SIMPONI ARIA (Page 4 of 10)

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

7 DRUG INTERACTIONS

7.1 Methotrexate

SIMPONI ARIA should be used with MTX for the treatment of RA [see Clinical Studies (14.1)] . Following IV administration, concomitant administration of methotrexate decreases the clearance of SIMPONI ARIA by approximately 9% based on population pharmacokinetics (PK) analysis. In addition, concomitant administration of methotrexate decreases the SIMPONI ARIA clearance by reducing the development of antibodies to golimumab.

7.2 Biologic Products for RA, PsA, AS, and pJIA

An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI ARIA with other biologic products, including abatacept or anakinra, is not recommended [see Warnings and Precautions (5.6and 5.7)] . A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. The concomitant use of SIMPONI ARIA with biologics approved to treat RA, PsA, AS, and pJIA is not recommended because of the possibility of an increased risk of infection.

7.3 Live Vaccines/Therapeutic Infectious Agents

Live vaccines should not be given concurrently with SIMPONI ARIA [see Warnings and Precautions (5.10)] .

Therapeutic infectious agents should not be given concurrently with SIMPONI ARIA [see Warnings and Precautions (5.10)] .

Infants born to women treated with SIMPONI ARIA during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI ARIA in utero is not recommended for 6 months following the mother’s last SIMPONI ARIA infusion during pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)] .

7.4 Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI ARIA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled trials of SIMPONI ARIA in pregnant women. Monoclonal antibodies, such as golimumab, are transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. There are clinical considerations for the use of SIMPONI ARIA in pregnant women [see Clinical Considerations] . In an animal reproductive study, golimumab administered by the subcutaneous route to pregnant monkeys, during the period of organogenesis, at doses that produced exposures approximately 200 times the maximum recommended human dose (MRHD) had no adverse fetal effects.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and of miscarriage is 15–20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Golimumab crosses the placenta during pregnancy. Another TNF-blocking monoclonal antibody administered during pregnancy was detected for up to 6 months in the serum of infants. Consequently, these infants may be at increased risk of infection. Administration of live vaccines to infants exposed to SIMPONI ARIA in utero is not recommended for 6 months following the mother’s last SIMPONI ARIA infusion during pregnancy [see Warnings and Precautions (5.10)and Drug Interactions (7.3)] .

Data

Human Data

Limited data on use of SIMPONI ARIA in pregnant women from observational studies, published case reports, and postmarketing surveillance are insufficient to inform a drug associated risk.

Animal Data

In an embryofetal developmental toxicology study in which pregnant cynomolgus monkeys were treated with golimumab during the period of organogenesis from gestation days (GD) 20 to 51, exposures up to 200 times greater than the exposure at the MRHD (on an area under the curve (AUC) basis with maternal subcutaneous doses up to 50 mg/kg twice weekly) produced no evidence of fetal malformations or embryotoxicity. There was no evidence of maternal toxicity. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation.

In a pre- and postnatal developmental study in which pregnant cynomolgus monkeys were treated with golimumab from gestation day 50 to postpartum day 33, maximal drug concentrations up to 33 times greater than that found with the MRHD (on a maximum blood concentration (C max ) basis at steady-state with maternal subcutaneous doses up to 50 mg/kg twice weekly) were not associated with any evidence of developmental defects in infants. There was no evidence of maternal toxicity. Golimumab was present in fetal serum at the end of the second trimester and in neonatal serum from the time of birth and for up to 6 months postpartum.

8.2 Lactation

Risk Summary

There is no information regarding the presence of SIMPONI ARIA in human milk, the effects on breastfed infants, or the effects on milk production. Maternal IgG is known to be present in human milk. If golimumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to golimumab are unknown. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for SIMPONI ARIA and any potential adverse effects on the breast-fed infants from SIMPONI ARIA, or from the underlying maternal condition.

Data

Animal Data

In the pre- and postnatal 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.

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