Sildenafil (Revatio®)
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Indications: Sildenafil is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The efficacy of sildenafil has not been adequately evaluated in patients taking bosentan concurrently.
Mechanism: Sildenafil is an inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degrading cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells, resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vasculature and, to a lesser degree, vasodilatation in the systemic circulation.
Dosing: Tablet and oral suspension: 20 mg three times a day, 4-6 hours apart. Injection: 10 mg (12.5 mL)
three times a day administered as an intravenous bolus injection.
Efficacy: There were 2 studies included in the prescribing information for sildenafil. The first was a randomized, double-blind, placebo-controlled study of sildenafil (Study 1) conducted in 277 patients with PAH. Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n=69), 40 mg (n=67) or 80 mg (n=71) TID for a period of 12 weeks.
The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 1), indicating no additional clinical benefit from doses higher than 20 mg TID. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.
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Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo.
The second study was a randomized, double-blind, placebo controlled study (Study 2) conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients were
randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.
There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 was 30 meters for the sildenafil group compared with 4 meters for the placebo group, giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p=0.0009).
Kaplan-Meier estimates demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced
a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0074) (Figure 2).
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Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil compared to placebo. Thirty-six percent (36%) of sildenafil-treated patients versus 14% of placebo-treated patients showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.
Adverse Events: Most common adverse reactions >3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis.
Warnings:
- Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients.
- Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy.
- Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended.
- Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs.
- Pulmonary hypertension secondary to sickle cell disease: sildenafil may cause serious vaso-occlusive crises.
Contraindications:
- Use with organic nitrates.
- History of hypersensitivity reaction to sildenafil or any component of the tablet, injection, or oral suspension.
Metabolism/Drug interactions:
- Sildenafil is cleared predominantly by the CYP3A and to a lesser extent 2C9.
- Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects.
- Use with ritonavir and other potent CYP3A inhibitors: Not recommended.
- Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors.
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| Access Program: None |
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| Full US Prescribing Information can be found here: http://labeling.pfizer.com/ShowLabeling.aspx?id=645
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