Ambrisentan, bosentan, and macitentan are FDA-approved for treatment of pulmonary arterial hypertension (PAH); aprocitentan is approved for treatment of hypertension and sparsentan is approved to slow kidney function decline in patients with primary immunoglobulin A nephropathy (IgAN).

The embryofetal toxicity REMS requirement for these drugs was based on studies in pregnant animals. Removal of the REMS requirement was based on an analysis in humans showing that exposure to an endothelin receptor antagonist during pregnancy was not associated with the congenital malformations observed in animal studies.1

All of these drugs still include a boxed warning in their labels about the risk of embryofetal toxicity associated with their use in animals. Pregnancy should be excluded before starting treatment with an endothelin receptor antagonist, and women with reproductive potential should use effective contraception while taking any of these drugs.

Because of increased risks of hepatotoxicity associated with their use, bosentan and sparsentan are still only available through a REMS program.