New indication: Tadalafil (Adcirca), a phosphodiesterase type 5 inhibitor, was approved on May 22, 2009, for the treatment of pulmonary arterial hypertension (WHO Group I)
Phosphodiesterase type 5 (PDE5) is the enzyme that degrades cyclic guanosine monophosphate (cGMP). Tadalafil inhibits PDE5 and thereby increases the concentration of cGMP, leading to relaxation of the pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. This agent was approved on May 22, 2009, for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I patients) to improve exercise ability.
Efficacy. The efficacy of tadalafil for the treatment of PAH was assessed in a randomized, double-blind, 16-week, placebo-controlled study. Patients (N=405) were randomized 1:1:1:1:1 to treatment with tadalafil 2.5, 10, 20, or 40 mg, or placebo. The primary end point was change from baseline to Week 16 in 6-minute walk distance (6-MWD). Among patients treated with tadalafil 40 mg, the placebo-adjusted mean change in 6-MWD was 33 m (95% CI, 15–50 m; P=.0004); this improvement was observed at 8 weeks and maintained through Weeks 12 and 16. Patients treated with tadalafil 40 mg also demonstrated less clinical worsening (ie, death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy, or worsening WHO functional class) (5% of patients) than patients treated with placebo (16%) or with lower doses of tadalafil (12%, 9%, and 10% in patients treated with tadalafil 2.5, 10, and 20 mg, respectively).
Safety. In patients taking tadalafil who experience anginal chest pain, nitrates should be administered under close medical supervision. PDE5 inhibitors are associated with mild systemic vasodilatory properties that could cause transient decreases in blood pressure. Healthcare professionals should weigh the risks and benefits of tadalafil treatment in patients with underlying cardiovascular disease who could be adversely affected by these vasodilatory effects. Tadalafil treatment is not recommended in patients with veno-occlusive disease. Use of alpha-adrenergic blocking agents or alcohol during tadalafil treatment may lead to an additive effect on blood pressure. Tadalafil treatment should be avoided in patients taking potent inhibitors or inducers of CYP3A. Patients who experience a sudden loss of vision in 1 or both eyes or a sudden decrease or loss of hearing during tadalafil treatment should immediately seek medical attention. Rarely, patients have experienced prolonged erections lasting >4 hours or priapism during tadalafil treatment. The most common adverse events associated with tadalafil include headache, myalgia, dyspepsia, back pain, and nausea.
Dosing. The recommended dose of tadalafil for the treatment of PAH is 40 mg/d, administered as two 20-mg tablets taken once/d with or without food. Dividing the dose is not recommended. This agent should be avoided in patients with severe renal or hepatic impairment. In patients with mild or moderate renal or hepatic impairment, treatment should be initiated at 20 mg/d.