REVATIO® (sildenafil citrate) Tablets Clinical Studies

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Prescribing Information

REVATIO^® (sildenafil citrate) Tablets
Clinical Studies


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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 were observed with all doses of sildenafil. These increases were highly significantly different from placebo, but the dose groups were not different from each other (Figure 1). The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.

Figure 1: Change From Baseline in 6-Minute Walk Distance (meters): Mean (95% Confidence Interval)

Pre-defined subpopulations in the pivotal study were also evaluated for efficacy, including patient differences in baseline walk distance, disease etiology, functional class, gender, age, and secondary hemodynamic parameters (Figure 2).

Figure 2: Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) by study subpopulation: Mean (95% Confidence Interval)

Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. Doses of
20 mg, 40 mg, and 80 mg t.i.d. produced a placebo-corrected decrease in mPAP of
-2.7 mmHg, -3.0 mmHg, and -5.1 mmHg, respectively. There was no evidence of a difference in effect between sildenafil 20 mg t.i.d. and the higher doses tested. Data from other hemodynamic parameters can be found in Table 1. The relationship between these effects and improvements in 6-minute walk distance is unknown.

Table 1. Change From Baseline to Week 12 in Hemodynamic Parameters at Sildenafil 20 mg t.i.d. Dose

259 of the 277 treated patients entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously.

PRINTER-FRIENDLY

REVATIO Safety Information

REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability. The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy.

The use of REVATIO and organic nitrates in any form, at any time, is contraindicated.

Co-administration of REVATIO with potent CYP3A4 inhibitors, eg, ketoconazole, itraconazole, and ritonavir, is not recommended as serum concentrations of sildenafil substantially increase. Co-administration of REVATIO with CYP3A4 inducers, including bosentan; and more potent inducers such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, and rifabutin, may alter plasma levels of either or both medications. Dosage adjustment may be necessary.

Before starting REVATIO, physicians should carefully consider whether their patients with underlying conditions could be adversely affected by the mild and transient vasodilatory effects of REVATIO on blood pressure. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD) and administration of REVATIO to these patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, the possibility of associated PVOD should be considered.

The most common side effects of REVATIO (placebo-subtracted) were epistaxis (8%), headache (7%), dyspepsia (6%), flushing (6%), and insomnia (6%). Adverse events were generally transient and mild to moderate.

At doses higher than the recommended 20 mg tid, there was a greater incidence of some adverse events including flushing, diarrhea, myalgia, and visual disturbances.

Caution is advised when PDE5 inhibitors, such as REVATIO, are administered with α−blockers as both are vasodilators with blood pressure lowering effects.

Patients with the following characteristics did not participate in the preapproval clinical trial: patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months, unstable angina, hypertension (BP>170/110), retinitis pigmentosa, or patients on bosentan. The safety of REVATIO is unknown in patients with bleeding disorders and patients with active peptic ulceration. In these patients, physicians should prescribe REVATIO with caution.

REVATIO should be used with caution in patients with anatomical deformation of the penis or patients who have conditions which may predispose them to priapism.

In PAH patients, the concomitant use of vitamin K antagonists and REVATIO resulted in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo. The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%).

Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely post-marketing in temporal association with the use of PDE5 inhibitors for the treatment of erectile dysfunction, including sildenafil. It is not possible to determine if these events are related to PDE5 inhibitors or to other factors. Physicians should advise patients to seek immediate medical attention in the event of sudden loss of vision while taking PDE5 inhibitors, including REVATIO.

Sudden decrease or loss of hearing has been rarely reported in temporal association with the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE5 inhibitors, including REVATIO.

Please see full prescribing information.

REVATIO^® (sildenafil citrate) Tablets

revatio_safety_information.htm