What are the recommended doses of tadalafil (phosphodiesterase type 5 inhibitor) and ambrisentan (endothelin receptor antagonist) for treating pulmonary arterial hypertension (PAH)?

Recommended Doses of Tadalafil and Ambrisentan for Pulmonary Arterial Hypertension

For treating pulmonary arterial hypertension (PAH), the recommended doses are 40 mg once daily for tadalafil and 10 mg once daily for ambrisentan, which have been shown to improve clinical outcomes when used in combination therapy. 1

Dosing Guidelines

Tadalafil

• FDA-approved dose for PAH: 40 mg once daily 1, 2
• Higher dose compared to erectile dysfunction treatment reflects the more aggressive approach needed for this life-threatening condition 2
• Demonstrated efficacy at this dose in improving exercise capacity, reducing clinical worsening, and improving cardiopulmonary hemodynamics 3

Ambrisentan

• Recommended dose: 10 mg once daily 1
• Starting dose may be 5 mg once daily with potential to increase to 10 mg if well tolerated 1
• Belongs to the endothelin receptor antagonist class, selectively targeting the endothelin-A receptor 1

Combination Therapy Evidence

• The AMBITION trial demonstrated superior outcomes with initial combination therapy of ambrisentan 10 mg daily plus tadalafil 40 mg daily compared to either monotherapy 1, 4
• Combination therapy reduced the risk of clinical failure events by 50% compared to pooled monotherapy (HR 0.50; 95% CI, 0.35-0.72; P<0.001) 4
• Benefits included:
  • Greater improvement in 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001) 4
  • Higher percentage of patients with satisfactory clinical response (39% vs. 29%; P=0.03) 4
  • Greater reductions in N-terminal pro-brain natriuretic peptide levels 4

Special Populations

• In connective tissue disease-associated PAH, including systemic sclerosis, combination therapy with ambrisentan 10 mg and tadalafil 40 mg also showed benefit (HR 0.43; 95% CI 0.24 to 0.77) 5
• Patients with multiple risk factors for left ventricular diastolic dysfunction may experience attenuated response to combination therapy but still show directionally similar benefits 6

Safety Considerations

• No clinically significant pharmacokinetic interactions between ambrisentan and tadalafil have been observed, making dose adjustments unnecessary when used in combination 7
• Common adverse events with combination therapy include:
  • Peripheral edema 4, 5
  • Headache 4
  • Nasal congestion 4
  • Anemia 4
• Monthly liver function tests are recommended for patients on ambrisentan 1

Clinical Approach

• For treatment-naive PAH patients with WHO Functional Class II and III, initial combination therapy with ambrisentan 10 mg daily and tadalafil 40 mg daily is recommended 1
• For patients already on ambrisentan monotherapy, adding tadalafil 40 mg daily can improve exercise capacity 1
• The 2019 CHEST guidelines provide a weak recommendation with moderate quality evidence for this combination in treatment-naive patients 1

Potential Pitfalls

• Avoid using lower doses of tadalafil (such as those used for erectile dysfunction) when treating PAH, as the 40 mg dose is specifically approved for this condition 2
• Be vigilant for peripheral edema, which occurs more frequently with combination therapy than with monotherapy 4, 5
• Remember that these medications are contraindicated with nitrates due to the risk of severe hypotension 3