These highlights do not include all the information needed to use SIMPONI (golimumab) safely and effectively. See full prescribing information for SIMPONI. SIMPONI (golimumab)Injection, solution for subcutaneous useInitial U.S. Approval: 2009

SIMPONI - golimumab injection, solution 
Centocor Ortho Biotech Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SIMPONI (golimumab) safely and effectively. See full prescribing information for SIMPONI.
 
SIMPONI (golimumab)
Injection, solution for subcutaneous use
Initial U.S. Approval: 2009


WARNINGS:

SERIOUS INFECTIONS

See full prescribing information for complete boxed warning

  • Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal, and other opportunistic infections have occurred in patients receiving SIMPONI (5.1).
  • SIMPONI should be discontinued if a patient develops a serious infection or sepsis (5.1).
  • Perform test for latent TB; if positive, start treatment for TB prior to starting SIMPONI (5.1).
  • Monitor all patients for active TB during treatment, even if initial latent TB test is negative (5.1)

MALIGNANCY

  • Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI is a member (5.2)

RECENT MAJOR CHANGES

Boxed Warning, MALIGNANCY11/2009
Warnings and Precautions, Malignancies (5.2)11/2009

INDICATIONS AND USAGE

SIMPONI is a tumor necrosis factor (TNF) blocker indicated for the treatment of:

  • Moderately to severely active Rheumatoid Arthritis (RA) in adults, in combination with methotrexate (1.1)
  • Active Psoriatic Arthritis (PsA) in adults, alone or in combination with methotrexate (1.2)
  • Active Ankylosing Spondylitis in adults (AS) (1.3)

DOSAGE AND ADMINISTRATION

Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis (2.1)

  • 50 mg administered by subcutaneous injection once a month.

DOSAGE FORMS AND STRENGTHS

  • 50 mg/0.5 mL in a single dose prefilled SmartJect autoinjector (3)
  • 50 mg/0.5 mL in a single dose prefilled syringe (3)

CONTRAINDICATIONS

  • None (4)

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 or travel to regions where mycoses are endemic (5.1).
  • Hepatitis B reactivation – Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop SIMPONI and begin anti-viral therapy (5.1).
  • Malignancies – The incidence of lymphoma was seen more often than in the general U.S. population. Cases of other malignancies have been observed among patients receiving TNF-blockers (5.2).
  • Heart failure – Worsening, or new onset, may occur. Stop SIMPONI if new or worsening symptoms occur (5.3).
  • Demyelinating disease, exacerbation or new onset, may occur (5.4).

ADVERSE REACTIONS

Most common adverse reactions (incidence > 5%): upper respiratory tract infection, nasopharyngitis (6.1).


To report SUSPECTED ADVERSE REACTIONS, contact Centocor Ortho Biotech Inc. at 1-800-457-6399 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


DRUG INTERACTIONS

  • Abatacept – increased risk of serious infection (5.1, 5.5, 7.2)
  • Anakinra – increased risk of serious infection (5.1, 5.6, 7.2).
  • Live vaccines – should not be given with SIMPONI (5.8, 7.3).


See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide

Revised: 11/2009

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

WARNINGS

1.0 INDICATIONS AND USAGE

1.1 Rheumatoid Arthritis

1.2 Psoriatic Arthritis

1.3 Ankylosing Spondylitis

2.0 DOSAGE AND ADMINISTRATION

2.1 Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

2.2 Monitoring to Assess Safety

2.3 General Considerations for Administration

3.0 DOSAGE FORMS AND STRENGTHS

4.0 CONTRAINDICATIONS

5.0 WARNINGS AND PRECAUTIONS

5.1 Serious Infections

5.2 Malignancies

5.3 Congestive Heart Failure

5.4 Demyelinating Disorders

5.5 Use with Abatacept

5.6 Use with Anakinra

5.7 Hematologic Cytopenias

5.8 Vaccinations

6.0 ADVERSE REACTIONS

6.1 Clinical Studies Experience

7.0 DRUG INTERACTIONS

7.1 Methotrexate

7.2 Biologic Products for RA, PsA, and/or AS

7.3 Live Vaccines

7.4 Cytochrome P450 Substrates

8.0 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10.0 OVERDOSAGE

11.0 DESCRIPTION

12.0 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.0 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.0 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

14.2 Psoriatic Arthritis

14.3 Ankylosing Spondylitis

15.0 REFERENCES

16.0 HOW SUPPLIED/STORAGE AND HANDLING

17.0 PATIENT COUNSELING INFORMATION

17.1 Patient Counseling

17.2 Instruction on Injection Technique

17.3 Medication Guide


FULL PRESCRIBING INFORMATION

WARNINGS

SERIOUS INFECTIONS

Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

SIMPONI should be discontinued if a patient develops a serious infection.

Reported infections include:

The risks and benefits of treatment with SIMPONI should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warning and Precautions (5.1)].

MALIGNANCY

 Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI is a member [see Warning and Precautions (5.2)].

1.0 INDICATIONS AND USAGE

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.

2.0 DOSAGE AND ADMINISTRATION

2.1 Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

The SIMPONI dose regimen is 50 mg administered by subcutaneous (SC) 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 non-biologic DMARDs. For patients with RA, PsA, or AS, corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with SIMPONI.

2.2 Monitoring to Assess Safety

Prior to initiating SIMPONI and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection [see Warnings and Precautions (5.1)].

2.3 General Considerations for Administration

SIMPONI is intended for use under the guidance and supervision of a physician. After proper training in subcutaneous injection technique, a patient may self inject with SIMPONI if a physician determines that it is appropriate. Patients should be instructed to follow the directions provided in the Medication Guide [see Medication Guide (17.3)]. To ensure proper use, allow the prefilled syringe or autoinjector to sit at room temperature outside the carton for 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 should be clear to slightly opalescent and colorless to light yellow. The solution should not be used if discolored, or cloudy, or if foreign particles are present. Any leftover product remaining in the prefilled syringe or prefilled autoinjector should not be used. NOTE: The needle cover on the prefilled syringe as well as the prefilled syringe in the autoinjector contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

3.0 DOSAGE FORMS AND STRENGTHS

SmartJect™ Autoinjector

Each single dose SmartJect autoinjector contains a prefilled glass syringe (27 gauge ½ inch) providing 50 mg of SIMPONI per 0.5 mL of solution.

Prefilled Syringe

Each single dose prefilled glass syringe (27 gauge ½ inch) contains 50 mg of SIMPONI per 0.5 mL of solution.

4.0 CONTRAINDICATIONS

None.

5.0 WARNINGS AND PRECAUTIONS

(see Boxed WARNINGS)

5.1 Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving TNF-blockers including SIMPONI. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. 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 Warning and Precautions (5.5, 5.6) and Drug Interactions (7.2)].

Treatment with SIMPONI should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating SIMPONI in patients:

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI. SIMPONI should be discontinued if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with SIMPONI should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

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 5.4 (95% CI: 4.0, 7.2) for the SIMPONI group and 5.3 (95% CI: 3.1, 8.7) for the placebo group. Serious infections observed in SIMPONI-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection.

Tuberculosis

Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating SIMPONI and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating SIMPONI, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).

Anti-tuberculosis therapy should also be considered prior to initiation of SIMPONI in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Tuberculosis should be strongly considered in patients who develop a new infection during SIMPONI treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 SIMPONI-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occurred in countries with a high incidence rate of TB.

Invasive Fungal Infections

For SIMPONI-treated patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Hepatitis B Virus Reactivation

The use of TNF-blockers including SIMPONI has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.

In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely.

5.2 Malignancies

 Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which SIMPONI is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.

The risks and benefits of TNF-blocker treatment including SIMPONI should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy.

In the controlled portions of clinical trials of TNF-blockers including SIMPONI, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 SIMPONI-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.  Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined SIMPONI group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in SIMPONI-treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1

In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener's granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of SIMPONI in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the SIMPONI groups compared to none in the control group. Three of the 6 patients were in the 200 mg SIMPONI group.

5.3 Congestive Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI has not been studied in patients with a history of CHF and SIMPONI should be used with caution in patients with CHF. If a decision is made to administer SIMPONI to patients with CHF, these patients should be closely monitored during therapy, and SIMPONI should be discontinued if new or worsening symptoms of CHF appear.

5.4 Demyelinating Disorders

Use of TNF-blockers has been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). While no trials have been performed evaluating SIMPONI in the treatment of patients with MS, another TNF-blocker was associated with increased disease activity in patients with MS. Therefore, prescribers should exercise caution in considering the use of TNF-blockers including SIMPONI in patients with CNS demyelinating disorders including MS.

5.5 Use with Abatacept

In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI and abatacept is not recommended [see Drug Interactions (7.2)].

5.6 Use with Anakinra

Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI, is not recommended [see Drug Interactions 7.2].

5.7 Hematologic Cytopenias

There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Although, there were no cases of severe cytopenias seen in the SIMPONI clinical trials, caution should be exercised when using TNF-blockers, including SIMPONI, in patients who have significant cytopenias.

5.8 Vaccinations

Patients treated with SIMPONI may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination or the risk of infection, or transmission of infection after the administration of live vaccines to patients receiving SIMPONI. In the Phase 3 PsA study, after pneumococcal vaccination, a similar proportion of SIMPONI-treated and placebo-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both SIMPONI-treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that SIMPONI does not suppress the humoral immune response to the pneumococcal vaccine.

6.0 ADVERSE REACTIONS

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.

6.1 Clinical Studies Experience

The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Studies 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. The proportion of 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 through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%).

The most serious adverse reactions were:

Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials 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 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 Warnings and Precautions (5.1)].

Liver Enzyme Elevations

There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI in patients with RA, PsA, and AS through Week 16, ALT elevations ≥ 5 × ULN occurred in 0.2% of control-treated patients and 0.7% of SIMPONI-treated patients and ALT elevations ≥ 3 × ULN occurred in 2% of control-treated patients and 2% of SIMPONI-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between golimumab and liver elevation is not clear.

Autoimmune Disorders and Autoantibodies

The use of TNF-blockers has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of SIMPONI treatment and the development of newly positive anti-dsDNA antibodies.

Injection Site Reactions

In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of SIMPONI-treated patients had injection site reactions compared with 2% of control-treated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, and AS, no patients treated with SIMPONI developed anaphylactic reactions.

Psoriasis: New-Onset and Exacerbations

Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, have been reported with the use of TNF-blockers, including SIMPONI. Cases of exacerbation of pre-existing psoriasis have also been reported with the use of TNF-blockers. Many of these patients were taking concomitant immunosuppressants (e.g., MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of SIMPONI should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Immunogenicity

Antibodies to SIMPONI were detected in 57 (4%) of SIMPONI-treated patients across the Phase 3 RA, PsA and AS trials through Week 24. Similar rates were observed in each of the three indications. Patients who received SIMPONI with concomitant MTX had a lower proportion of antibodies to SIMPONI than patients who received SIMPONI without MTX (approximately 2% versus 7%, respectively). Of the patients with a positive antibody response to SIMPONI in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to SIMPONI limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures.

The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI with the incidence of antibodies to other products may be misleading.

Other Adverse Reactions

Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the combined SIMPONI groups during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS.

Table 1. Adverse Drug Reactions Reported by ≥ 1% of Patients in the Phase 3 Trials of RA, PsA, and AS through Week 16*
Placebo ± DMARDsSIMPONI ± DMARDs
*
Patients may have taken concomitant MTX, sulfasalazine, hydroxychloroquine, low dose corticosteroids (≤ 10 mg of prednisone/day or equivalent), and/or NSAIDs during the trials).
Patients treated6391659
Adverse Reaction (Preferred Term)
Upper respiratory tract infection37 (6%)120 (7%)
Nasopharyngitis31 (5%)91 (6%)
Alanine aminotransferase increased18 (3%)58 (4%)
Injection site erythema6 (1%)56 (3%)
Hypertension9 (1%)48 (3%)
Aspartate aminotransferase increased10 (2%)44 (3%)
Bronchitis9 (1%)31 (2%)
Dizziness7 (1%)32 (2%)
Sinusitis 7 (1%)27 (2%)
Influenza 7 (1%)25 (2%)
Pharyngitis 8 (1%)22 (1%)
Rhinitis 4 (< 1%)20 (1%)
Pyrexia4 (< 1%)20 (1%)
Oral herpes 2 (< 1%)16 (1%)
Paraesthesia2 (< 1%)16 (1%)

7.0 DRUG INTERACTIONS

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 (14.1) and Clinical Pharmacology (12.3)].

7.2 Biologic Products for RA, PsA, and/or AS

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 with abatacept or anakinra is not recommended [see Warnings and Precautions (5.5 and 5.6)]. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information to provide recommendations regarding the concomitant use of SIMPONI and other biologic products approved to treat RA, PsA, or AS.

7.3 Live Vaccines

Live vaccines should not be given concurrently with SIMPONI [see Warnings and Precautions (5.8)].

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.

8.0 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI should be used during pregnancy only if clearly needed.

An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus.

A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants.

8.3 Nursing Mothers

It is not known whether SIMPONI is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SIMPONI, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations.

8.4 Pediatric Use

Safety and effectiveness of SIMPONI in pediatric patients less than 18 years of age have not been established.

8.5 Geriatric Use

In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in SIMPONI-treated patients ages 65 or older (N = 155) compared with younger SIMPONI-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI.

10.0 OVERDOSAGE

In a clinical study, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of SIMPONI. There were no SIMPONI overdoses in the clinical studies.

11.0 DESCRIPTION

SIMPONI (golimumab) is a human IgG1қ monoclonal antibody specific for human tumor necrosis factor alpha (TNFα) that exhibits multiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. SIMPONI was created using genetically engineered mice immunized with human TNF, resulting in an antibody with human-derived antibody variable and constant regions. SIMPONI is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.

The SIMPONI drug product is a sterile solution of the golimumab antibody supplied as either a single dose prefilled syringe (with a passive needle safety guard) or a single dose prefilled autoinjector. The Type 1 glass syringe has a coated stopper. The fixed stainless steel needle (5 bevel, 27G, half-inch) is covered with a needle shield to prevent leakage of the solution through the needle and to protect the needle during handling prior to administration. The needle shield is made of a dry natural rubber containing latex.

SIMPONI does not contain preservatives. The solution is clear to slightly opalescent, colorless to light yellow with a pH of approximately 5.5. SIMPONI is provided in one strength: 50 mg of the golimumab antibody in 0.5 mL of solution. Each 0.5 mL of SIMPONI contains 50 mg of the golimumab antibody, 0.44 mg of L-histidine and L-histidine monohydrochloride monohydrate, 20.5 mg of sorbitol, 0.08 mg of polysorbate 80, and Water for Injection.

12.0 CLINICAL PHARMACOLOGY

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).

12.2 Pharmacodynamics

In clinical studies, decreases in C-reactive protein (CRP), interleukin (IL)-6, matrix metalloproteinase 3 (MMP-3), intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were observed following SIMPONI administration in patients with RA, PsA, and AS.

12.3 Pharmacokinetics

Following subcutaneous (SC) administration of SIMPONI to healthy subjects and patients with active RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A SC injection of 50 mg SIMPONI to healthy subjects produced a mean maximum serum concentration (Cmax) of approximately 2.5 µg/mL. SIMPONI exhibited dose-proportional pharmacokinetics (PK) in patients with active RA over the dose range of 0.1 to 10.0 mg/kg following a single intravenous (IV) dose. Following a single IV administration over the same dose range in patients with active RA, mean systemic clearance of SIMPONI was estimated to be 4.9 to 6.7 mL/day/kg, and mean volume of distribution ranged from 58 to 126 mL/kg. The volume of distribution for SIMPONI indicates that SIMPONI is distributed primarily in the circulatory system with limited extravascular distribution. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with active RA, PsA or AS. By cross-study comparisons of mean AUCinf values following an IV or SC administration of SIMPONI, the absolute bioavailability of SC SIMPONI was estimated to be approximately 53%.

When 50 mg SIMPONI was administered SC to patients with RA, PsA or AS every 4 weeks, serum concentrations appeared to reach steady state by Week 12. With concomitant use of methotrexate (MTX), treatment with 50 mg SIMPONI SC every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4–0.6 µg/mL in patients with active RA, approximately 0.5 µg/mL in patients with active PsA, and approximately 0.8 µg/mL in patients with active AS. Patients with RA, PsA and AS treated with SIMPONI 50 mg and MTX had approximately 52%, 36% and 21% higher mean steady-state trough concentrations of golimumab, respectively compared with those treated with SIMPONI 50 mg without MTX. The presence of MTX also decreased anti-golimumab antibody incidence from 7% to 2% [see Adverse Reactions (6.1)]. For RA, SIMPONI should be used with MTX. In the PsA and AS trials, the presence or absence of concomitant MTX did not appear to influence clinical efficacy and safety parameters [see Drug Interactions (7.1) and Clinical Studies (14.1)].

Population PK analyses indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of SIMPONI.

Population PK analyses showed there was a trend toward higher apparent clearance of SIMPONI with increasing weight. However, across the PsA and AS populations, no meaningful differences in clinical efficacy were observed among the subgroups by weight quartile. The RA trial in MTX-experienced and TNF-blocker-naïve patients (Study RA-2) did show evidence of a reduction in clinical efficacy with increasing body weight, but this effect was observed for both tested doses of SIMPONI (50 mg and 100 mg). Therefore, there is no need to adjust the dosage of SIMPONI based on a patient's weight.

Population PK analyses suggested no PK differences between male and female patients after body weight adjustment in the RA and PsA trials. In the AS trial, female patients showed 13% higher apparent clearance than male patients after body weight adjustment. Subgroup analysis based on gender showed that both female and male patients achieved clinically significant response at the proposed clinical dose. Dosage adjustment based on gender is not needed.

Population PK analyses indicated that PK parameters of SIMPONI were not influenced by age in adult patients. Patients with age ≥ 65 years had apparent clearance of SIMPONI similar to patients with age < 65 years. No ethnicity-related PK differences were observed between Caucasians and Asians, and there were too few patients of other races to assess for PK differences.

Patients who developed anti-SIMPONI antibodies generally had lower steady-state serum trough concentrations of SIMPONI.

No formal study of the effect of renal or hepatic impairment on the PK of golimumab was conducted.

13.0 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies of golimumab have not been conducted to evaluate its carcinogenic potential. Mutagenicity studies have not been conducted with golimumab. A fertility study conducted in mice using an analogous anti-mouse TNFα antibody showed no impairment of fertility.

14.0 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

The efficacy and safety of SIMPONI were evaluated in 3 multicenter, randomized, double-blind, controlled trials (Studies RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least 3 months prior to administration of study agent. Patients were required to have at least 4 swollen and 4 tender joints. SIMPONI was administered subcutaneously at doses of 50 mg or 100 mg every 4 weeks. Double-blinded controlled efficacy data were collected and analyzed through Week 24. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials.

Study RA-1 evaluated 461 patients who were previously treated (at least 8 to 12 weeks prior to administration of study agent) with one or more doses of a biologic TNF-blocker without a serious adverse reaction. Patients may have discontinued the biologic TNF-blocker for a variety of reasons. Patients were randomized to receive placebo (n = 155), SIMPONI 50 mg (n = 153), or SIMPONI 100 mg (n = 153). Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

Study RA-2 evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with a biologic TNF-blocker. Patients were randomized to receive background MTX (n = 133), SIMPONI 50 mg + background MTX (n = 89), SIMPONI 100 mg + background MTX (n = 89), or SIMPONI 100 mg monotherapy (n = 133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.

Study RA-3 evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with a biologic TNF-blocker. Patients were randomized to receive MTX (n = 160), SIMPONI 50 mg + MTX (n = 159), SIMPONI 100 mg + MTX (n = 159), or SIMPONI 100 mg monotherapy (n = 159). For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.

The primary endpoint in Study RA-1 and Study RA-2 was the percentage of patients achieving an ACR 20 response at Week 14 and the primary endpoint in Study RA-3 was the percentage of patients achieving an ACR 50 response at Week 24.

In Studies RA-1, RA-2, and RA-3, the median duration of RA disease was 9.4, 5.7, and 1.2 years; and 99%, 75%, and 54% of the patients used at least one DMARD in the past, respectively. Approximately 77% and 57% of patients received concomitant NSAIDs and low dose corticosteroids, respectively, in the 3 pooled RA trials.

Clinical Response

In the 3 RA trials, a greater percentage of patients treated with the combination of SIMPONI and MTX achieved ACR responses at Week 14 (Studies RA-1 and RA-2) and Week 24 (Studies RA-1, RA-2, and RA-3) versus patients treated with the MTX alone. There was no clear evidence of improved ACR response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). In Studies RA-2 and RA-3, the SIMPONI monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. Table 2 shows the proportion of patients with the ACR response for the SIMPONI 50 mg and control groups in Studies RA-1, RA-2, and RA-3. In the subset of patients who received SIMPONI in combination with MTX in Study RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at week 14 were 40%, 18%, and 13%, respectively, in the SIMPONI 50 mg + MTX group (N = 103) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N = 107). Table 3 shows the percent improvement in the components of the ACR response criteria for the SIMPONI 50 mg + MTX and MTX groups in Study RA-2. The percent of patients achieving ACR 20 responses by visit for Study RA-2 is shown in Figure 1. ACR 20 responses were observed in 38% of patients in the SIMPONI 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 2. Studies RA-1, RA-2, and RA-3 Proportion of Patients with an ACR Response*
Study RA-1
Active RA previously treated with one or more doses of TNF-blockers
Study RA-2
Active RA, despite MTX
Study RA-3
Active RA, MTX Naïve
Placebo
±
DMARDs
SIMPONI
50 mg
±
DMARDs
Background MTXSIMPONI 50 mg + Background MTXMTXSIMPONI
50 mg
+
MTX
NA Not applicable, as data was not collected at Week 14 in Study RA-3.
*
Approximately 78% and 58% of the patients received concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and NSAIDs, respectively, during the 3 pooled RA trials.
DMARDs in Study RA-1 included MTX, HCQ, and/or SSZ (about 68%, 8%, and 5% of patients received MTX, HCQ,and SSZ, respectively).
N reflects randomized patients.
§
Not significantly different from MTX monotherapy.
N15515313389160159
ACR 20
Week 1418%35%33%55%NANA
Week 2417%34%28%60%49%62%
ACR 50
Week 146%16%10%35%NANA
Week 245%18%14%37%29%40%
ACR 70
Week 142%10%4%13%NANA
Week 243%12%5%20%16%24%§
Table 3. Study RA-2 — Median Percent Improvement from Baseline in the Individual ACR Components at Weeks 14*
Background MTXSIMPONI 50 mg +
Background MTX
Note: Baseline values are medians.
*
In Study RA-2, about 70% and 85% of patients received concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs during the trials, respectively.
N reflects randomized patients; actual number of patients evaluable for each endpoint may vary.
N13389
Number of swollen joints (0–66)
Baseline 1213
Week 1438%62%
Number of tender joints (0–68)
Baseline 2126
Week 1430%60%
Patient's assessment of pain (0–10)
Baseline 5.76.1
Week 1418%55%
Patient's global assessment of disease activity (0–10)
Baseline 5.36.0
Week 1415%45%
Physician's global assessment of disease activity (0–10)
Baseline 5.76.1
Week 1435%55%
HAQ score (0–3)
Baseline 1.251.38
Week 1410%29%
CRP (mg/dl)
Baseline 0.81.0
Week 142%44%
*
The same patients may not have responded at each timepoint.
Figure 1. Study RA - 2 – Percent of Patients Achieving ACR 20 Response by Visit: Randomized Patients*
Figure

Physical Function Response in Patients with RA

In Studies RA-1 and RA-2, the SIMPONI 50 mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.25 vs. 0.05 in RA-1, 0.47 vs. 0.13 in RA-2, respectively. Also in Studies RA-1 and RA-2, the SIMPONI 50 mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 44% vs. 28%, 65% vs. 35%, respectively.

14.2 Psoriatic Arthritis

The safety and efficacy of SIMPONI were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Study PsA). Patients in this study had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter. Previous treatment with a biologic TNF-blocker was not allowed. Patients were randomly assigned to placebo (n = 113), SIMPONI 50 mg (n = 146), or SIMPONI 100 mg (n = 146) given subcutaneously every 4 weeks. Patients were allowed to receive stable doses of concomitant MTX (≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24.

Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids.

Clinical Response in Patients with PsA

SIMPONI ± MTX, compared with placebo ± MTX, resulted in significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Study PsA (see Table 4). There was no clear evidence of improved ACR response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). ACR responses observed in the SIMPONI-treated groups were similar in patients receiving and not receiving concomitant MTX. Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes. However, the number of patients with arthritis mutilans was too small to allow meaningful assessment. SIMPONI 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Study PsA (Table 5). Treatment with SIMPONI resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of SIMPONI in the treatment of patients with plaque psoriasis has not been established.

The percent of patients achieving ACR 20 responses by visit for Study PsA is shown in Figure 2. ACR 20 responses were observed in 31% of patients in the SIMPONI 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 4. Study PsA - Proportion of Patients with ACR Responses
Placebo ± MTX*SIMPONI
50 mg ± MTX*
Bold text indicates primary endpoint
*
In Study PsA, about 48%, 16%, and 72% of the patients received stable doses of MTX (≤ 25 mg/day), low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and NSAIDs, respectively.
N reflects randomized patients.
N113146
ACR 20
Week 149 %51 %
Week 2412 %52 %
ACR 50
Week 142 % 30 %
Week 244 % 32 %
ACR 70
Week 141 % 12 %
Week 241 % 19 %
Table 5. Study PsA - Percent Improvement in ACR Components at Week 14
Placebo± MTX*SIMPONI 50 mg ± MTX*
Note: Baseline are median values
*
In Study PsA, about 48%, 16%, and 78% of the patients received stable doses of MTX (≤ 25 mg/day), low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and NSAIDs, respectively.
N reflects randomized patients; actual number of patients evaluable for each endpoint may vary by timepoint
N113146
Number of swollen joints (0–66)
Baseline10.011.0
Week 148 %60 %
Number of tender joints (0–68)
Baseline18.019.0
Week 140 %54 %
Patient's assessment of pain (0–10)
Baseline5.45.8
Week 14 -1 %48 %
Patient's global assessment
of disease activity (0–10)
Baseline5.25.2
Week 14 2 %49 %
Physician's global assessment
of disease activity (0–10)
Baseline5.25.4
Week 14 7 %59 %
HAQ score (0–10)
Baseline1.01.0
Week 14 0 %28 %
CRP (mg/dL) (0–10)
Baseline0.60.6
Week 14 0 %40 %
*
The same patients may not have responded at each timepoint.
Figure 2. Study PsA – Percent of ACR 20 PsA Responders by Visit: Randomized Patients*
Figure

Physical Function Response in Patients with PsA

In Study PsA, SIMPONI 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively). In addition, the SIMPONI 50 mg group compared to the placebo group had a greater proportion of HAQ responders (≥ 0.3 change from baseline) at Week 24: 43% vs. 22%, respectively.

14.3 Ankylosing Spondylitis

The safety and efficacy of SIMPONI were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 356 adult patients with active ankylosing spondylitis according to modified New York criteria for at least 3 months (Study AS). Patients had symptoms of active disease [defined as a Bath AS Disease Activity Index (BASDAI) ≥ 4 and VAS for total back pain of ≥ 4, on scales of 0 to 10 cm] despite current or previous NSAID therapy. Patients were excluded if they were previously treated with a biologic TNF-blocker or if they had complete ankylosis of the spine. Patients were randomly assigned to placebo (n = 78), SIMPONI 50 mg (n = 138), or SIMPONI 100 mg (n = 140) administered subcutaneously every 4 weeks. Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

The primary endpoint was the percentage of patients achieving an ASsessment in Ankylosing Spondylitis (ASAS) 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24.

In Study AS, the median duration of AS disease was 5.6 years, median duration of inflammatory back pain was 12 years, 83% were HLA-B27 positive, 24% had prior joint surgery or procedure, and 55% received at least one DMARD in the past. During the trial, the use of concomitant DMARDs and/or NSAIDs was as follows: MTX (20%), SSZ (26%), HCQ (1%), low dose oral steroids (16%), and NSAIDs (90%).

Clinical Response in Patients with AS

In Study AS, SIMPONI ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14 (see Table 6). There was no clear evidence of improved ASAS response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI 50 mg ± DMARDs and placebo ± DMARDs groups in Study AS.

The percent of patients achieving ASAS 20 responses by visit for Study AS is shown in Figure 3. ASAS 20 responses were observed in 48% of patients in the SIMPONI 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 6. Study AS – Proportion of ASAS Responders at Weeks 14 and 24
Placebo ± DMARDs*SIMPONI
50 mg ± DMARDs*
Bold text indicates primary endpoint
*
During the trial, the concomitant use of stable doses of DMARDS was as follows: MTX (21%), SSZ (25%), and HCQ (1%). About 16% and 89% of patients received stable doses of low dose oral steroids and NSAIDs during the trial, respectively.
N reflects randomized patients.
N78138
Responders, % of patients
ASAS 20
Week 1422% 59%
Week 2423%56%
ASAS 40
Week 1415%45%
Week 2415%44%
Table 7. Study AS — Median Percent Improvement in ASAS Components at Week 14
Placebo ± DMARDs*SIMPONI 50 mg ± DMARDs*
*
During the trial, the concomitant use of stable doses of DMARDS was as follows: MTX (21%), SSZ (25%), and HCQ (1%). About 16% and 89% of patients received stable doses of low dose oral steroids and NSAIDs during the trial, respectively.
N reflects randomized patients
BASFI is Bath Ankylosing Spondylitis Functional Index
§
Inflammation is the mean of two patient-reported stiffness self-assessments in the Bath AS Disease Activity Index (BASDAI)
N78138
ASAS components
Patient global assessment (0–10)
Baseline 7.27.0
Week 1413%47%
Total back pain (0–10)
Baseline 7.67.5
Week 149%50%
BASFI (0–10)
Baseline 4.95.0
Week 14-3%37%
Inflammation (0–10)§
Baseline 7.17.1
Week 146%59%
*
The same patients may not have responded at each timepoint.
Figure 3. Study AS – Percent of AS Patients Achieving ASAS 20 Response by Visit: Randomized Patients*
Figure

15.0 REFERENCES

  1. SEER [database online]. US Population Data – 1969–2004. Bethesda, MD: National Cancer Institute. Release date: January 3, 2007. Available at: http//seer.cancer.gov/popdata/.

16.0 HOW SUPPLIED/STORAGE AND HANDLING

Each SIMPONI prefilled autoinjector or prefilled syringe is packaged in a light-blocking, cardboard outer carton. SIMPONI is available in packs of 1 prefilled syringe NDC 57894-070-01 or 1 prefilled SmartJect autoinjector NDC 57894-070-02.

Prefilled SmartJect Autoinjector

Each single dose SmartJect autoinjector contains a prefilled glass syringe (27 gauge ½ inch) providing 50 mg of SIMPONI per 0.5 mL of solution.

Prefilled Syringe

Each single dose prefilled glass syringe (27 gauge ½ inch) contains 50 mg of SIMPONI per 0.5 mL of solution.

Storage and Stability

SIMPONI must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) and protected from light. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Do not use SIMPONI beyond the expiration date (EXP) on the carton or the expiration date on the prefilled syringe (observed through the viewing window) or the prefilled SmartJect autoinjector.

17.0 PATIENT COUNSELING INFORMATION

See Medication Guide (17.3)

17.1 Patient Counseling

Patients should be advised of the potential benefits and risks of SIMPONI. Physicians should instruct their patients to read the Medication Guide before starting SIMPONI therapy and to read it each time the prescription is renewed.

Infections

Inform patients that SIMPONI may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation.

Malignancies

Patients should be counseled about the risk of lymphoma and other malignancies while receiving SIMPONI.

Allergic Reactions

Advise latex-sensitive patients that the needle cover on the prefilled syringe as well as the prefilled syringe in the prefilled SmartJect autoinjector contains dry natural rubber (a derivative of latex).

Other Medical Conditions

Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis.

17.2 Instruction on Injection Technique

The first self-injection should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer SIMPONI, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of SIMPONI [see Medication Guide (17.3)].

Prior to use, remove the prefilled syringe or the prefilled SmartJect autoinjector from the refrigerator and allow SIMPONI to sit at room temperature outside of the carton for 30 minutes and out of the reach of children.

Do not warm SIMPONI in any other way. For example, do not warm SIMPONI in a microwave or in hot water.

Do not remove the prefilled syringe needle cover or SmartJect autoinjector cap while allowing SIMPONI to reach room temperature. Remove these immediately before injection.

Do not pull the autoinjector away from the skin until you hear a first "click" sound and then a second "click" sound (the injection is finished and the needle is pulled back). It usually takes about 3 to 6 seconds but may take up to 15 seconds for you to hear the second "click" after the first "click". If the autoinjector is pulled away from the skin before the injection is completed, a full dose of SIMPONI may not be administered.

A puncture-resistant container for disposal of needles and syringes should be used. Patients or caregivers should be instructed in the technique of proper syringe and needle disposal, and be advised not to reuse these items.

17.3 Medication Guide

MEDICATION GUIDE
SIMPONI™ (SIM-po-nee)
(golimumab)

Read the Medication Guide that comes with SIMPONI before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. It is important to remain under your doctor's care while using SIMPONI.

What is the most important information I should know about SIMPONI?

SIMPONI is a medicine that affects your immune system. SIMPONI can lower the ability of your immune system to fight infections. Some people have serious infections while taking SIMPONI, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that spread throughout their body. Some people have died from these serious infections.

You should not start taking SIMPONI if you have any kind of infection unless your doctor says it is okay.

Before starting SIMPONI, tell your doctor if you:

After starting SIMPONI, call your doctor right away if you have any symptoms of an infection. SIMPONI can make you more likely to get infections or make worse any infection that you have.

Cancer

What is SIMPONI?

SIMPONI is a prescription medicine called a Tumor Necrosis Factor (TNF) blocker. SIMPONI is used in adults:

You may continue to use other medicines that help treat your condition while taking SIMPONI, such as non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as recommended by your doctor.

What should I tell my doctor before starting treatment with SIMPONI?

SIMPONI may not be right for you. Before starting SIMPONI, tell your doctor about all your medical conditions, including if you:

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially, tell your doctor if you use:

Ask your doctor if you are not sure if your medicine is one listed above.

Keep a list of all your medications with you to show your doctor and pharmacist each time you get a new medicine.

How should I use SIMPONI?

What are the possible side effects with SIMPONI?

SIMPONI can cause serious side effects, including:

See "What is the most important information I should know about SIMPONI?"

Serious Infections

Hepatitis B infection in people who carry the virus in their blood.

Heart failure, including new heart failure or worsening of heart failure that you already have. New or worse heart failure can happen in people who use TNF-blocker medicines like SIMPONI.

Nervous System Problems

Rarely, people using TNF-blocker medicine have nervous system problems such as multiple sclerosis.

Liver Problems

Liver problems can happen in people who use TNF-blocker medicines, including SIMPONI. These problems can lead to liver failure and death. Call your doctor right away if you have any of these symptoms:

Blood Problems

Low blood counts have been seen with other TNF-blockers. Your body may not make enough blood cells that help fight infections or help stop bleeding. Symptoms include fever, bruising or bleeding easily, or looking pale. Your doctor will check your blood counts before and during treatment with SIMPONI.

Common side effects with SIMPONI include:

  • upper respiratory tract infection
  • nausea
  • abnormal liver tests
  • redness at the site of injection
  • high blood pressure
  • bronchitis
  • dizziness
  • sinus infection (sinusitis)
  • flu
  • runny nose
  • fever
  • cold sores
  • numbness or tingling

Other side effects with SIMPONI include:

These are not all of the side effects with SIMPONI. Tell your doctor about any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How do I store SIMPONI?

Keep SIMPONI and all medicines out of the reach of children.

General Information about SIMPONI

What are the ingredients in SIMPONI?

Active ingredient: golimumab.

Inactive ingredients: L-histidine, L-histidine monohydrochloride monohydrate, sorbitol, polysorbate 80, and water for injection. SIMPONI does not contain preservatives.

Patient Instructions for Use
SIMPONI™ (SIM-po-nee)
(golimumab)
SmartJect™ autoinjector

If your doctor decides that you or a caregiver may be able to give your injections of SIMPONI at home, you should receive training on the right way to prepare and inject SIMPONI. Do not try to inject SIMPONI yourself until you have been shown the right way to give the injections by your doctor or nurse.

It is important to read, understand, and follow these instructions so that you inject SIMPONI the right way. Call your doctor if you or your caregiver has any questions about the right way to inject SIMPONI.

Important information about your SmartJect autoinjector:

Do not:

Step 1: Gather and inspect the supplies for your injection

You will need these supplies for an injection of SIMPONI. See Figure 1.

Figure 1
Figure

The figure below shows what the SmartJect autoinjector looks like. See Figure 2.

Figure 2
Figure

1.1 Check Expiration Date

1.2 Check Security Seal

1.3 Wait 30 minutes

  • To ensure proper injection, allow the autoinjector to sit at room temperature outside the carton for 30 minutes and out of the reach of children.
Figure

Do not warm the SmartJect autoinjector in any other way (For example, do not warm it in a microwave or in hot water).

Do not remove the SmartJect autoinjector cap while allowing it to reach room temperature.

1.4 Check the Liquid in the SmartJect autoinjector

Figure 3
Figure
Step 2: Choose and prepare the injection site

2.1 Choose the Injection Site

2.2 Prepare the Injection Site

Step 3: Injecting SIMPONI using the single dose SmartJect autoinjector

3.1 Remove the Cap

3.2 Push the SmartJect autoinjector against the skin

3.3 Press button to inject

3.4 Wait for Second "Click"

Figure

Step 4: After the injection

4.1 Check the Viewing Window

4.2 Dispose of the used SmartJect autoinjector

4.3 Use Cotton Ball or Gauze

Patient Instructions for Use
SIMPONI™
Prefilled Syringe

If your doctor decides that you or a caregiver may be able to give your injections of SIMPONI at home, you should receive training on the right way to prepare and inject SIMPONI. Do not try to inject SIMPONI yourself until you have been shown the right way to give the injections by your doctor or nurse.

It is important to read, understand, and follow these instructions so that you inject SIMPONI the right way. Call your doctor if you or your caregiver has any questions about the right way to inject SIMPONI.

Important information about your prefilled syringe:

Do not:

Step 1: Gather the supplies for your injection

You will need these supplies for an injection of SIMPONI. See Figure 1.

Figure 1
Figure

The diagram below shows what the prefilled syringe looks like. See Figure 2.

Figure 2
Figure

Step 2: Get ready to use your prefilled syringe

2.1 Check the Expiration Date

2.2 Wait 30 minutes

  • To ensure proper injection, allow the prefilled syringe to sit at room temperature outside of the carton for 30 minutes and out of the reach of children.
  • Do not warm the prefilled syringe in any other way (For example, Do not warm it in a microwave or in hot water).
  • Do not remove the prefilled syringe needle cover while allowing it to reach room temperature.
Figure

2.3 Check the Liquid in the Prefilled Syringe

Step 3: Choose and prepare the injection site

3.1 Choose the Injection Site

Figure 5
Figure

Do not inject into areas where the skin is tender, bruised, red, scaly, or hard. Avoid areas with scars or stretch marks.

3.2 Prepare the Injection Site

Step 4: Inject SIMPONI

Do not remove the needle cover until you are ready to inject SIMPONI. Inject SIMPONI within 5 minutes after you remove the needle cover.

4.1 Remove the Needle Cover

4.2 Position the prefilled syringe and inject SIMPONI

Step 5: After the injection

5.1 Dispose of the used prefilled syringe

5.2 Use Cotton Ball or Gauze

Manufactured by:
Centocor Ortho Biotech Inc.
Horsham, PA 19044
US License No. 1821

Revised: 11/2009

This Medication Guide has been approved by the U.S. Food and Drug Administration.

PRINCIPAL DISPLAY PANEL - Syringe Carton

NDC 57894-070-01

FOR SUBCUTANEOUS INJECTION

Sterile solution in a single dose
prefilled syringe. Discard unused portion.

See package inset for dosing information.

No U.S. standard of potency.

This Product Contains
Dy Natural Rubber.

Rx only.

Simponi™
golimumab

50 mg / 0.5 mL

One single dose prefilled syringe

PRINCIPAL DISPLAY PANEL - Syringe Carton

SIMPONI 
golimumab   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)57894-070
Route of AdministrationSUBCUTANEOUSDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
golimumab (golimumab) golimumab50 mg  in 0.5 mL
Inactive Ingredients
Ingredient NameStrength
sorbitol20.5 mg  in 0.5 mL
histidine0.44 mg  in 0.5 mL
histidine monohydrochloride monohydrate0.44 mg  in 0.5 mL
polysorbate 800.08 mg  in 0.5 mL
water 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
157894-070-011 SYRINGE In 1 CARTONcontains a SYRINGE, GLASS
10.5 mL In 1 SYRINGE, GLASSThis package is contained within the CARTON (57894-070-01)
257894-070-021 SYRINGE In 1 CARTONcontains a SYRINGE
20.5 mL In 1 SYRINGEThis package is contained within the CARTON (57894-070-02)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
BLABLA12528904/25/2009

Labeler - Centocor Ortho Biotech Inc. (099091753)
Establishment
NameAddressID/FEIOperations
Baxter Pharmaceutical Solutions 604719430Manufacture, Analysis
Establishment
NameAddressID/FEIOperations
Centocor, BV409612918API Manufacture, Analysis
Establishment
NameAddressID/FEIOperations
Cilag AG119237597Analysis
Revised: 11/2009Centocor Ortho Biotech Inc.