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 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
• Increase to 10 mg once daily at 4-week intervals if the medication is well tolerated and treatment goals remain unmet 1, 2
• The 10 mg dose demonstrated greater improvement in 6-minute walk distance (+43.6 m vs +22.8 m for 5 mg) without an observed increase in adverse effects 1

Evidence Supporting Dose Escalation

The rationale for this dosing approach comes from the ARIES trials, which showed dose-dependent efficacy:

• ARIES-1: The 10 mg dose produced a placebo-corrected improvement of 51 m in 6-minute walk distance compared to 31 m for the 5 mg dose 3
• ARIES-2: The 5 mg dose produced a placebo-corrected improvement of 59 m compared to 32 m for the 2.5 mg dose 3
• Treatment with 10 mg ambrisentan resulted in greater improvement in exercise capacity than 5 mg without increased adverse effects 1

Administration Details

• Take once daily without regard to meals 2
• Do not split, crush, or chew tablets 2
• Available as 5 mg (pink, round) and 10 mg (white, oval) tablets 2

Combination Therapy Dosing

When used in combination therapy with tadalafil for treatment-naive WHO Functional Class II-III PAH patients:

• Ambrisentan 10 mg once daily plus tadalafil 40 mg once daily is the recommended regimen 4
• This combination is based on evidence from the AMBITION trial 4

Mandatory Monitoring Requirements

Due to FDA REMS program requirements and class effects of endothelin receptor antagonists:

• Monthly liver function tests are required throughout treatment 1, 4
• Monthly pregnancy tests for females of reproductive potential during treatment and for 1 month after discontinuation 2
• Hemoglobin/hematocrit monitoring periodically to detect anemia 1
• The incidence of aminotransferase elevations >3× upper limit of normal is approximately 2% per year 1, 5

Common Pitfalls to Avoid

• Do not exceed 10 mg once daily - higher doses have not been studied and are not recommended 1
• Do not use in pregnancy - ambrisentan is contraindicated due to teratogenic effects and is only available through a restricted REMS program for females 2
• Do not use in idiopathic pulmonary fibrosis (WHO Group 3 PH) - ambrisentan is contraindicated in this population 2
• Do not start at 10 mg - always initiate at 5 mg to assess tolerability before escalation 1, 2

Long-Term Efficacy

• At 2 years, the 10 mg dose maintained a mean improvement of +28 m in 6-minute walk distance from baseline 5
• Survival estimates at 2 years were 88% with freedom from clinical worsening at 72% 5
• The sustained improvement in exercise capacity and low risk of clinical worsening support the use of the 10 mg maintenance dose when tolerated 5