Vasodilator
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of ambrisentan in human pregnancy have been located. The animal data suggest risk if the drug is used in human pregnancy. In a black-box warning, the manufacturer classifies ambrisentan as contraindicated in women who are or may become pregnant (1). Pregnancy must be excluded before the initiation of therapy and women of reproductive potential must use two reliable methods of contraception. Monthly pregnancy tests are required. In addition, ambrisentan is available only through a special restricted distribution program because of the dual risk of teratogenicity and the potential for liver injury. Only physicians and pharmacies registered in this program can prescribe and distribute the drug.
FETAL RISK SUMMARY
Ambrisentan is an oral endothelin receptor antagonist in the same class as bosentan. It is indicated for the treatment of pulmonary arterial hypertension (WHO group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. The molecule is a carboxylic acid with a pKa of 4.0 and is water soluble at higher pH. Plasma protein binding is 99%. The terminal elimination half-life is 15 hours but the effective half-life is 9 hours (1).
Animal reproduction studies have been conducted in rats and rabbits, but the doses used were not compared with the human dose. The drug was teratogenic in both species causing abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. The malformations were similar to those observed with other endothelin receptor antagonists and were thought to be a class effect. In rats given doses that were 17, 51, and 170 times, respectively, the maximum oral human dose of 10 mg based on BSA during late gestation and through weaning, decreased newborn pup survival was observed with the middle and high doses. The high dose was also associated with adverse effects on testicle size and fertility of pups (1).
It is not known if ambrisentan crosses the human placenta. Although the molecular weight (about 378) and the elimination half-life suggest that the drug will cross the placenta, the low lipid solubility and the high plasma binding might mitigate the amount reaching the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of ambrisentan during human lactation have been located. Although the molecular weight (about 378) and the elimination half-life (15 hours) suggest that the drug will be excreted into breast milk, the low lipid solubility and the high plasma binding (99%) might mitigate the amount in milk. The effect of exposure on a nursing infant is unknown, but the potential for toxicity is a concern. Therefore, until human data are available, the safest course is to not breastfeed during treatment with ambrisentan.
Reference
1.Product information. Letairis. Gilead Sciences, 2008.