What is the recommended dose of Ambrisentan (Endothelin receptor antagonist) for pulmonary arterial hypertension?

Ambrisentan Dosing for Pulmonary Arterial Hypertension

Start ambrisentan at 5 mg once daily, then increase to 10 mg once daily at 4-week intervals if well tolerated and treatment goals have not been reached. 1, 2

Initial Dosing Strategy

• Begin with 5 mg once daily as the starting dose for all patients with PAH 1, 2
• Do not split, crush, or chew tablets 2
• The 5 mg starting dose balances efficacy with tolerability, allowing assessment of individual patient response 1

Dose Titration

• Increase to 10 mg once daily after 4 weeks if the patient tolerates the initial dose well and has not achieved treatment goals 1, 2
• The 10 mg dose provides greater improvement in 6-minute walk distance (6MWD) compared to 5 mg without an observed increase in adverse effects 1
• In the ARIES trials, the 10 mg dose showed placebo-corrected improvements in 6MWD of 51 m (ARIES-1) and the 5 mg dose showed 59 m improvement (ARIES-2) 3

Evidence Supporting This Dosing

The 2014 CHEST guidelines provide the strongest recommendation framework, noting that treatment with 10 mg ambrisentan resulted in greater improvement in 6MWD than 5 mg without increased adverse effects 1. This dose-response relationship was established in the pivotal ARIES-1 and ARIES-2 trials, which demonstrated significant improvements in exercise capacity across all doses (2.5-10 mg), with the higher doses showing numerically greater benefits 3.

The FDA-approved dosing reflects this evidence, mandating initiation at 5 mg with potential escalation to 10 mg 2. European guidelines similarly recommend 5-10 mg daily dosing 1.

WHO Functional Class Considerations

• For WHO FC II patients: Ambrisentan 5-10 mg daily is recommended to improve 6MWD (Grade 1C recommendation) 1
• For WHO FC III patients: Ambrisentan 5-10 mg daily is recommended to improve 6MWD (Grade 1C recommendation) and suggested to delay time to clinical worsening 1
• The majority of clinical trial data comes from FC III patients, though FC II patients also demonstrated benefit 1

Combination Therapy Dosing

• When used with tadalafil: Ambrisentan 10 mg daily plus tadalafil 10 mg daily is the recommended combination for treatment-naive PAH patients with WHO FC II-III 4
• This combination is based on the AMBITION trial, which showed superior outcomes compared to monotherapy 4

Monitoring Requirements

• Monthly liver function tests are recommended, though the incidence of aminotransferase elevations is low (0.8-3%) 1
• Monthly pregnancy tests are mandatory for females of reproductive potential during treatment and for 1 month after discontinuation 2
• Hemoglobin monitoring should be performed periodically 1

Common Pitfalls to Avoid

• Do not exceed 10 mg daily: No data support higher doses, and this is the maximum FDA-approved dose 2
• Do not use in idiopathic pulmonary fibrosis: Ambrisentan is contraindicated in IPF patients, including those with pulmonary hypertension (WHO Group 3) 2
• Do not start at 10 mg: Always initiate at 5 mg to assess tolerability before escalation 1, 2
• Do not use in pregnancy: Ambrisentan carries a black box warning for embryo-fetal toxicity and is contraindicated in pregnant females 2

Adverse Effects Profile

• Peripheral edema is the most common adverse effect (17% incidence), particularly in patients over 65 years of age (29%) 1, 5
• Nasal congestion (6%), palpitations (5%), and flushing (4%) are other common effects 5
• Hepatotoxicity risk is low: The incidence of liver enzyme elevations >3x upper limit of normal is 0.8-3%, significantly lower than with bosentan (10-11%) 1, 3