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 Drugs.com on Mar 17, 2025. Written by ASHP.

Introduction

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

General

Pretreatment Screening

• Perform a pregnancy test prior to starting ambrisentan in females of reproductive potential.

• Monitor hemoglobin concentrations prior to starting ambrisentan therapy.

Patient Monitoring

• Perform monthly pregnancy tests in females of reproductive potential.

• Monitor for signs of fluid retention (with or without weight gain).

• Monitor hemoglobin concentrations at 1 month of treatment, and periodically thereafter.

• Monitor liver function tests as clinically indicated.

Dispensing and Administration Precautions

• Handling and disposal: Ambrisentan is a hazardous drug based on reproductive concerns; follow procedures for proper handling (e.g. use of gloves) when handling the oral tablets.

REMS

• Because of the risk of embryofetal toxicity, ambrisentan is available to female patients only through a restricted distribution program called the Ambrisentan Risk Evaluation and Mitigation Strategy (REMS). All female patients regardless of childbearing potential must enroll in the REMS program prior to initiating ambrisentan; in addition, females of childbearing potential must comply with all pregnancy testing and contraception requirements of the program. Male patients are exempt from these restrictions and do not need to enroll in the program. Certain restrictions and conditions also apply to prepubertal females.

  As a condition of the REMS program, ambrisentan therapy should be initiated in females of childbearing potential only after a negative pregnancy test is obtained; pregnancy tests should be performed monthly during therapy and at 1 month following discontinuance of therapy.

• Clinicians and pharmacies must also be registered with the Ambrisentan REMS and comply with all terms of the program before they can prescribe or dispense ambrisentan. In addition, pharmacies must only dispense the drug to authorized patients.

• For additional information about the Ambrisentan REMS program, clinicians may call 888-417-3172 or visit www.ambrisentanrems.us.com.

Administration

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.

Dosage

Adults

PAH

Oral

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

Adults

PAH

Oral

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

Contraindications

• Pregnancy.

• Idiopathic pulmonary fibrosis, with or without pulmonary hypertension (WHO group 3).

Warnings/Precautions

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

Pregnancy

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

Lactation

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

Ambrisentan Pharmacokinetics

Absorption

Bioavailability

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

Food

Food does not affect absorption.

Distribution

Extent

Detected in plasma 2 hours after administration.

Plasma Protein Binding

99%.

Elimination

Metabolism

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.

Half-life

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 Cl_cr 20–150 mL/minute).

Stability

Storage

Oral

Tablets

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

Actions

• Exhibits specific, selective antagonism of ET-1 type A receptor in the endothelium and vascular smooth muscle. Increased concentrations of ET-1, a potent vasoconstrictor, have been detected in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disorder.

• Pharmacologically related to other ET-1 receptor antagonists (e.g., bosentan), but exhibits 4000-fold greater selectivity for ET-1 type A receptor versus type B receptor. Clinical implications of receptor selectivity currently not established.

• Improves exercise capacity in PAH patients by inhibiting ET-1 type A receptor-mediated vasoconstriction and cell proliferation.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Risk of fetal harm; advise women of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of therapy. Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], progesterone implant, or tubal sterilization) or a combination of methods (either one hormonal and one barrier method or 2 barrier methods where one form is the male condom). Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections. Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide. If the partner has had a vasectomy, an additional hormonal or barrier method must be used.

• Advise women to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected; clinicians should perform a pregnancy test if pregnancy is suspected for any reason and provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or known or suspected contraceptive failure. Apprise patient of potential risk to fetus if pregnancy occurs.

• Advise female patients to enroll in the Ambrisentan Risk Evaluation and Mitigation Strategy (REMS) program and comply with all contraceptive and pregnancy testing requirements. Advise prepubertal females to monitor their reproductive status and immediately report changes (e.g., breast development, pubic hair) to their clinician.

• Potential risk of liver toxicity. Advise patients to inform their clinicians of any unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.

• Advise patients of the importance of periodic monitoring of RBC counts during treatment.

• Advise patients of the risk for decreases in sperm count (in male patients) and fluid overload.

• Advise patients of the importance of taking ambrisentan as prescribed and of not interrupting or discontinuing therapy without consulting a clinician.

• Advise patients to not take a double dose to make up for a missed dose but instead take the next scheduled dose.

• Advise patients to swallow tablets whole and not to split, chew, or crush tablets.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy including prescription (e.g., cyclosporine) and OTC drugs, as well as any concomitant illnesses.

• Inform patients of other important precautionary information. (See Cautions.)

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.

Preparations

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

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