Ambrisentan, a selective propionic-acid endothelin-1 (ET-1) type A receptor antagonist, is a vasodilator.1
Pulmonary Arterial Hypertension
Ambrisentan is used in the management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) in adults to improve exercise capacity and to delay clinical worsening.1, 9, 23 Ambrisentan is also used in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability.1, 44 Clinical studies establishing efficacy of ambrisentan were conducted 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.1, 23 Ambrisentan has been designated an orphan drug by FDA for use in the treatment of PAH.39
Efficacy of ambrisentan for the management of PAH has been established in 2 randomized, double-blind, multicenter, placebo-controlled trials (ARIES-1 and ARIES-2) of 12 weeks' duration in a total of 393 adults with WHO group 1 PAH; 64% of the patients had idiopathic or familial PAH and 36% had PAH associated with other disorders (connective tissue diseases [32%], HIV infection [3%], use of anorexigenic agents [1%]).1, 2, 4, 23, 24 Most patients enrolled in these trials had WHO functional class II (38%) or III (55%) PAH at study entry.1, 2, 4, 23 The trials were identically designed except for differences in the ambrisentan dosages studied.1, 2, 4, 23, 24 Patients in these 2 trials were randomized to receive ambrisentan (2.5, 5, or 10 mg once daily) or placebo in addition to standard therapy (e.g., anticoagulants, diuretics, calcium-channel blocking agents, and/or cardiac glycosides, but not prostacyclin analogs [e.g., epoprostenol, treprostinil, iloprost], other endothelin receptor antagonists [e.g., bosentan], or PDE type 5 inhibitors [e.g., sildenafil]).1, 2, 4, 23, 24 The primary end point, exercise capacity, was assessed using the 6-minute walking test.1, 2, 4, 23 Treatment with ambrisentan resulted in significant improvements in walking distance (placebo-corrected mean increases of 31-59 meters in the 5-mg group and 51 meters in the 10-mg group at 12 weeks).1, 2, 4, 23 Clinical worsening (defined as the time to first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, or early termination based on disease progression), evaluated as a secondary outcome measure in these studies, was substantially delayed in patients receiving ambrisentan compared with those receiving placebo.1, 2, 4, 23 At 12 weeks, 94-97% of ambrisentan-treated patients remained free of a clinical worsening event versus 79-89% of placebo-treated patients.1 In an open-label extension of the 2 randomized controlled studies, improvements in exercise capacity were maintained in patients who continued to receive ambrisentan;26 estimated rates of survival for the overall study group were 93, 85, and 79% at 1, 2, and 3 years, respectively.1
Use of ambrisentan in combination with tadalafil in patients with PAH was evaluated in a randomized, double-blind, active-controlled trial (AMBITION) in 605 patients with WHO group II (32%) or III (68%) PAH.1, 44 Patients were randomized to receive once daily therapy with the combination of ambrisentan 5 mg plus tadalafil 20 mg, monotherapy with ambrisentan 5 mg (plus placebo), or monotherapy with tadalafil 20 mg (plus placebo).1, 44 The dose of ambrisentan was increased to 10 mg at 8 weeks, and tadalafil was increased to 40 mg at 4 weeks, if tolerated.1, 44 The primary endpoint was time to first occurrence of clinical failure, defined as a composite of death, hospitalization for worsening PAH, short-term clinical worsening (>15% reduction from baseline in the 6-minute walk distance test plus WHO group III or IV symptoms experienced at 2 visits over 14 days), or inadequate long-term clinical response (reduction in 6-minute walk distance experienced at 2 visits over 14 days plus WHO class III or IV symptoms experienced at 2 visits over at least 6 months).1, 44 Patients in this study had idiopathic PAH (55%), heritable PAH (3%), or PAH associated with connective tissue diseases, congenital heart disease, stable HIV infection, or drugs or toxins (42%).1, 44 The median time from diagnosis to first study drug was 25 days.1 At baseline, the mean age was 55.7 years; most patients were white (90%) and female (76%).1 The risk of clinical failure events occurred in fewer patients receiving combination therapy (18%) than those receiving monotherapy with ambrisentan (34%) or monotherapy with tadalafil (28%).44 An improvement in the 6-minute walk distance test also occurred in the combination group compared to each monotherapy group.1 In a secondary analysis, there were numerically fewer deaths in the combination group (10%) compared to the pooled monotherapy group (14%) at the end of the study; however, the difference was not statistically different.45 A post-hoc analysis from randomization until 7 days after the end of each treatment also found that mortality was reduced with combination therapy (1%) compared with the pooled monotherapy group (4%).45
Current expert consensus guidelines recommend that all adult patients with symptomatic (World Health Organization [WHO] or New York Heart Association [NYHA] functional classification [FC] II-IV) pulmonary arterial hypertension (PAH) be treated with established PAH-specific medications (e.g., prostacyclin derivative [e.g., epoprostenol, treprostinil], PDE type 5 inhibitor [i.e. sildenafil, tadalafil], endothelin receptor antagonist [e.g., ambrisentan, bosentan, macitentan], or a soluble guanylate cyclase stimulator [e.g., riociguat]) to reduce symptoms, improve functional capacity, and to delay progression of PAH, hospitalization, and death.700 Selection of drug therapy should be based on disease severity (WHO/NYHA class), risk of further short-term deterioration, comorbid illnesses, concomitant medications, expected tolerance of known side effects, route of administration (i.e., oral, parenteral, inhaled), costs of therapy, and patient preferences.700 In addition, patients with PAH should receive supportive care (e.g., oxygen, diuretics, anticoagulants).700
For treatment-naïve PAH patients with WHO/NYHA FC II or III symptoms who are not candidates for, or who have failed calcium-channel blocking agent therapy, experts recommend initial combination therapy with ambrisentan and tadalafil, but give this a weak recommendation based on moderate quality evidence.700 Monotherapy with an endothelin-receptor antagonist (e.g., ambrisentan, bosentan, macitentan), phosphodiesterase type 5 inhibitor (e.g., sildenafil, tadalafil), or soluble guanylate cyclase stimulator (e.g., riociguat) can be initiated for patients who are intolerant to or unwilling to take combination treatment.700 Initial treatment with continuous IV epoprostenol, IV treprostinil, or subcutaneous treprostinil is recommended in patients with WHO/NYHA FC III who have evidence of rapid disease progression or poor prognosis; inhaled or oral prostanoids are recommended in patients who are unwilling and not able to manage parenteral prostanoids.700 In patients with WHO FC III PAH who have evidence of disease progression and/or poor clinical prognosis despite treatment with one or two classes of oral agents, consideration should be given to the addition of a parenteral or inhaled prostanoid (e.g., IV epoprostenol, IV treprostinil, inhaled treprostinil, inhaled iloprost).700
The 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension recommend initial oral combination therapy with ambrisentan and tadalafil or macitentan and tadalafil in patients with idiopathic, heritable, or drug-associated PAH without cardiopulmonary comorbidities.701
Results of a randomized, placebo-controlled trial in patients with idiopathic pulmonary fibrosis†, with or without pulmonary hypertension (WHO group 3), demonstrated no clinical benefit with ambrisentan therapy, but a relatively greater risk of disease progression, reduced pulmonary function, hospitalization, and death; the study was terminated early for these safety findings and lack of efficacy.1, 43
Dispensing and Administration Precautions
Ambrisentan is administered orally without regard to meals.1 Ambrisentan tablets should not be split, chewed, or crushed.1
If a dose of ambrisentan is missed, the dose should be taken as soon as it is remembered that day, and the next dose taken at the regularly scheduled time; 2 doses should not be taken at the same time to make up for a missed dose.1
Store ambrisentan tablets in their original packaging at 25°C (excursions permitted to 15-30°C).1
Pulmonary Arterial Hypertension
The initial dosage of ambrisentan for the treatment of pulmonary arterial hypertension (PAH) in adults is 5 mg once daily with or without tadalafil 20 mg once daily.1 Either ambrisentan or tadalafil can be increased at 4-week intervals to ambrisentan 10 mg or tadalafil 40 mg as needed or tolerated.1
When administered concomitantly with cyclosporine, dosage of ambrisentan should be limited to 5 mg once daily.1, 34
Ambrisentan should be avoided in patients with preexisting moderate or severe hepatic impairment.1 The manufacturer makes no specific recommendation in patients with mild pre-existing hepatic impairment; however, exposure to ambrisentan may be increased in these patients.1
Dosage adjustment is not required in patients with mild or moderate renal impairment; the drug has not been studied in those with severe renal impairment or on hemodialysis.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Fetal/Neonatal Morbidity and Mortality
A boxed warning about the risk of fetal harm is included in the prescribing information for ambrisentan.1 Ambrisentan may cause fetal harm if used during pregnancy; teratogenic (e.g., craniofacial defects, cardiovascular malformations, agenesis of the thymus and thyroid glands) and embryotoxic (e.g., decreased survival) effects have been demonstrated in animals.1 Available human data for endothelin receptor antagonists (ERAs) do not establish the presence or absence of major birth defects related to ambrisentan therapy.1
Pregnancy must be excluded in females of childbearing potential prior to initiation of ambrisentan therapy and prevented thereafter by the use of acceptable methods of contraception during and for 1 month following cessation of therapy.1, 18 If ambrisentan is used during pregnancy or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.1 When pregnancy is detected, the clinician should discontinue ambrisentan as soon as possible.1
Other Warnings and Precautions
Peripheral edema, usually mild to moderate in severity, has been reported in patients receiving ambrisentan; peripheral edema has occurred with greater frequency and severity in geriatric patients.1, 26 Peripheral edema and fluid retention were also more common with ambrisentan and tadalafil than with ambrisentan or tadalafil alone.1 Peripheral edema is a known class effect of endothelin-receptor antagonists and also a clinical consequence of pulmonary arterial hypertension (PAH).1, 26 Fluid retention, sometimes requiring intervention (e.g., diuretic therapy, fluid management, hospitalization), has been reported during postmarketing experience.1
If clinically important fluid retention occurs (with or without weight gain), the patient should be further evaluated to determine the cause and to assess the need for specific treatment or discontinuance of ambrisentan therapy.1
Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
If acute pulmonary edema occurs during ambrisentan therapy, the possibility of pulmonary veno-occlusive disease should be considered; if confirmed, the drug should be discontinued.1
Reduced sperm counts have been observed in some men with PAH receiving several months of treatment with another endothelin receptor antagonist (bosentan); therefore, the possibility of adverse effects on spermatogenesis with ambrisentan cannot be excluded.1 Patients should be advised about the potential adverse effects of ambrisentan on fertility.1
Decreases in hemoglobin concentration and hematocrit have been reported within the first few weeks of ambrisentan therapy, followed by stabilization; decreases in hemoglobin concentration do not appear to be related to hemorrhage or hemolysis but have required transfusion in some cases.1, 4, 9, 26 In the principal efficacy studies of ambrisentan in patients with PAH, a mean decrease in hemoglobin concentration of 0.8 g/dL was reported in patients receiving the drug; hemoglobin concentration decreased by more than 15% from baseline in 7% of patients receiving ambrisentan compared with 4% of those receiving placebo.1 The reduction in hemoglobin concentrations persisted for up to 4 years of treatment in the long-term open-label extension studies.1 Reduction in hemoglobin concentration and hematocrit resulting in transfusion due to anemia have been reported in postmarketing.1
Hemoglobin concentrations should be monitored prior to initiation of ambrisentan therapy, at 1 month of treatment, and periodically thereafter during ambrisentan therapy.1 The manufacturer states that the drug is not recommended in patients with clinically important anemia.1 Discontinuance of therapy should be considered in those who experience clinically important, otherwise unexplained reductions in hemoglobin concentration during therapy.1
Serious hepatotoxicity, including cirrhosis and liver failure, has been reported in patients receiving some endothelin-receptor antagonists (e.g., bosentan, sitaxsentan [not commercially available in the US]).1, 20, 22 Because hepatotoxicity was previously thought to be a class effect of these drugs,10, 11, 14, 19, 20, 22 a boxed warning regarding a potential risk of liver injury was included in the original FDA-approved labeling for ambrisentan.20 However, further evaluation of the available clinical trial data and postmarketing information indicate that the risk of liver injury with ambrisentan is low.1, 19, 20 In the pivotal 12-week controlled clinical trials of ambrisentan, elevations in serum aminotransferase (AST/ALT) concentrations to at least 3 or more times the upper limit of normal (ULN) were not observed in any patient receiving the drug but occurred in 2.3% of those who received placebo.1, 23, 24 Approximately 2% of those who continued to receive ambrisentan for up to 2 years in the open-label extension of these studies experienced aminotransferase abnormalities exceeding 3 times the ULN; most events were mild and did not result in drug discontinuance.26 Elevations of serum aminotransferase concentrations have been reported in some patients receiving ambrisentan during postmarketing experience; however, alternative causes of liver dysfunction (e.g., heart failure, hepatic congestion, hepatitis, alcohol use, concomitant use of hepatotoxic drugs) could be identified in nearly all cases.1, 19 Based on these findings, FDA has concluded that the incidence of hepatic effects with ambrisentan is similar to that observed in the general population of patients with PAH and has removed the liver injury warning from the drug's approved labeling.1, 19
Liver function tests should be monitored as clinically indicated in patients receiving ambrisentan.1 The drug should be discontinued if AST or ALT concentrations exceed 5 times the upper limit of normal (ULN) or if elevations in aminotransferase concentrations are accompanied by bilirubin concentrations exceeding 2 times the ULN or by manifestations of hepatic injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, abdominal pain, jaundice, dark urine, pruritus) for which alternative causes have been excluded.1
Based on data from animal reproduction studies, ambrisentan may cause embryofetal toxicity, including birth defects and fetal death, when administered to pregnant females and is contraindicated during pregnancy.1 Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as ambrisentan have not identified an increased risk of major birth defects; however, these data are limited.1 If ambrisentan is used during pregnancy, or if the patient becomes pregnant while taking ambrisentan, clinicians should advise the patient of the fetal risk.1
It is not known whether ambrisentan is distributed into human milk.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to ambrisentan in nursing infants, a decision should be made to discontinue nursing or the drug.1
Females and Males of Reproductive Potential
Exclude pregnancy in females of childbearing potential prior to initiation of ambrisentan therapy and prevent thereafter by the use of acceptable methods of contraception during and for 1 month following cessation of therapy.1 If ambrisentan is used during pregnancy or if the patient becomes pregnant during therapy, apprise the patient of the potential hazard to the fetus.1
Ambrisentan may have an adverse effect on spermatogenesis.1
Safety and efficacy of ambrisentan have not been established in children and adolescents younger than 18 years of age.1 Juvenile animal data revealed a reduction in brain weight, but no morphologic or neurobehavioral changes following drug exposures 1.8 to 7 times the human pediatric exposures at 10 mg (based on AUC).1
A higher incidence of peripheral edema has been observed in geriatric patients 65 years of age or older relative to younger adults.1 Clinical trials of ambrisentan included 21% of patients ≥65 years of age and 5% of patients ≥75 years of age.1 Improvement in walk distance was less in elderly compared to younger patients, although the prescribing information states to interpret this information, which comes from subgroup analysis, with caution.1
Because ambrisentan is substantially metabolized and eliminated by the liver and biliary system, the drug should not be used in patients with preexisting moderate or severe hepatic impairment.1, 20 No information is available on the use of ambrisentan in patients with mild hepatic impairment; however, systemic exposure to the drug may be increased in such patients.1
Ambrisentan has not been studied in patients with severe renal impairment or in those undergoing hemodialysis.1
Mild or moderate renal impairment had no clinically important effect on ambrisentan disposition.1
The most common adverse effects (>3%) of ambrisentan in clinical studies were peripheral edema, nasal congestion, sinusitis, and flushing.1
When used in combination with tadalafil, the most common adverse effects (>5% compared to either monotherapy) were peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, and bronchitis.1
In vitro studies indicate that ambrisentan is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C19 and by uridine 5'-diphosphate glucuronosyltransferases (UGTs; uridine diphosphoglucuronosyltransferase, UDP-glucuronate β-d-glucuronosyltransferase [acceptor-unspecific]) 1A9S, 2B7S, and 1A3S.1, 14, 32 The drug appears to be a substrate, but not an inhibitor, of the organic anion transport protein (OATP) and the P-glycoprotein (P-gp) transport system.1, 34 At clinically relevant concentrations, ambrisentan does not inhibit or induce CYP enzymes.1, 31
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or Inducers of CYP2C19
Pharmacokinetic interactions are possible, but experience with concomitant use of a potent CYP2C19 inhibitor (omeprazole) or a potent CYP2C19 inducer (rifampin) suggests that such interactions are not likely to be clinically important.1
Inhibitors or Inducers of CYP3A4
Pharmacokinetic interactions are possible, but experience to date has demonstrated a clinically important interaction only with cyclosporine, a CYP3A4 inhibitor.1, 34
Drugs Affecting the Organic Anion Transport Protein
Pharmacokinetic interaction (e.g., increased ambrisentan exposure) is possible with drugs that inhibit OATP (e.g., cyclosporine).1, 34
Drugs Affecting the P-glycoprotein Transport System
Pharmacokinetic interaction is possible with drugs that induce P-gp (e.g., rifampin), but such interactions are not likely to be clinically important.1, 36 Pharmacokinetic interaction (e.g., increased ambrisentan exposure) is possible with drugs that inhibit P-gp (e.g., cyclosporine).1, 34
Drugs Affecting Uridine 5'-Diphosphate Glucuronosyltransferase Enzymes
Pharmacokinetic interaction is possible with drugs that induce UGT (e.g., rifampin), but such interactions are not likely to be clinically important.1
In healthy individuals, concomitant administration of ambrisentan and cyclosporine increased AUC and peak plasma concentrations of ambrisentan by a factor of 2 and 1.5, respectively, but did not alter systemic exposure to cyclosporine.1, 34 Dosage of ambrisentan should be reduced to 5 mg once daily if administered concomitantly with cyclosporine.1, 34 No adjustment of cyclosporine dosage is required.1
In healthy men, concomitant administration of ambrisentan and digoxin resulted in a modest increase in systemic exposure (increased plasma concentrations and AUC) to digoxin; however, such changes are not likely to be clinically important.1, 35 No dosage adjustments are necessary.1
In healthy men, concomitant administration of ambrisentan and ketoconazole (a potent CYP3A4 inhibitor) modestly increased systemic exposure to ambrisentan and slightly prolonged elimination half-life of the drug; however, such changes were not considered clinically important.1, 32 No dosage adjustments are necessary.1, 32
Peak plasma concentrations and systemic exposure of ambrisentan were not altered with concomitant use of mycophenolate mofetil; pharmacokinetics of the active metabolite of mycophenolate mofetil, mycophenolic acid, also were unchanged.1 No dosage adjustments are necessary.1
Concomitant administration of ambrisentan and omeprazole did not substantially alter peak plasma concentrations or systemic exposure of ambrisentan.1 No dosage adjustments are necessary.1
Concomitant use of ambrisentan with an oral contraceptive containing ethinyl estradiol and norethindrone did not result in any clinically important changes in systemic exposure to the hormonal contraceptive.1, 37 No dosage adjustments are necessary.1
Clinically important pharmacokinetic interactions have not been observed with concomitant use of ambrisentan and the phosphodiesterase (PDE) type 5 inhibitors sildenafil or tadalafil in healthy individuals.1, 24, 27, 31, 33 No dosage adjustments are necessary.1, 24, 27, 31, 33
In healthy individuals, concomitant administration of ambrisentan and rifampin (potent inducer of CYP3A4 and inhibitor of OATP) increased systemic exposure to ambrisentan by twofold, but the effect was transient and not considered clinically important.1, 36 No dosage adjustments are necessary.1, 36
Peak plasma concentrations and systemic exposure of ambrisentan were not altered with concomitant use of ritonavir; no dosage adjustments are necessary.1
Peak plasma concentrations and systemic exposure of ambrisentan were not altered with concomitant use of tacrolimus; no dosage adjustments are necessary.1
No clinically important interaction has been observed with concomitant use of ambrisentan and warfarin.2, 4, 9, 14, 24, 26, 30 In a study in healthy individuals, administration of a single dose of warfarin (25 mg) with ambrisentan (10 mg daily) did not substantially alter the pharmacokinetics of either drug and had no clinically important effect on prothrombin time (PT) or international normalized ratio (INR).1, 24, 30 No dosage adjustments are necessary.1, 24, 30
Ambrisentan, a selective endothelin-1 (ET-1) type A receptor antagonist, is a vasodilator.1, 2, 4, 9, 12 Increased concentrations of ET-1, a potent vasoconstrictor, have been detected in the plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), suggesting a pathogenic role for ET-1 in this disorder.5, 7 Two ET-1 receptor subtypes, type A and type B, have been identified; activation of ET-1 type A receptors primarily mediates vasoconstriction and smooth muscle cell proliferation, while activation of ET-1 type B receptors results in vasodilation and facilitates clearance of ET-1.1, 8, 10 Ambrisentan is approximately 4000-fold more selective for the type A receptor compared with the type B receptor; however, the clinical implications of this selectivity remain to be established.1
Ambrisentan exhibits dose proportional pharmacokinetics in healthy adults.1 The absolute bioavailability is unknown, and peak concentrations occur approximately 2 hours after oral administration in healthy subjects and PAH patients.1 Food does not affect bioavailability of the drug.1 Ambrisentan is highly protein bound (99%).1 The drug is predominantly eliminated by non-renal pathways.1 The terminal half-life is 15 hours, but the effective half-life is about 9 hours.1 In vitro evidence indicates that ambrisentan is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C19, and by uridine diphosphate-glucuronosyltransferases (UGT) 1A9, 2B7, and 1A3.1 In vitro studies suggest that ambrisentan also is a substrate of the transporters p-glycoprotein and organic anion transport protein (OATP).1
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 5 mg* | Ambrisentan Tablets | |
10 mg* | Ambrisentan Tablets | |||
Letairis® | Gilead |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Gilead Sciences, Inc. Letairis® (ambrisentan) tablets prescribing information. Foster City, CA; 2025 Apr.
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