Ambrisentan
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: EMBRYO-FETAL TOXICITY Letairis is contraindicated for use during pregnancy because it may cause major birth defects if used by pregnant patients, based on studies in animals [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ] . Therefore, for females of reproductive potential, exclude pregnancy before the initiation of treatment with Letairis. Advise use of effective contraception before initiation, during treatment, and for one month after treatment with Letairis [see Dosage and Administration (2.2) Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ].
When pregnancy is detected, discontinue Letairis as soon as possible ( 5.1 ). WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Based on animal data Letairis may cause fetal harm if used during pregnancy ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: Exclude pregnancy before the start of treatment. Use effective contraception prior to initiation of treatment, during treatment, and for one month after treatment with Letairis ( 2.2 , 4.1 , 5.1 , 8.1 , 8.3 ) When pregnancy is detected, discontinue Letairis as soon as possible ( 5.1 ).
Handling and access
NIOSH hazardous drug
Table 2NIOSH lists ambrisentan as a hazardous drug. AHFS class: 48:48 vasodilating agents; 24:12.92 vasodilating agents, miscellaneous.
- Meets the NIOSH definition of a hazardous drug (carcinogenicity, developmental or reproductive toxicity, organ toxicity at low doses, or genotoxicity) without MSHI or a Group 1 or 2A carcinogen classification.
- Only a developmental and/or reproductive hazard: precautions matter most for workers who are pregnant, breastfeeding, or trying to conceive.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
REMS
Some productsStated in 2 other labels; not in the label quoted here.
- Restricted distribution (ETASU)
- Prescriber certification or enrollment
- Pharmacy certification
- Medication Guide
Endothelin Receptor Antagonist
Dosing in kidney impairment
Renal Impairment The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure to ambrisentan [see Clinical Pharmacology ] .
Dose adjustment of Letairis in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment. The impact of hemodialysis on the disposition of ambrisentan has not been investigated.
Dosing in liver impairment
Hepatic Impairment Pre-existing Hepatic Impairment The influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology] .
Letairis is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Letairis in patients with mild pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients. Elevation of Liver Transaminases Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure [see Adverse Reactions (6.1 , 6.2) ].
In patients who develop hepatic impairment after Letairis initiation, the cause of liver injury should be fully investigated. Discontinue Letairis if elevations of liver aminotransferases are >5 × ULN or if elevations are accompanied by bilirubin >2 × ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.
Drug interactions
Check ambrisentan against a medication listLabel text (1 paragraph)
Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine [see Clinical Pharmacology (12.3) ] . Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily ( 7 ).
Contraindications
Pregnancy ( 4.1 ) Idiopathic Pulmonary Fibrosis ( 4.2 )
4.1 Pregnancy Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in females who are pregnant. Letairis was consistently shown to have teratogenic effects when administered to animals. 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 [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ] .
4.2 Idiopathic Pulmonary Fibrosis Letairis is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.4) ].
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
ELikelihood score E: Unlikely cause of clinically apparent liver injury.
Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, Letairis may cause fetal harm, including birth defects and fetal death, when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on Letairis use in pregnant women. Available data from post-marketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as Letairis have not identified an increased risk of major birth defects; however, these data are limited.
Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data ] .
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications (4.1) , Warnings and Precautions (5.1) ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data Animal Data Letairis was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•µg/mL) in rats and ≥7 mg/kg/day (24.7 h•µg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•µg/mL) based on AUC. 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.
A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 ×, and 170 × (on a mg/m 2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects…
Breastfeeding (LactMed)
No information is available on the use of ambrisentan during breastfeeding. Because ambrisentan is more than 99% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during ambrisentan therapy. Ambrisentan and its active metabolite should be completely eliminated from milk in 3 days.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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