Side Effects of Simponi (golimumab)

Simponi (golimumab) is an injectable synthetic protein used in combination with methotrexate to treat rheumatoid arthritis and alone or combined with methotrexate to treat psoriatic arthritis. It also is used to treat ankylosing spondylitis.

Simponi binds to tumor necrosis factor alpha (TNFα) in the body and blocks the effects of TNFα and as a result, the inflammation caused by these diseases and its consequences are reduced. Inflammation is the body's reaction to injury and is a necessary process for the repair of injury.

TNF is a protein that the body produces when there is inflammation. TNF promotes inflammation and the signs of inflammation, which, in the case of arthritis, include fever as well as pain, tenderness, and swelling of joints.

The unchecked inflammation of rheumatoid and psoriatic arthritis as well as ankylosing spondylitis eventually leads to destruction of the joints. Simponi binds to TNF in the body and thereby blocks the effects of TNF. As a result, inflammation and its inflammatory consequences in joints are reduced, and the progressive destruction of the joints is slowed or prevented.

Common side effects of Simponi include

• flu,
• elevated liver function test results,
• fever,
• injection site reactions (redness, swelling),
• reduced levels of blood cells,
• reactivation of hepatitis B virus,
• new onset or worsening of psoriasis, and
• abnormal prickling, tingling, tickling, or burning sensation.

Less common side effects of Simponi include

• congestive heart failure,
• dizziness,
• high blood pressure (hypertension),
• skin rash, and
• constipation.

Serious side effects of Simponi include

• tuberculosis,
• herpes infection,
• cancer,
• serious allergic reactions,
• liver toxicity,
• sepsis (bacteria in the blood),
• fungal infections,
• worsening of or new diseases of the nervous system, and
• causing or worsen congestive heart failure. 

Drug interactions of Simponi include anakinra, abatacept, rituximab because it may result in a reduction of white blood cells in the blood (neutropenia), serious infections, and no additional benefit.

Simponi may interfere with the effectiveness of vaccines. Live vaccines, including attenuated vaccines, should not be given to patients receiving Simponi.

There are no adequate studies of Simponi in pregnant women. It is unknown if Simponi is excreted in breast milk. Consult your doctor before breastfeeding. 

Common side effects include:

1. Flu
2. Elevated liver function test results
3. Fever
4. Abnormal prickling, tingling, tickling, or burning sensation (paraesthesia)

Other side effects include:

1. Injection site reactions (redness, swelling)
2. Reduced levels of blood cells
3. Reactivation of hepatitis B virus
4. New onset or worsening of psoriasis

Less common side effects include:

1. Congestive heart failure
2. Dizziness
3. Hypertension
4. Skin rash
5. Constipation

Possible serious side effects include:

1. Tuberculosis
2. Herpes infection
3. Cancer
4. Serious allergic reactions
5. Liver toxicity
6. Sepsis (bacteria in the blood)
7. Fungal infections

Individuals with active infections should not be treated with golimumab. This drug may worsen or cause new diseases of the nervous system. It also may cause or worsen congestive heart failure. In studies, some patients who used golimumab or other TNFα blocking drugs developed cancer.

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 5 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).
• 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 safety data in 1233 Simponi-treated patients with ulcerative colitis from 3 pooled, randomized, double-blind, controlled Phase 2/3 trials are also described below (Trials UC-1, UC-2, and UC-3).
• 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 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 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.

The most serious adverse reactions were:

• Serious Infections
• Malignancies

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 the Warnings and Precautions section.
• In the controlled Phase 2/3 trial of Simponi induction through Week 6 in UC, 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 portion of the UC trial.

Demyelinating Disorders

• In the controlled Phase 2/3 trial 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, there were no cases of demyelination in the Simponi 100-mg group during maintenance.
• One case of CNS demyelination was observed in the placebo maintenance group in a patient who received Simponi 400/200 mg during induction.

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 x ULN occurred in 0.2% of control-treated patients and 0.7% of Simponi-treated patients and ALT elevations ≥ 3 x ULN occurred in 2% of control-treated patients and 2% of Simponi-treated patients.
• Since many of the patients in the Phase 3 trials for RA, PsA, and AS were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between Simponi and liver enzyme elevation is not clear.
• In Phase 2/3 UC trials, the incidence of ALT elevations ≥ 5 x ULN was similar in Simponi-treated patients and placebo-treated patients, or approximately 1%, with an average duration of follow-up of 46 weeks and 18 weeks, respectively.
• ALT elevations ≥ 3 x ULN occurred in 2.0% of Simponi-treated patients compared with 1.5% of placebo-treated patients with an average duration of follow-up of 46 weeks and 18 weeks, respectively.

Autoimmune Disorders And Autoantibodies

• 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.
• In Phase 3 trials in RA, PsA, and AS through 1 year of follow-up, 4.0% of Simponi-treated patients and 2.6% of control patients were newly antinuclear antibody (ANA)-positive (at titers of 1:160 or greater).
• The frequency of anti-dsDNA antibodies at 1 year of follow-up was uncommon in patients who were anti-dsDNA negative at baseline.
• Through Week 60 of the UC trials, 3.5% of patients who received Simponi induction and 100 mg during maintenance were newly ANA-positive (at titers of 1:160 or greater) compared with 3.5% of patients who received Simponi induction and placebo during the maintenance portion of the UC trial.
• The frequency of anti-dsDNA antibodies at 1 year of follow-up in patients who were anti-dsDNA negative at baseline was 0.5% in patients receiving Simponi induction and 100 mg during maintenance compared with 0% in patients who received Simponi induction and placebo during maintenance.

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 the controlled Phase 2/3 trial through Week 6 in UC, 3.4% of Simponi-treated patients had injection site reactions compared with 1.5% in control-treated patients.
• The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema.
• In controlled Phase 2 and 3 trials in RA, PsA, AS, and Phase 2/3 UC trials, no patients treated with Simponi developed anaphylactic reactions.

Other Adverse Reactions

• Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the Simponi ± DMARD group and with a higher incidence than in the placebo ± DMARD group 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 Simponi-Treated Patients and With a Higher Incidence Than Placebo-Treated Patients in the Phase 3 Trials of RA, PsA, and AS through Week 16^a

Less Common Clinical Trial Adverse Drug Reactions

• Adverse drug reactions that occurred <1% in Simponi-treated patients during the Simponi clinical trials that do not appear in the Warnings and Precautions section included the following events listed by system organ class:
  • Infections and infestations: Septic shock, atypical mycobacterial infection, pyelonephritis, arthritis bacterial, bursitis infective
  • Neoplasms benign, malignant and unspecified: Leukemia
  • Skin and subcutaneous tissue disorders: Psoriasis (new onset or worsening, palmar/plantar and pustular), vasculitis (cutaneous)
  • Vascular disorders: Vasculitis (systemic)

Other Clinical Trial Adverse Drug Reactions In Ulcerative Colitis Clinical Trials

• In the Phase 2/3 trials in UC evaluating 1233 Simponi-treated patients, no new adverse drug reactions were identified and the frequency of adverse drug reactions was similar to the safety profile observed in patients with RA, PsA and AS.

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.

Results From The EIA Method

• Using an enzyme immunoassay (EIA method), antibodies to golimumab 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 3 indications. Patients who received Simponi with concomitant MTX had a lower proportion of antibodies to golimumab than patients who received Simponi without MTX (approximately 2% vs. 7%, respectively).
• With the EIA method, the presence of serum concentrations of golimumab can interfere with the detection of antibodies to golimumab leading to inconclusive results.
• In UC trials, 34 (3%), 341 (28%) and 823 (69%) of Simponi-treated patients were positive, negative and inconclusive for antibodies to golimumab, respectively.
• Treatment with concomitant immunomodulators (AZA, 6-MP or MTX) resulted in a lower proportion of patients with antibodies to golimumab than patients receiving Simponi without immunomodulators (2% vs. 4%, respectively).
• Of the patients with a positive antibody response to golimumab in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay.

Results From The Drug-Tolerant EIA Method

• A drug-tolerant enzyme immunoassay (drug-tolerant EIA) method for detecting antibodies to golimumab was developed and validated, which eliminated the inconclusive category as reported above.
• This method is approximately 16-fold more sensitive than the original EIA method with less interference from golimumab in serum.
• Based on the drug tolerant EIA method, 246 (23%) of Simponi-treated patients across the Phase 3 RA, PsA and AS trials, antibodies to golimumab were detected in 59 (16%), 106 (28%), and 81 (24%) patients, respectively.
• Treatment with concomitant MTX resulted in a lower proportion of patients with antibodies to golimumab than in patients receiving Simponi without MTX in RA patients (7% vs. 35%), in PsA patients (18% vs. 38%) and in AS patients (6% vs. 29%).
• A trend of decreasing drug concentrations with increasing antibody titers was observed.
• While an overall decrease in clinical efficacy for ADA positive patients compared with ADA negative patients was not observed in patients with RA (ACR 20: 75% vs. 75%), PsA (ACR 20: 72% vs. 66%) and AS (ASAS 20: 57% vs. 65%), higher titer antibodies may be associated with diminished efficacy.
• In the UC trials, 254 (21%) of Simponi-treated patients were positive for antibodies to golimumab through week 54 while the remaining 941 (79%) patients were negative.
• Treatment with concomitant immunomodulators (AZA, 6-MP or MTX) in the UC trials resulted in a lower proportion of patients with antibodies to golimumab than in patients receiving Simponi without immunomodulators (12% vs. 26%).
• There is a trend of decreasing drug concentrations with increasing antibody titers.
• Although the development of antibodies to golimumab did not preclude clinical response, a trend toward decreased efficacy in ADA positive patients was observed compared to ADA negative patients in the UC trials (clinical response 38% vs. 53%).

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 Simponi exposure.

• Immune system disorders: Serious systemic hypersensitivity reactions (including anaphylactic reaction), sarcoidosis
• Neoplasms benign, malignant and unspecified: Melanoma, Merkel cell carcinoma
• Respiratory, thoracic and mediastinal disorders: Interstitial lung disease
• Skin and subcutaneous tissue disorders: Skin exfoliation, lichenoid reactions, rash, bullous skin reactions

Methotrexate

• For the treatment of RA, Simponi should be used with methotrexate (MTX).
• 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.

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.
• 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.

Live Vaccines/Therapeutic Infectious Agents

• Live vaccines should not be given concurrently with Simponi.
• Therapeutic infectious agents should not be given concurrently with Simponi.
• 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.

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.