REMS lifted for endothelin receptor antagonists

FDA removes REMS requirements for embryofetal toxicity risk from all endothelin receptor antagonist medicines

Based on a new analysis of human pregnancy data compiled from the use of endothelin receptor antagonist (ERA) medicines for two decades, FDA has determined that risk evaluation and mitigation strategy (REMS) requirements related to embryofetal toxicity (EFT) risk are no longer necessary to ensure the benefits of ERA medicines outweigh those risks. The Agency’s current assessment is that labeling alone is adequate to communicate the risk, and labeling will continue to inform health care professionals and patients of the risk.

In April 2025, FDA eliminated the REMS for the following ERA medicines:

Eliminated REMS ERA Medicine

Ambrisentan Shared System REMS Letairis and generics (ambrisentan)

Macitentan-Containing Products Shared System REMS Opsumit and generics (macitentan)

Opsynvi (macitentan and tadalafil)

Tryvio REMS Tryvio (aprocitentan)

Elimination of these REMS means:

• Health care professionals can prescribe and dispense ambrisentan, macitentan-containing products, and Tryvio (aprocitentan) without enrolling or participating in a REMS.

• Patients can receive ambrisentan and macitentan-containing products without enrolling in a REMS; the Tryvio REMS did not require patient enrollment.

• Pharmacies and health care facilities can dispense ambrisentan, macitentan-containing products, and Tryvio (aprocitentan) without enrolling or participating in a REMS.

Additionally, FDA notified manufacturers of the following ERA medicines that they must modify the REMS to remove requirements related to EFT risk. FDA approved these REMS modifications in fall 2025. REMS requirements related to hepatotoxicity (liver damage) risk for these ERA medicines will remain in effect.

Modified REMS ERA Medicine

Bosentan Shared System REMS Tracleer and generics (bosentan)

Filspari REMS Filspari (sparsentan)

ERA prescribing information and EFT risk

Information about EFT and mitigation of this risk will remain in the prescribing information for ERA medicines. Use of ERA medicines is contraindicated in pregnancy. Based on data from animal EFT studies, pregnant patients should not use ERA medicines as they may cause fetal harm. Patients who can get pregnant should ensure they are not pregnant prior to starting treatment with an ERA medicine and use effective contraception while taking an ERA medicine. Prescribers should exclude pregnancy prior to treatment initiation and advise patients who can get pregnant of the potential risk to a fetus and of the need to use effective contraception while they are treated with an ERA medicine.

Basis for removing ERA REMS requirements for EFT risk

FDA regularly assesses the benefits and risks of REMS programs and may eliminate a REMS or remove certain components of a REMS if, after review of REMS assessments or other information, we determine that the extra measures in a REMS are no longer necessary to ensure a medication’s benefits outweigh its risks.

FDA’s ERA REMS requirements for EFT risk were based on findings from animal studies. Over time, the Agency monitored clinical outcomes reported in patients exposed to ERA medicines during pregnancy and observed that these data did not show a pattern of congenital malformations consistent with what was observed in animal EFT studies. Given the Agency's new analysis and understanding of clinical risk, FDA determined that labeling for all ERA medicines is sufficient to provide information about EFT risk and its mitigation.

Whom do I contact?

Prescribers, pharmacies, and patients may contact the FDA at (855) 543-3784 or (301) 796-3400, or by email at druginfo@fda.hhs.gov with questions. Adverse events, medication errors, or quality problems experienced with ERA medicines should be reported to FDA's MedWatch Adverse Event Reporting program. FDA’s top priority is patient safety, and we will continue to monitor the safety of these drugs.