Tadalafil 40 mg Once‑Daily Dosing for Pulmonary Arterial Hypertension in Adults

Recommended Dosing and Administration

The recommended regimen for adults with pulmonary arterial hypertension (PAH) is tadalafil 40 mg taken once daily; this dose alone met the primary efficacy endpoint in the pivotal PHIRST trial, establishing it as the standard dose【1】.
Doses higher than 40 mg daily have not been studied and are therefore not recommended【2】.
No dose titration is required; patients should be initiated directly on the 40 mg daily dose, unlike some other PAH agents that require gradual uptitration【3】.

In the combined study population (with and without background endothelin‑receptor antagonist therapy), the 40 mg daily dose produced a mean placebo‑adjusted increase of 33 m in the 6‑minute walk distance (6MWD)【1】 (Level A evidence from a pivotal randomized trial).
Treatment with tadalafil 40 mg daily significantly reduced clinical worsening events (including death, lung transplantation, atrial septostomy, PAH‑related hospitalization, or initiation of new PAH therapy) compared with placebo【1】 (Level A evidence).

World Health Organization (WHO) Functional Class II patients experienced a mean 24‑m improvement in 6MWD after 40 mg daily dosing【1】.
WHO Functional Class III–IV patients experienced a mean 36‑m improvement in 6MWD with the same dose【1】.
The same 40 mg daily dose is appropriate for all WHO functional classes; no dose adjustment based on functional class is required【1】.

Co‑administration with riociguat is contraindicated because combined use of phosphodiesterase‑5 inhibitors and riociguat can cause systemic hypotension【2】.

Lower doses of tadalafil (2.5 mg, 10 mg, or 20 mg) did not achieve the pre‑specified primary endpoint (placebo‑adjusted 6MWD improvement; P < 0.01) in the pivotal trial, confirming that only the 40 mg dose provides a statistically significant benefit【1】.

The FDA-approved dose for tadalafil in PAH is 40 mg once daily, as recommended by the FDA 4, 5
The recommended dose for ambrisentan is 10 mg once daily, with a starting dose of 5 mg once daily that can be increased to 10 mg if well tolerated, as suggested by the European Heart Journal and Nature Reviews Rheumatology 6, 7, 8, 9, 10

The American Thoracic Society recommends initial combination therapy of ambrisentan 10 mg daily plus tadalafil 40 mg daily for treatment-naive PAH patients with WHO Functional Class II and III, based on evidence from the AMBITION trial 6, 7, 8, 11

Monthly liver function tests are recommended for patients on ambrisentan, as advised by the European Heart Journal and Nature Reviews Rheumatology 9, 10

The American College of Chest Physicians provides a weak recommendation with moderate quality evidence for the use of combination therapy with ambrisentan and tadalafil in treatment-naive PAH patients, as stated in the 2019 CHEST guidelines 6, 7, 8, 11
The European Society of Cardiology suggests that adding tadalafil 40 mg daily to patients already on ambrisentan monotherapy can improve exercise capacity, based on evidence from clinical trials 6, 7, 8