Macitentan-Containing Products REMS Update

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On April 2, 2025, the United States (U.S.) Food and Drug Administration (FDA) released OPSYNVI and OPSUMIT from the Macitentan-Containing Products Risk Evaluation and Mitigation Strategies (REMS) program requirements.¹ 

The release of the REMS program requirements, specific to the risk associated with embryo-fetal toxicity, applies to the endothelin receptor antagonist (ERA) pharmacologic class.

The REMS program for Macitentan-Containing Products was established to ensure its safe use, particularly to address the potential risks of embryo-fetal toxicity. It included elements that ensure safe use of the drug, an implementation system for these elements, and a timetable for assessing the REMS. It was applicable for female patients.¹ 

The REMS program for Macitentan-Containing Products was discontinued because the U.S. FDA determined that a REMS is no longer necessary to ensure the benefits of OPSYNVI and OPSUMIT outweigh the risk of embryo-fetal toxicity. This was based on an evaluation of human fetal outcomes reports from 2001 to 2024 after exposure to a drug in the ERA pharmacologic class.¹ Macitentan-containing products still carry some risks, particularly regarding embryo-fetal toxicity.^2,3 However, the FDA determined that labeling is sufficient to convey the safety information about the embryo-fetal risk and its mitigation, and additional elements of the REMS are not necessary.¹ 

OPSYNVI and OPSUMIT still have the following black box warnings:^2,3  

• Based on animal data, OPSYNVI/OPSUMIT may cause fetal harm if used during pregnancy
• Females of reproductive potential: exclude pregnancy before the start of treatment with OPSYNVI/OPSUMIT. Prevent pregnancy during treatment and for 1 month after treatment by using effective methods of contraception.
• When pregnancy is detected, discontinue OPSYNVI/OPSUMIT as soon as possible. 

The following changes have been determined:¹ 

• Wholesaler-Distributors: Elements to Assure Safe Use, which previously required wholesaler-distributors to be specially registered to distribute macitentan-containing products and required certification confirmation for pharmacy enrollment and wholesaler-distributor registration are no longer necessary.
• Outpatient Pharmacies and pharmacy staff: Elements to Assure Safe Use, which previously required outpatient pharmacies to be specially certified to dispense macitentan-containing products and generate a REMS dispense authorization for each prescription prior to dispensing product are no longer necessary.
• Inpatient Pharmacies and pharmacy staff: Elements to Assure Safe Use, which previously required inpatient pharmacies to be specially certified to dispense macitentan-containing products and required verification that a female patient is under the supervision and care of a certified prescriber, the female patient is enrolled or will be enrolled prior to discharge and that females of reproductive potential had to confirm pregnancy test is complete are no longer necessary.
• Prescribers/Office Contacts: Elements to Assure Safe Use, which previously required prescribers to be specially certified to prescribe macitentan-containing products and required female patients to enroll to receive product, and females of reproductive potential had to confirm pregnancy test to their pharmacy on a monthly basis are no longer necessary.
• Patients/Caregivers: Elements to Assure Safe Use, which previously required female patients to enroll in the REMS to receive product, and females of reproductive potential had to confirm pregnancy test to their pharmacy on a monthly basis are no longer necessary.
• For all stakeholders: The implementation system designed to implement these elements is also no longer required.

Stakeholders no longer need to enroll or certify in the REMS. The Macitentan-Containing Products REMS administrator (Syneos) has informed the certified specialty pharmacies and enrolled wholesalers that the REMS is discontinued. The REMS administrator is in the process of informing certified prescribers and certified inpatient pharmacies that the REMS is being discontinued. The Macitentan-Containing Products REMS call center is expected to remain open to answer any questions.¹