Letairis (Ambrisentan)
ambrisentan
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Pulmonary arterial hypertension (WHO Group 1) — to improve exercise ability and delay clinical worsening | Adults (WHO FC II-III) | Monotherapy; also studied in combination with tadalafil (AMBITION) | FDA Approved |
Ambrisentan is indicated for the treatment of pulmonary arterial hypertension in adult patients with WHO functional class II or III symptoms. The pivotal ARIES-1 and ARIES-2 trials enrolled predominantly patients with idiopathic or heritable PAH (60%) and connective tissue disease-associated PAH (34%). The AMBITION trial subsequently established initial combination therapy with ambrisentan plus tadalafil as a preferred first-line strategy, demonstrating a 50% reduction in clinical failure events compared with either agent alone (FDA PI; NEJM 2015).
Chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4): Limited data from the ARIES-3 open-label study included a small subset of CTEPH patients. Evidence quality: Low. Not a substitute for surgical pulmonary endarterectomy in operable disease.
Pediatric PAH: Small pharmacokinetic and safety studies suggest ambrisentan may be tolerated in children, but safety and efficacy have not been established by the FDA. Evidence quality: Low.
Dosing
Adult Dosing — By Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PAH monotherapy — new diagnosis, WHO FC II-III | 5 mg once daily | 5-10 mg once daily | 10 mg/day | Titrate at 4-week intervals based on tolerability Do not split, crush, or chew tablets; food does not affect absorption |
| PAH — initial combination with tadalafil (AMBITION regimen) | 5 mg once daily + tadalafil 20 mg once daily | 10 mg once daily + tadalafil 40 mg once daily | 10 mg/day | Uptitrate ambrisentan at 8 weeks; tadalafil at 4 weeks ESC/ERS 2022 Class I recommendation for initial combination in iPAH/hPAH |
| PAH with concurrent cyclosporine use | 5 mg once daily | 5 mg once daily | 5 mg/day | Cyclosporine approximately doubles ambrisentan exposure; do not exceed 5 mg FDA PI mandates dose cap |
| PAH in elderly patients (age 65 and older) | 5 mg once daily | 5-10 mg once daily | 10 mg/day | Higher incidence of peripheral edema (29% vs 14% in younger adults) Smaller improvement in 6MWD observed in subgroup analyses |
| Transition from bosentan due to hepatotoxicity | 5 mg once daily | 5-10 mg once daily | 10 mg/day | Ensure aminotransferases have normalized before switching Lower risk of hepatic enzyme elevations compared with bosentan |
Unlike bosentan, ambrisentan does not require dose-dependent titration through a mandatory initial period. However, starting at 5 mg with optional uptitration at 4 weeks allows assessment of tolerability, particularly regarding peripheral edema. Doses above 10 mg daily have not been studied in PAH patients. No dose adjustment is needed for renal impairment, including severe renal impairment, although hemodialysis clearance has not been characterized.
Pharmacology
Mechanism of Action
Ambrisentan is a propanoic acid-derived, non-sulfonamide endothelin receptor antagonist with high selectivity for the endothelin type-A (ETA) receptor over the ETB receptor (selectivity ratio exceeding 4,000:1). In pulmonary arterial hypertension, endothelin-1 (ET-1) concentrations are elevated up to 10-fold in plasma and 9-fold in pulmonary vascular endothelium, driving pathological vasoconstriction and smooth muscle proliferation through ETA receptor activation. By selectively blocking ETA, ambrisentan inhibits vasoconstriction and cell proliferation while preserving ETB-mediated vasodilation, nitric oxide release, and endothelin clearance. This selectivity profile distinguishes ambrisentan from dual-receptor antagonists like bosentan. The clinical significance of this selectivity difference, however, has not been established in comparative outcome trials.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; Tmax ~2 h; food does not affect bioavailability; dose-linear PK over 1-100 mg | Can be taken with or without food; predictable exposure across dose range |
| Distribution | 99% protein bound; substrate of P-glycoprotein (P-gp) and OATP | Highly protein-bound; P-gp and OATP substrate status relevant to cyclosporine interaction |
| Metabolism | Primarily hepatic glucuronidation (phase II UGTs); minor oxidative metabolism via CYP3A4 and CYP2C19; active metabolite (4-hydroxymethyl) ~4% of parent AUC | Minimal CYP-mediated metabolism explains low drug interaction potential compared with bosentan; not a CYP inducer or clinically significant inhibitor |
| Elimination | Predominantly non-renal (hepatic/biliary); t1/2 ~15 h at steady state; steady state reached in 3-4 days | Once-daily dosing supported by 15 h half-life; no renal dose adjustment required; not studied in hemodialysis |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Peripheral edema | 17% (vs 11% placebo) | Class effect of ERAs; higher in elderly (29%); may require diuretics; distinguish from worsening right heart failure |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nasal congestion | 6% (vs 2% placebo) | Dose-dependent; related to vasodilatory effects; usually mild |
| Flushing | 4% (vs 1% placebo) | Vasodilatory mechanism; tends to diminish over time |
| Sinusitis | 3% (vs 0% placebo) | May overlap with nasal congestion; treat symptomatically |
| Headache | Common (higher with 10 mg; EMA SmPC) | Not in FDA PI Table 1 (>3% placebo-adjusted); classified as common (1-10%) in EMA SmPC; dose-related; generally self-limiting |
| Hemoglobin decrease | 7% marked decrease (>15% from baseline) | Mean decrease 0.8 g/dL over 12 weeks; onset within first few weeks, then stabilizes; not from hemorrhage or hemolysis; 10% incidence at 10 mg dose |
| Palpitations | Common (EMA SmPC) | Classified as common (1-10%) in EMA SmPC; likely secondary to vasodilation; not listed in FDA PI Table 1 |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Embryo-fetal toxicity | Expected if exposed | First trimester | Absolute contraindication; pregnancy test before start, monthly during, and 1 month after; discontinue immediately if pregnancy detected |
| Heart failure / fluid retention requiring hospitalization | Rare (postmarketing) | Weeks after initiation | Assess volume status; initiate diuretics; evaluate for decompensated right heart failure; consider discontinuation |
| Anemia requiring transfusion | Rare (postmarketing) | First weeks to months | Exclude other causes; consider discontinuation if clinically significant and unexplained |
| Hepatotoxicity (aminotransferase elevation >3x ULN) | 0% in ARIES trials (vs 2.3% placebo); rare postmarketing | Variable | Discontinue if ALT/AST >5x ULN or elevated with bilirubin >2x ULN; investigate cause fully |
| Hypersensitivity (angioedema, rash) | Rare (postmarketing) | Any time | Discontinue permanently; standard allergy management |
| Pulmonary edema (PVOD-related) | Very rare | Early in therapy | Consider pulmonary veno-occlusive disease; discontinue if confirmed |
| Decreased sperm count | Frequency unknown (class effect) | With prolonged use | Counsel male patients about potential fertility effects before initiation |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Peripheral edema | <1% | Most common non-PAH-related cause in both monotherapy and combination arms |
| Dyspnea | <1% | Often difficult to distinguish from disease progression |
Peripheral edema is the most frequently encountered adverse effect of ambrisentan. It is important to distinguish ERA-related fluid retention from worsening right ventricular failure. If weight gain exceeds 2-3 kg over days, assess jugular venous pressure, hepatic congestion markers, and BNP levels. Mild edema can generally be managed with loop diuretics. Hospitalization for fluid management has been reported in postmarketing surveillance, particularly in patients with advanced right heart disease.
Drug Interactions
Ambrisentan has a notably favorable drug interaction profile compared with other ERAs. It is primarily cleared by glucuronidation rather than CYP-mediated oxidation, does not induce or significantly inhibit CYP enzymes, and does not alter warfarin pharmacokinetics. It is, however, a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP), and CYP3A4, making it susceptible to inhibitors of these transporters and enzymes.
Unlike bosentan, which induces CYP2C9 and CYP3A4 and alters warfarin and hormonal contraceptive metabolism, ambrisentan does not significantly affect CYP enzymes. This means no warfarin dose adjustment is needed and hormonal contraceptives can be used as part of the required pregnancy prevention strategy without efficacy concerns related to the ERA itself.
Monitoring
-
Pregnancy Test
Before initiation, then as clinically indicated
Routine Negative pregnancy test required before starting. Advise effective contraception during treatment and for 1 month after stopping. Discontinue immediately if pregnancy is detected. -
Hemoglobin / Hematocrit
Baseline, 1 month, then periodically
Routine Mean Hb decrease ~0.8 g/dL. Marked decreases (>15% from baseline) in 7% of patients overall, 10% at 10 mg. Do not initiate in patients with clinically significant anemia. Exclude other causes if significant drop occurs. -
Liver Function (ALT, AST, Bilirubin)
Baseline, then as clinically indicated
Trigger-based Routine periodic LFT monitoring is no longer mandated by the FDA label for ambrisentan specifically (unlike bosentan). However, monitor if symptoms of hepatic injury appear. Discontinue if AST/ALT >5x ULN or if elevations accompany bilirubin >2x ULN. -
Weight and Edema Assessment
Each visit
Routine Assess for peripheral edema and weight gain at every clinic visit. Rapid weight gain (>2-3 kg) should prompt evaluation for fluid retention versus worsening right heart failure. -
Functional Capacity (6MWD, WHO FC)
Baseline, 3-6 months, then 6-12 monthly
Routine Improvement in 6MWD expected by 4-12 weeks. Declining walk distance may indicate disease progression or the need for combination therapy escalation. -
BNP / NT-proBNP
Baseline, then every 3-6 months
Routine Rising natriuretic peptides suggest clinical worsening. Use in conjunction with functional class and echocardiographic findings per ESC/ERS risk stratification.
Contraindications & Cautions
Absolute Contraindications
- Pregnancy: Ambrisentan is teratogenic in animals at exposures near or below human therapeutic levels. It caused jaw, palate, heart, and great vessel malformations in rats and rabbits. Absolutely contraindicated in pregnant women or women who may become pregnant without effective contraception.
- Idiopathic pulmonary fibrosis (IPF): The ARTEMIS trial was terminated early because ambrisentan increased disease progression and hospitalization in IPF patients. This contraindication applies regardless of whether pulmonary hypertension (WHO Group 3) is present.
Relative Contraindications (Specialist Input Recommended)
- Moderate or severe hepatic impairment: Not recommended. No data on use in patients with pre-existing moderate or severe liver disease. Exposure may be increased and hepatic safety has not been established in this population.
- Clinically significant anemia (Hb below lower limit of normal): Ambrisentan reduces hemoglobin further; initiation is not recommended until anemia is corrected or an informed risk-benefit decision is made.
- Suspected pulmonary veno-occlusive disease: Vasodilators including ERAs can precipitate acute pulmonary edema in PVOD. If acute pulmonary edema develops during initiation, PVOD should be considered and the drug discontinued.
Use with Caution
- Elderly patients (age 65 and older): Higher rates of peripheral edema (29%) and smaller functional improvements observed in subgroup analyses.
- Males desiring fertility: Endothelin receptor antagonists as a class have been associated with decreased sperm counts in animal and human studies. Counsel regarding potential effect on spermatogenesis before starting therapy.
- Mild hepatic impairment: Limited data; use with monitoring for hepatic enzyme elevations.
- Concurrent cyclosporine use: Requires dose cap at 5 mg daily due to approximately 2-fold increase in ambrisentan exposure.
Ambrisentan is contraindicated during pregnancy because it may cause major birth defects based on animal studies. In both rats and rabbits, ambrisentan caused malformations of the jaw, palate, heart, and great vessels, as well as failure of thymus and thyroid formation. For females of reproductive potential, exclude pregnancy before starting treatment, advise effective contraception during treatment and for one month after discontinuation, and discontinue immediately if pregnancy is detected. As of April 2025, the FDA removed the REMS program (including elements to assure safe use) from the ambrisentan labeling, determining that a REMS was no longer necessary. The boxed warning and contraception requirements remain in the prescribing information.
Patient Counselling
Purpose of Therapy
Ambrisentan works by blocking a substance called endothelin that narrows blood vessels in the lungs. Taking this medication daily helps lower the pressure in lung arteries, improves the ability to exercise, and slows worsening of the disease. It does not cure pulmonary arterial hypertension but is an important part of long-term management.
How to Take
Take one tablet once daily at the same time each day, with or without food. Swallow the tablet whole; do not split, crush, or chew. If a dose is missed, take it as soon as remembered and continue with the regular schedule. Do not take two doses to make up for a missed one. Store at room temperature in the original packaging.
Sources
- Letairis (ambrisentan) tablets. Full Prescribing Information. Gilead Sciences, Inc. Revised 2025. Gilead PI Primary reference for all dosing, pharmacokinetics, adverse reactions, and contraindications.
- Ambrisentan tablets. DailyMed (generic label, Mylan). Updated April 2025. DailyMed Updated generic label reflecting 2025 REMS modifications and boxed warning revisions.
- Ambrisentan Viatris. Summary of Product Characteristics (SmPC). European Medicines Agency. EMA SmPC European regulatory reference with frequency-based adverse reaction classification (MedDRA).
- Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ARIES study 1 and 2. Circulation. 2008;117(23):3010-3019. doi:10.1161/CIRCULATIONAHA.107.742510 Pivotal phase III trials establishing efficacy in 6MWD improvement across 2.5-10 mg doses.
- Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844. doi:10.1056/NEJMoa1413687 AMBITION trial: 50% reduction in clinical failure with initial combination therapy; landmark trial informing ESC/ERS guidelines.
- Hoeper MM, McLaughlin VV, Barberá JA, et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with PAH. Lancet Respir Med. 2016;4(11):894-901. doi:10.1016/S2213-2600(16)30307-1 Secondary mortality analysis of AMBITION suggesting potential survival advantage with combination therapy.
- Coghlan JG, Galiè N, Barberà JA, et al. Initial combination therapy with ambrisentan and tadalafil in CTD-PAH: subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017;76(7):1219-1227. doi:10.1136/annrheumdis-2016-210236 Demonstrates combination therapy benefit in CTD-PAH and SSc-PAH subgroups.
- Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237 Current comprehensive guideline recommending initial ambrisentan + tadalafil combination as Class I for treatment-naive iPAH/hPAH.
- Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019;155(3):565-586. doi:10.1016/j.chest.2018.11.030 CHEST 2019 guideline with conditional recommendation for ambrisentan + tadalafil in treatment-naive WHO FC II-III PAH.
- Galiè N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46(3):529-535. doi:10.1016/j.jacc.2005.04.050 Phase II dose-ranging study establishing the 5-10 mg therapeutic range and ETA selectivity profile.
- Barst RJ. A review of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag. 2007;3(1):11-22. PMC1994051 Comprehensive early review covering ambrisentan PK profile including steady-state half-life, protein binding, and glucuronidation pathway.
- Rivera-Lebron BN, Risbano MG. Ambrisentan: a review of its use in pulmonary arterial hypertension. Ther Adv Respir Dis. 2017;11(5):233-244. doi:10.1177/1753465817696040 Clinical review synthesizing pharmacokinetics, ARIES long-term extension data, and AMBITION trial outcomes.
- McGoon MD, Frost AE, Oudiz RJ, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2009;135(1):122-129. doi:10.1378/chest.08-1028 Key study supporting ambrisentan use in patients with prior ERA-related hepatotoxicity; no recurrence of aminotransferase elevations.