ldenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.4/5.5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS ).
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg t.i.d. to patients with pulmonary arterial hypertension, no clinically relevant effects on ECG were reported.
After chronic dosing of 80 mg t.i.d. sildenafil to healthy patients, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.
After chronic dosing of 80 mg t.i.d. sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.
After chronic dosing of 80 mg t.i.d. sildenafil to patients with pulmonary arterial hypertension, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).
Effects of REVATIO on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An eva luation of visual function at doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or pupillometry.
Clinical Studies
A randomized, double-blind, placebo-controlled study was conducted in 277 patients with pulmonary arterial hypertension (PAH, defined as a mean pulmonary artery pressure of >/=25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly functional classes II-III. Allowed background therapy included a combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction <45% or left ventricular shortening fraction <0.2 also were not studied.
Patients were randomized to receive placebo (n=70) or REVATIO 20 mg (n=69), 40 mg (n=67) or 80 mg (n=71) t.i.d. for a period of 12 weeks. They had either primary pulmonary hypertension (63%), PAH associated with connective tissue disease (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk test distance between 100 and 450 meters.
The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance at least 4 hours after the last dose. Placebo-corrected mean increases in walk distance of 45-50 meters
