinitis) 12% 13% Viral infections (such as influenza and herpes) 3% 4% Bacterial infections 0% 1% Bronchitis 1% 3% Vascular disorders Hypertension 2% 3% Skin and subcutaneous disorders Rash 1% 3% General disorders and administration site conditions Pyrexia 1% 2% Blood and lymphatic disorders Leukopenia 0% 1% Other and Less Common Clinical Trial Adverse Drug Reactions Adverse drug reactions that do not appear in Table 1 or that occurred < 1% in SIMPONI ARIA-treated patients during Trial RA through Week 24 that do not appear in the Warnings and Precautions section included the following events listed by system organ class: Infections and infestations: Superficial fungal infection, sinusitis, abscess, lower respiratory tract infection (pneumonia), pyelonephritis Investigations: Alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, neutrophil count decreased Nervous system disorders: Dizziness, paresthesia Gastrointestinal disorders: Constipation Psoriatic Arthritis Trial PsA evaluated 480 patients [see Clinical Studies (14.2) ] .

The adverse reactions were similar to those observed in patients with RA, with the exception of psoriasis (new onset or worsening, palmar/plantar and pustular), which occurred in <1% of SIMPONI ARIA-treated patients.

The incidence of the adverse reactions reported in Trial PsA were similar to Trial RA with the exceptions of higher incidence in SIMPONI ARIA for ALT increased (7.9% vs.

2.1% in placebo), AST increased (5.4% vs.

2.1% in placebo), and neutrophil count decreased (4.6% vs.

2.1% in placebo).

Ankylosing Spondylitis Trial AS evaluated 208 patients [see Clinical Studies (14.3) ] .

The adverse reactions were similar to those reported in patients with RA, with the exception of the higher incidence of ALT increased, which occurred in 2.9% of SIMPONI ARIA-treated patients compared with none of the placebo-treated patients.

Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis Trial pJIA evaluated 127 patients with JIA with active polyarthritis [see Use in Specific Populations (8.4) and Clinical Studies (14.4) ].

The adverse reactions observed were consistent with the established safety profile of SIMPONI ARIA in adult patients with RA and PsA.

6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies to golimumab in the trials described below with the incidence of antibodies in other trials or to other products may be misleading.

Using an enzyme immunoassay (EIA) method, antibodies to golimumab were detected in 13 (3%) golimumab-treated patients following IV administration of SIMPONI ARIA in combination with MTX through Week 24 of Trial RA, of which all were neutralizing antibodies.

A drug-tolerant enzyme immunoassay (drug-tolerant EIA) method for detecting antibodies to golimumab was developed and validated.

This method is approximately 16-fold more sensitive than the original EIA method with less interference from golimumab in serum.

Through approximately 6 months, the incidence of antibodies to golimumab with the drug-tolerant EIA method for Trials RA, PsA, AS, and pJIA was 21%, 19%, 19% and 31%, respectively.

Where tested, approximately one-third to one-half were neutralizing.

Patients with RA, PsA, AS and pJIA who developed antibodies to golimumab generally had lower trough steady-state serum concentrations of golimumab [see Clinical Pharmacology (12.3) ].

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of golimumab.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to golimumab exposure: General Disorders and Administration Site Conditions: Infusion-related reactions [see Warnings and Precautions (5.11) ] Neoplasm benign and malignant : Melanoma, Merkel cell carcinoma [see Warnings and Precautions (5.2) ] Immune system disorders : Serious systemic hypersensitivity reactions (including anaphylactic reaction) [see Warnings and Precautions (5.11) ] , sarcoidosis Respiratory, thoracic and mediastinal disorders : Interstitial lung disease Skin and subcutaneous tissue disorders : Skin exfoliation, lichenoid reactions, bullous skin reactions