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Ambrisentan (Monograph)

Brand name: Letairis
Drug class: Endothelin receptor antagonists
Chemical name: (+)-(2S)-2-[(4,6-Diamethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
Molecular formula: C22H22N2O4
CAS number: 177036-94-1

Medically reviewed by on Mar 27, 2023. Written by ASHP.


Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for ambrisentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of ambrisentan and consists of the following: elements to assure safe use and implementation system. See


  • May cause fetal harm; contraindicated in pregnant women.

    Exclude pregnancy in females of childbearing potential before initiation of treatment and prevent thereafter by using acceptable methods of contraception during and for 1 month following discontinuance of therapy.

  • Distribution of ambrisentan is restricted in all female patients.


Vasodilator; a propionic-acid, endothelin-1 (ET-1) type A receptor-selective antagonist.

Uses for Ambrisentan

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and delay clinical worsening. Also used in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability.

Efficacy established principally in patients with WHO functional class II or III PAH (idiopathic, heritable, or associated with connective tissue diseases) as monotherapy or in combination with tadalafil.

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. Endothelin-receptor antagonists such as ambrisentan are recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

Has been designated an orphan drug by FDA for treatment of PAH.

Pulmonary Fibrosis

No clinical benefit observed in a controlled study in patients with pulmonary fibrosis [off-label] with or without pulmonary hypertension (WHO group 3); relatively greater risk of disease progression and death observed with ambrisentan versus placebo.

Ambrisentan Dosage and Administration


Pretreatment Screening

Patient Monitoring

Dispensing and Administration Precautions



Oral Administration

Administer orally without regard to meals.

Do not split, chew, or crush tablets.

If a dose is missed, take as soon as it is remembered that day, and take next dose at regularly scheduled time; do not take 2 doses at the same time to make up for a missed dose.




Initially, 5 mg once daily with or without tadalafil 20 mg once daily. May increase either ambrisentan or tadalafil at 4-week intervals to ambrisentan 10 mg or tadalafil 40 mg as needed or tolerated.

Do not exceed 5 mg once daily if administered concomitantly with cyclosporine.

Prescribing Limits



Safety and efficacy of dosages >10 mg daily not established.

Special Populations

Hepatic Impairment

Avoid use in patients with preexisting moderate or severe hepatic impairment. Manufacturer makes no specific recommendation in patients with mild pre-existing hepatic impairment; however, exposure to ambrisentan may be increased.

Renal Impairment

Dosage adjustment not required in patients with mild or moderate renal impairment; not studied in patients with severe renal impairment or on hemodialysis.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Ambrisentan



Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals. (See Boxed Warning.)

If ambrisentan used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.

Fluid Retention

Peripheral edema reported, usually mild to moderate in severity; occurred with greater frequency and severity in geriatric patients. Peripheral edema and fluid retention more common with ambrisentan and tadalafil than with ambrisentan or tadalafil alone.

Peripheral edema is a known class effect of endothelin-receptor antagonists and also a consequence of PAH.

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported.

If clinically important fluid retention occurs, further evaluate to determine cause; initiate appropriate treatment or discontinue ambrisentan if necessary.

Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)

If acute pulmonary edema occurs during therapy, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue drug.

Fertility in Males

Reduced sperm counts observed in some men with PAH following treatment with another endothelin receptor antagonist (bosentan); possibility of adverse effects on spermatogenesis with ambrisentan cannot be excluded.

Hematologic Effects

Decreases in hemoglobin and hematocrit reported within first few weeks of treatment, followed by stabilization; hemoglobin decreases do not appear to be related to hemorrhage or hemolysis.

Monitor hemoglobin concentrations prior to initiation, at 1 month, and periodically during therapy.

Not recommended in patients with clinically important anemia. Consider discontinuance of therapy if clinically important, otherwise unexplained reductions in hemoglobin occur.

Hepatic Effects

Serious hepatotoxicity (e.g., cirrhosis, liver failure) reported with some endothelin-receptor antagonists (e.g., bosentan, sitaxsentan [not commercially available in the US]).

Monitor AST/ALT concentrations if clinically indicated. Discontinue therapy if AST/ALT >5 times ULN or if elevations are accompanied by bilirubin concentrations >2 times ULN or by manifestations of liver impairment and alternative causes have been excluded.

Specific Populations


May cause fetal harm. Exclude pregnancy prior to starting ambrisentan and perform monthly pregnancy tests during and for 1 month after stopping treatment.


Not known whether distributed into human milk. Discontinue nursing or the drug.

Females and Males of Reproductive Potential

Perform a pregnancy test prior to starting ambrisentan in females of reproductive potential. Because of risk of fetal harm, highly effective contraception required for females of reproductive potential during treatment and for 1 month after discontinuance.

Potential adverse effect on spermatogenesis.

Pediatric Use

Safety and efficacy not established.

Juvenile animal data revealed a reduction in brain weight but no morphologic or neurobehavioral changes with drug exposure.

Geriatric Use

Higher incidence of peripheral edema observed in geriatric patients ≥65 years of age relative to younger adults. Improvement in walk distance was less in elderly compared to younger patients, although prescribing information states to interpret this information, which comes from subgroup analysis, with caution.

Hepatic Impairment

Substantially metabolized and eliminated by the liver and biliary system. Avoid use in patients with moderate to severe hepatic impairment. No information on use in patients with mild hepatic impairment; possible increased systemic exposure.

Renal Impairment

Not studied in patients with severe renal impairment or in those undergoing hemodialysis.

No clinically important effect of mild or moderate renal impairment on ambrisentan disposition.

Common Adverse Effects

Common adverse effects (>3%): peripheral edema, nasal congestion, sinusitis, flushing.

When used in combination with tadalafil, common adverse effects (>5%): peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, bronchitis.

Drug Interactions

Metabolized by UGT enzymes 1A9S, 2B7S, and 1A3S and by CYP3A4 and CYP2C19 isoenzymes in vitro.

Appears to be a substrate of P-glycoprotein and organic anion transport protein (OATP).

Does not inhibit OATP or P-glycoprotein.

Does not inhibit or induce CYP enzymes at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP2C19: Pharmacokinetic interaction possible but not likely to be clinically important.

Inhibitors or inducers of CYP3A4: Pharmacokinetic interaction possible but clinically important interaction demonstrated to date only with cyclosporine (a CYP3A4 inhibitor).

Drugs Affecting OATP

Potential pharmacokinetic interaction with drugs that inhibit OATP.

Drugs Affecting the P-glycoprotein Transport System

Pharmacokinetic interactions possible with inhibitors or inducers of P-glycoprotein.

Drugs Affecting Uridine Diphosphate Glucuronosyltransferase Enzymes

Pharmacokinetic interactions possible with drugs that induce UGT but not likely to be clinically important.

Specific Drugs





Increased AUC and peak plasma ambrisentan concentrations by 2- and 1.5-fold, respectively; no change in cyclosporine exposure

Limit ambrisentan dosage to 5 mg once daily

No adjustment of cyclosporine dosage required


Modest increase in digoxin exposure

Not considered clinically important; no dosage adjustments necessary

Hormonal contraceptives

Ethinyl estradiol/norethindrone: No clinically important change in systemic exposure to oral contraceptive

No dosage adjustments necessary


Modest increase in ambrisentan exposure and half-life

Not considered clinically important; no dosage adjustments necessary

Mycophenolate mofetil

Pharmacokinetics of either drug not altered

No dosage adjustments necessary


Peak plasma concentrations and systemic exposure of ambrisentan not substantially altered

No dosage adjustments necessary

PDE type 5 inhibitors (sildenafil, tadalafil)

Clinically important pharmacokinetic interaction not observed

No dosage adjustments necessary


Increased ambrisentan exposure by twofold, but effect was transient and not considered clinically important

No dosage adjustments necessary


Peak plasma concentrations and systemic exposure of ambrisentan not altered

No dosage adjustments necessary


Peak plasma concentrations and systemic exposure of ambrisentan not altered

No dosage adjustments necessary


Clinically important interaction not observed

No dosage adjustments necessary

Ambrisentan Pharmacokinetics



Rapidly absorbed following oral administration, with peak plasma concentrations occurring within approximately 2 hours. Absolute bioavailability unknown.


Food does not affect absorption.



Detected in plasma 2 hours after administration.

Plasma Protein Binding




Undergoes hepatic metabolism, principally by glucuronidation and to a lesser extent by hydroxylation.

Elimination Route

Predominantly nonrenal pathways; contributions of metabolism and biliary excretion not well characterized. Most of radiolabeled dose recovered in feces as unchanged drug or glucuronide metabolite. Undergoes enterohepatic recycling.


Terminal half-life 15 hours; effective half-life approximately 9 hours.

Special Populations

Potential for increased exposure to ambrisentan in patients with hepatic impairment.

Serum ambrisentan concentrations not affected in patients with mild or moderate renal impairment (based on studies in individuals with Clcr 20–150 mL/minute).





25°C (excursions permitted between 15–30°C) in original package.


Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of ambrisentan is restricted in female patients ([Web]). (See REMS under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name



Dosage Forms


Brand Names



Tablets, film-coated

5 mg*

Ambrisentan Tablets



10 mg*

Ambrisentan Tablets



AHFS DI Essentials™. © Copyright 2024, Selected Revisions March 27, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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