X

FDA News: Issue 31, October 2020

Author: [AUTHOR] Published on 10/13/2020 8:01:00 AM


FDA Approves SIMPONI ARIA (Golimumab) for Patients 2 Years of Age and Older for the Treatment of Active Psoriatic Arthritis or Active Polyarticular Juvenile Idiopathic Arthritis

On September 29, 2020, the US Food and Drug Administration (FDA) approved efficacy supplements for SIMPONI ARIA for patients 2 years of age and older for the treatment of active psoriatic arthritis (PsA) or active polyarticular juvenile idiopathic arthritis (pJIA). In addition to the treatment of children ages 2 years and older with active pJIA or active PsA, SIMPONI ARIA is approved for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate, active PsA, or active ankylosing spondylitis (AS). 

The approved recommended dosage of SIMPONI ARIA is:
  • Adult patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: 2 mg/kg intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter.
  • Pediatric patients with polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis: 80 mg/m2 intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter.
Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal (such as histoplasmosis), and other opportunistic infections have occurred in patients receiving SIMPONI ARIA. Discontinue SIMPONI ARIA if a patient develops a serious infection or sepsis. Perform test for latent TB; if positive, start treatment for TB prior to starting SIMPONI ARIA. Monitor all patients for active TB during treatment, even if initial latent TB test is negative. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI ARIA is a member.

Additional information regarding dosage and administration as well as warnings and precautions about serious infection, invasive fungal infections, hepatitis B reactivation, malignancies, congestive heart failure, demyelinating disorders, autoimmunity, use with anakinra or abatacept, switching between biological disease modifying antirheumatic drugs, hematologic cytopenias, vaccinations/therapeutic infectious agents, or hypersensitivity reactions can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD):
  • MOA: Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. 
  • General PK: Golimumab exhibited approximately dose-proportional pharmacokinetics in patients with RA over the dose range of 0.1 to 10.0 mg/kg (0.05 to 5 times the approved recommended adult dosage) following a single intravenous dose. 
  • Absorption: Following a single intravenous administration of 2 mg/kg SIMPONI ARIA, a mean Cmax of 44.4 ± 11.3 mcg/mL was observed in patients with RA. Data directly comparing 2 mg/kg intravenous administration and 50 mg subcutaneous administration are not available. 
  • Distribution: Following a single intravenous administration of 2 mg/kg SIMPONI ARIA, the mean volume of distribution was estimated to be 115 ± 19 mL/kg in healthy subjects, and 151 ± 61 mL/kg in patients with RA. The volume of distribution of golimumab may indicate that golimumab is distributed primarily in the circulatory system with limited extravascular distribution. 
  • Elimination: Following a single intravenous administration of 2 mg/kg SIMPONI ARIA, the systemic clearance of golimumab was estimated to be 6.9 ± 2.0 mL/day/kg in healthy subjects and 7.6 ± 2.0 mL/day/kg in patients with RA. The mean terminal half-life was estimated to be 12 ± 3 days in healthy subjects and the mean terminal half-life in RA patients was 14 ± 4 days. 
  • PD: Following treatment with SIMPONI ARIA in patients with RA, decreases from baseline were observed in tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3), resistin, interleukin-6 (IL-6), macrophage inflammatory protein-1 (MIP-1b), vascular endothelial growth factor (VEGF), serum amyloid A (SAA), S100A12, and high sensitivity C-Reactive protein (hsCRP). Conversely, increases from baseline were observed in tartrate-resistant acid phosphatase (TRAP-5b). The clinical relevance of this information is not known. 
  • Immunogenicity: 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. Through approximately 6 months, the incidence of antibodies to golimumab for 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. The immune response effect on golimumab clearance in patients with JIA with active polyarthritis was comparable to adults with RA. 

Drug Interactions
  • Methotrexate: SIMPONI ARIA should be used with MTX for the treatment of RA. 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. 
  • 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. 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. 
  • Live Vaccines/Therapeutic Infectious Agents: Live vaccines should not be given concurrently with SIMPONI ARIA. Therapeutic infectious agents should not be given concurrently with SIMPONI ARIA. 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. 
  • 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. 
Use in Specific Populations
No formal study of the effect of renal or hepatic impairment on the PK of golimumab was conducted.
  • Body Weight: Following intravenous administration, patients with higher body weight tended to have slightly higher serum golimumab concentrations than patients with lower body weights when golimumab was administered on a mg/kg (body weight) basis. However, based on population PK analysis, there were no clinically relevant differences in golimumab exposure following intravenous administration of 2 mg/kg SIMPONI ARIA in adult patients across a range of different body weights. Consistent with the intravenous data in adult patients with RA, population pharmacokinetic analyses for intravenous SIMPONI ARIA in pJIA revealed that there were no clinically relevant differences in golimumab exposure following intravenous administration of 80 mg/m2 SIMPONI ARIA in pediatric patients across a range of age and different body weights. The immune response effect on golimumab clearance in patients with JIA with active polyarthritis was comparable to adults with RA. 
  • Pediatrics: When 80 mg/m2 SIMPONI ARIA was administered intravenously to patients with JIA with active polyarthritis at weeks 0, 4 and every 8 weeks thereafter, serum concentrations reached steady-state by Week 12. With concomitant use of MTX, treatment with 80 mg/m2 SIMPONI ARIA resulted in a mean steady-state trough serum golimumab concentration of approximately 0.5 ± 0.4 mcg/mL and a mean steady-state AUC of 425 ± 125 mcg∙day/mL in patients with JIA with active polyarthritis. Overall, the observed steady-state golimumab trough concentrations in patients with JIA with active polyarthritis were within the range of those observed for adult RA and PsA after administration of SIMPONI ARIA. 

Efficacy and Safety
  • Psoriatic Arthritis: The efficacy of SIMPONI ARIA in pediatric patients with PsA is based on the pharmacokinetic exposure and extrapolation of the established efficacy of SIMPONI ARIA in adult PsA patients. The efficacy and safety of SIMPONI ARIA were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial in 480 patients ≥ 18 years of age with active psoriatic arthritis despite NSAID or DMARD therapy. Previous treatment with a biologic was not allowed. The primary endpoint was the percentage of patients achieving an American College of Rheumatology (ACR) 20 response at Week 14. 
  • Polyarticular Juvenile Idiopathic Arthritis: The efficacy of SIMPONI ARIA in pediatric patients with pJIA is based on the pharmacokinetic exposure and extrapolation of the established efficacy of SIMPONI ARIA in RA patients. Efficacy of SIMPONI ARIA was also assessed in a multicenter, open-label, single-arm study in 127 children (2 to < 18 years of age) with JIA with active polyarthritis despite treatment with MTX for at least 2 months. Efficacy was assessed as supportive endpoints through Week 52. Additional information regarding the efficacy trials can be found in the full prescribing information linked below. 
  • Rheumatoid Arthritis: The efficacy and safety of SIMPONI ARIA were evaluated in one multicenter, randomized, double-blind, controlled trial in 592 patients ≥ 18 years of age with moderately to severely active RA despite concurrent MTX therapy and had not previously been treated with a biologic TNF-blocker. The primary endpoint in Trial RA was the percentage of patients achieving an ACR 20 response at Week 14. 
  • Ankylosing Spondylitis: The efficacy and safety of SIMPONI ARIA were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial in 208 patients ≥ 18 years of age with active ankylosing spondylitis (AS) and inadequate response or intolerance to NSAIDs. The primary endpoint was the percentage of patients achieving an Assessment in Ankylosing Spondylitis (ASAS) 20 response at Week 16. 

Additional information regarding the efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 3%) are: upper respiratory tract infection, alanine aminotransferase increased, viral infection, aspartate aminotransferase increased, neutrophil count decreased, bronchitis, hypertension, and rash.

Full prescribing information is available at https://go.usa.gov/xG6Zf.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

print
Sort by:
Photo Gallery
Recent News
  • Call for Papers: Pharmacogenetics & Pharmacogenomics
    October 26, 2020
  • ASCPT Early Career (EC) Community and Oncology (ONC) Community Members-Only Webinar
    October 23, 2020
  • ASCPT Members-Only Webinar Presented by the Translational Informatics (TI) Community
    October 23, 2020
Contact Us