Version July 2025
Ambrisentan is contraindicated for use during pregnancy because it may cause major birth defects if used by pregnant patients, based on studies in animals.
Therefore, for females of reproductive potential, exclude pregnancy before the initiation of treatment with ambrisentan. Advise use of effective contraception before initiation, during treatment, and for 1 month after treatment with ambrisentan. When pregnancy is detected, discontinue ambrisentan as soon as possible.
Pulmonary arterial hypertension:
Note: Consult a pulmonary arterial hypertension specialist for all management decisions; choice of therapy is dependent on etiology, risk stratification, and cardiopulmonary comorbidities (Ref).
Oral: Initial: 5 mg once daily; may increase to 10 mg once daily after ~4 weeks as tolerated.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
US labeling:
Mild-to-moderate impairment: No dosage adjustment necessary.
Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Canadian labeling: No dosage adjustment necessary.
Preexisting impairment:
US labeling:
Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; exposure may be increased.
Moderate or severe impairment: Use not recommended.
Canadian labeling:
Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely.
Severe impairment: Use is contraindicated.
ALT or AST >3 times ULN at baseline: Use is contraindicated.
Impairment developing during therapy:
US labeling:
ALT or AST >5 times ULN: Discontinue therapy.
ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.
Canadian labeling:
ALT or AST >3 times ULN: Discontinue therapy.
ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.
May consider reinitiation after ALT or AST levels normalize and if there are no signs/symptoms of hepatic injury or jaundice.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not always defined.
Cardiovascular: Peripheral edema (14% to 38%), flushing (4%)
Central nervous system: Headache (34%)
Gastrointestinal: Dyspepsia (3%)
Genitourinary: Oligospermia
Hematologic & oncologic: Decreased hemoglobin (7% to 10%; dose-dependent), anemia (7%), decreased hematocrit
Respiratory: Nasal congestion (6% to 16%), cough (13%), bronchitis (4%), sinusitis (3%)
<1%, postmarketing, and/or case reports: Cardiac failure, dizziness, fatigue, fluid retention, hypersensitivity, hypotension, increased liver enzymes, nausea, vomiting, weakness
Pregnancy; idiopathic pulmonary fibrosis, including idiopathic pulmonary fibrosis with pulmonary hypertension (WHO Group 3)
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ambrisentan or any component of the formulation; severe hepatic impairment (with or without cirrhosis); ALT or AST >3 times ULN at baseline; breastfeeding
Concerns related to adverse effects:
• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur; a higher incidence is seen with concomitant use of tadalafil and in elderly patients. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy.
• Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy. Use not recommended in patients with clinically significant anemia.
• Hepatic effects: Increases in serum liver aminotransferases have been reported during postmarketing use; however, in the majority of the cases, alternative causes of hepatotoxicity could be identified. Perform liver enzyme testing when clinically indicated. Discontinue therapy if signs/symptoms of hepatic injury appear, if serum liver aminotransferases >5 times ULN (US labeling) or >3 times ULN (Canadian labeling) are observed, or if aminotransferases are increased in the presence of bilirubin >2 times ULN. Hepatotoxicity has been reported with other endothelin receptor antagonists (eg, bosentan); however, ambrisentan may be tried in patients that have experienced asymptomatic increases in liver enzymes caused by another endothelin receptor antagonist after the liver enzymes have returned to normal.
Disease-related concerns:
• Hepatic impairment: Use caution in patients with mild hepatic impairment; ambrisentan exposure may be increased. The US labeling does not recommend use in patients with moderate or severe impairment. The Canadian labeling recommends use with caution in moderate impairment with monthly monitoring of ALT/AST during therapy and contraindicates use in severe hepatic impairment (with or without cirrhosis) and in patients with ALT or AST >3 times ULN at baseline.
• Pulmonary veno-occlusive disease (PVOD): Discontinue in any patient with pulmonary edema suggestive of PVOD.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Letairis: 5 mg, 10 mg [contains fd&c red #40(allura red ac)aluminum lake]
Generic: 5 mg, 10 mg
Yes
Tablets (Ambrisentan Oral)
5 mg (per each): $242.67 - $368.91
10 mg (per each): $242.67 - $368.91
Tablets (Letairis Oral)
5 mg (per each): $549.85
10 mg (per each): $549.85
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Volibris: 5 mg, 10 mg [contains fd&c red #40(allura red ac)aluminum lake]
Generic: 5 mg, 10 mg
Oral: Swallow tablet whole. Do not split, crush, or chew tablets. Administer with or without food.
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022081s041lbl.pdf#page=26, must be dispensed with this medication.
Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening; in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).
Ambrisentan may be confused with Ambien
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Letaris, a formerly marketed Dutch brand name product for letrozole, may be confused with Letairis, a US brand name for ambrisentan.
Substrate of CYP2C19 (Minor), CYP3A4 (Minor), OATP1B1/1B3, P-glycoprotein (Minor), UGT1A3, UGT1A9, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Asciminib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Belumosudil: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid coadministration of belumosudil with these substrates of OATP1B1/1B3 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the OATP1B1/1B3 substrate may be required. Risk D: Consider Therapy Modification
Bulevirtide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Coadministration of bulevirtide with OATP1B1/1B3 (also known as SLCO1B1/1B3) substrates should be avoided when possible. If used together, close clinical monitoring is recommended. Risk D: Consider Therapy Modification
Ceftobiprole Medocaril: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid
CycloSPORINE (Systemic): May increase serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg daily and monitor for ambrisentan adverse reactions in patients receiving cyclosporine. Risk D: Consider Therapy Modification
Darolutamide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Eltrombopag: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Encorafenib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Gemfibrozil: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Leflunomide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Leniolisib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid
Pretomanid: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Sparsentan: May increase adverse/toxic effects of Endothelin Receptor Antagonists. Risk X: Avoid
Teriflunomide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Trofinetide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider Therapy Modification
Voclosporin: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Verify pregnancy status prior to initiating treatment; exclude pregnancy prior to use in patients who could become pregnant. Conduct additional pregnancy testing if the onset of menses is delayed or if pregnancy is suspected during treatment.
Patients who could become pregnant should use effective contraception prior to starting treatment, during therapy, and for 1 month after the last dose of ambrisentan.
Sperm counts may be reduced during treatment (as observed with bosentan).
Based on data from animal reproduction studies and postmarketing data from other endothelin receptor antagonists, in utero exposure to ambrisentan may cause fetal harm, including birth defects and fetal death.
Outcome data following maternal use of ambrisentan during pregnancy are limited (Amann 2023). Ambrisentan is contraindicated in patients who are pregnant; discontinue as soon as possible if pregnancy occurs during treatment.
Untreated maternal pulmonary arterial hypertension (PAH) is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction, and premature labor. Patients with PAH are encouraged to avoid becoming pregnant (ESC [Regitz-Zagrosek 2018]; ESC/ERS [Humbert 2022]).
It is not known if ambrisentan is present in human milk.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, considering the importance of treatment to the mother.
Monitor for significant peripheral edema and evaluate etiology if it occurs; hepatic enzyme testing when clinically appropriate. The Canadian labeling recommends hepatic function testing at baseline then as clinically indicated (all patients) and monthly during therapy (patients with moderate impairment or other risk factors [eg, significant right heart failure, preexisting hepatic disease or previously elevated transaminases, concurrent medications known to increase transaminases]).
Exclude pregnancy prior to initiating therapy in patients who could become pregnant. Hemoglobin and hematocrit should be measured at baseline, at 1 month, and periodically thereafter (generally stabilizes after the first few weeks of treatment).
Blocks endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of ETA receptors, located primarily in pulmonary vascular smooth muscle cells is associated with vasoconstriction and cellular proliferation. Stimulation of ETB receptors, located in both pulmonary vascular endothelial cells and smooth muscle cells is associated with vasodilation, antiproliferative effects, and endothelin clearance. Although ambrisentan blocks both ETA and ETB receptors, the affinity is greater for the ETA receptor (>4,000-fold higher affinity).
Protein binding: 99%
Metabolism: Hepatic via CYP3A4, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S; in vitro studies also suggest it is a substrate of organic anion transporting polypeptides (OATP) 1B1 and 1B3 and P-glycoprotein (P-gp)
Half-life elimination: ~9 hours
Time to peak, plasma: ~2 hours
Excretion: Primarily nonrenal
