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Letairis (Ambrisentan) - Drug Interactions, Contraindications, Overdosage, etc



Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A4, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of Organic Anion Transport Protein (OATP). In vitro studies show ambrisentan is a substrate but not an inhibitor of P-gp.

The drug interaction potential of ambrisentan is not well characterized because in vivo drug interaction studies were not conducted with the following types of drugs: strong inhibitors of CYP3A4 (atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin), and CYP2C19 (omeprazole), strong inducers of CYP3A and 2C19 (rifampin), strong inhibitors of the transporters P-gp (cyclosporine A) and OATP (cyclosporine A, rifampin); and inducers of CYPs, UGTs and P-gp (rifampin). The impact of co-administration of such drugs on ambrisentan exposure is therefore unknown.

Cyclosporine A

Use caution when LETAIRIS is co-administered with cyclosporine A (see Warnings and Precautions 5.4).

Strong CYP3A or 2C19 Inhibitors

Use caution when LETAIRIS is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) or CYP2C19-inhibitors (e.g., omeprazole) [see Warnings and Precautions].

Inducers of P-gp, CYPs, and UGTs

Use caution when LETAIRIS is co-administered with inducers of P-gp, CYPs, and UGTs.


In healthy volunteers receiving warfarin, daily doses of LETAIRIS (10 mg once daily) did not have a clinically significant effect on prothrombin time (PT), International Normalized Ratio (INR), or the pharmacokinetics of S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate).

In patients with PAH receiving warfarin-type anticoagulants, concomitant administration of LETAIRIS did not result in a clinically relevant change in PT, INR or anticoagulant dose. Therefore, no dose-adjustments for warfarin or LETAIRIS are required when co-administered.


In healthy volunteers receiving a single dose of sildenafil (20 mg), daily doses of LETAIRIS (10 mg once daily) did not have a clinically relevant effect on the pharmacokinetics of sildenafil or the active metabolite, n-desmethyl sildenafil. Similarly, daily doses of sildenafil (20 mg tid) did not have a clinically relevant effect on the pharmacokinetics of a single dose of LETAIRIS (10 mg). Therefore, no dose-adjustments for sildenafil or LETAIRIS are required when co-administered.


There is no experience with overdosage of LETAIRIS. The highest single dose of LETAIRIS administered to healthy volunteers was 100 mg and the highest daily dose administered to patients with PAH was 10 mg once daily. Massive overdosage could potentially result in hypotension that may require intervention.


Pregnancy Category X

LETAIRIS may cause fetal harm when administered to a pregnant woman. Ambrisentan was teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; it was not studied at lower doses. In both species, there were 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. Teratogenicity is a class effect of endothelin receptor antagonists. There are no data on the use of LETAIRIS in pregnant women.

LETAIRIS is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Pregnancy must be excluded before the initiation of treatment with LETAIRIS and prevented thereafter by the use of two reliable methods of contraception [see Dosage and Administration].

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