LETAIRIS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LETAIRIS (LETAIRIS).
Ambrisentan is an endothelin receptor antagonist that selectively inhibits endothelin-1 (ET-1) binding to endothelin type A (ETA) receptors in pulmonary vascular smooth muscle cells, reducing vasoconstriction and smooth muscle proliferation.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2C19; also undergoes glucuronidation via UGT1A9 and UGT2B7. |
| Excretion | Primarily via biliary/fecal elimination (approximately 80% of metabolites and unchanged drug; ~20% renal as metabolites). |
| Half-life | Terminal elimination half-life is approximately 9 hours (range 6–12 hours) in healthy adults. |
| Protein binding | Protein binding is >90% (primarily to albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Volume of distribution is approximately 2.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Absolute oral bioavailability is 100% for the prodrug; active metabolite bioavailability is approximately 50% due to first-pass metabolism. |
| Onset of Action | Oral: Clinical effects observed within 15–30 minutes; maximal hemodynamic effects at 1–2 hours. |
| Duration of Action | Duration is approximately 12 hours with twice-daily dosing; clinical effects persist with regular administration. |
5 mg orally once daily, with or without food; may increase to 10 mg once daily if tolerated.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment. Not studied in end-stage renal disease. |
| Liver impairment | Avoid use in Child-Pugh class C; no dose adjustment in Child-Pugh class A or B, but use caution. |
| Pediatric use | Not indicated for pediatric use; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment; use with caution due to potential reduced renal or hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LETAIRIS (LETAIRIS).
| Breastfeeding | No human data available; M/P ratio unknown. In lactating rats, ambrisentan and/or its metabolites are excreted in milk. A risk to the breastfed infant cannot be excluded. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Letairis and any potential adverse effects on the infant. Alternative feeding methods are recommended during treatment. |
| Teratogenic Risk | Pregnancy Category X. Contraindicated in pregnancy. Based on animal studies and mechanism of action, there is evidence of fetal harm. In rats and rabbits, ambrisentan caused fetal malformations (e.g., craniofacial, cardiovascular) and fetal death at clinically relevant exposures. Risk of teratogenicity exists throughout pregnancy; use is contraindicated in all trimesters. Female patients must have two negative pregnancy tests before starting therapy and monthly thereafter. |
■ FDA Black Box Warning
Contraindicated in pregnancy due to fetal harm (teratogenicity). Females must be tested for pregnancy before starting therapy and monthly thereafter. Only available through restricted distribution program (LETAIRIS REMS).
| Serious Effects |
Pregnancy (absolute); idiopathic pulmonary fibrosis (IPF) with or without PAH; hypersensitivity to ambrisentan or any excipients.
| Precautions | Hepatotoxicity: Monitor liver function tests monthly. Fluid retention may occur; pre-existing edema may be exacerbated. Decreased sperm count has been observed. Monitor for signs of heart failure. |
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| Fetal Monitoring | Monitor hemoglobin/hematocrit at baseline and monthly for anemia. Monitor liver function tests (ALT, AST, bilirubin) at baseline and monthly. Monitor for fluid retention and heart failure. Female patients of reproductive potential require pregnancy testing at baseline, monthly during treatment, and one month after discontinuation. Obtain negative pregnancy test before starting therapy. |
| Fertility Effects | In animal studies, no adverse effects on male or female fertility were observed. In humans, Letairis may cause testicular tubular atrophy and decreased sperm count; effects on male fertility may be reversible. Effect on female fertility is unknown. Contraceptive advice is essential due to teratogenicity. |