What are the maximum recommended doses of ambisentan (Endothelin Receptor Antagonist) and tadalafil (Phosphodiesterase Type 5 Inhibitor) for primary Pulmonary Arterial Hypertension (PAH)?

Maximum Recommended Doses of Ambrisentan and Tadalafil for Primary PAH

The maximum recommended dose of ambrisentan is 10 mg once daily and tadalafil is 40 mg once daily for the treatment of primary pulmonary arterial hypertension (PAH). 1

Ambrisentan Dosing

• Starting dose: 5 mg once daily
• Maximum dose: 10 mg once daily
• Titration protocol: Start at 5 mg daily and, if well tolerated and treatment goals have not been reached, increase to the 10 mg dose 1
• Evidence basis: Treatment with 10 mg of ambrisentan resulted in greater improvement in 6-minute walk distance (6MWD) than 5 mg without an observed increase in adverse effects 1
• Monitoring: Monthly liver function tests are required due to potential hepatotoxicity (incidence of abnormal liver function tests ranges from 0.8% to 3%) 1
• Special consideration: Peripheral edema has been reported with ambrisentan use 1

Tadalafil Dosing

• Recommended dose: 40 mg once daily
• Maximum dose: 40 mg once daily
• Important note: Treatment with more than the recommended dose of tadalafil (40 mg once daily) has not been studied and is not recommended 1
• Administration: Can be taken without regard to food 2
• Dose adjustments:
  • Renal impairment:
    • Creatinine clearance 30-50 mL/min: Start with 20 mg once daily
    • Creatinine clearance <30 mL/min: Not recommended for once daily use 2
  • Hepatic impairment:
    • Mild/moderate impairment: Use with caution
    • Severe impairment: Not recommended 2

Combination Therapy Considerations

• Combination therapy with ambrisentan (10 mg daily) and tadalafil (40 mg daily) has shown superior efficacy compared to monotherapy with either agent 1, 3
• The AMBITION trial demonstrated that initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure compared to monotherapy in treatment-naive PAH patients 1, 4
• No clinically significant pharmacokinetic interactions have been observed between ambrisentan and tadalafil when used in combination 5
• When used in combination, the doses remain the same: ambrisentan 10 mg once daily and tadalafil 40 mg once daily 1

Important Warnings and Precautions

• Riociguat should not be used concomitantly with PDE5 inhibitors like tadalafil due to risk of systemic hypotension 1
• Male patients treated with tadalafil should be cautioned not to use PDE5 inhibitors for erectile dysfunction 1
• Substantial alcohol consumption in combination with tadalafil can increase the potential for orthostatic symptoms 2
• Patients with multiple risk factors for left ventricular diastolic dysfunction may experience higher rates of clinical failure events and reduced tolerability of combination therapy 6

Clinical Monitoring

• Regular evaluations every 3-6 months are recommended, including:
  • WHO functional class assessment
  • 6-minute walk distance
  • N-terminal pro-b-type natriuretic peptide levels
  • Echocardiography 7
• Treatment goals should focus on improving exercise capacity, symptoms, hemodynamics, and time to clinical worsening 1, 3

Remember that these maximum doses should not be exceeded as higher doses have not been adequately studied and may increase the risk of adverse effects without providing additional clinical benefit.