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Sildenafil

A Review of its Use in Pulmonary Arterial Hypertension

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Summary

Abstract

Sildenafil citrate (Revatio®), an inhibitor of phosphodiesterase type 5 (PDE5), is approved for use in the US, Europe and other countries for the treatment of pulmonary arterial hypertension (PAH). Oral sildenafil 20 mg three times daily added to conventional background therapy was significantly more effective than placebo at increasing exercise capacity in patients with idiopathic PAH or PAH associated with connective tissue diseases or repaired congenital systemic-to-pulmonary shunts. Sildenafil was also associated with improvements in WHO functional class and haemodynamic parameters, and was generally well tolerated. Sildenafil provides benefits in terms of exercise capacity when added to epoprostenol; however, these findings come from a trial that did not use the approved dosage of sildenafil. In conclusion, sildenafil is an effective oral treatment option for patients with PAH.

Pharmacological Properties

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate-specific PDE5, and causes relaxation of smooth muscle, in particular, in the pulmonary vasculature and corpus cavernosum. It causes pulmonary vasodilation in patients with pulmonary hypertension and is associated with improvements in mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and, in some studies, cardiac index. At the approved dosage of 20 mg three times daily, sildenafil does not affect systemic blood pressure. Sildenafil potentiates the hypotensive effect of nitrates and these drugs should not be coadministered.

Oral sildenafil is absorbed rapidly, reaching peak plasma concentrations after ≈1 hour. It is metabolized principally by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C9, and inducers or inhibitors of these isozymes can affect the clearance of sildenafil. It should not be coadministered with potent CYP3A4 inhibitors. Caution should be exercised when administering sildenafil with bosentan (a CYP3A4 and CYP2C9 inducer), because sildenafil plasma concentrations decrease and bosentan concentrations increase. Sildenafil is predominantly excreted as metabolites in the faeces and has a terminal elimination half-life of 3—5 hours. The major (N-desmethyl) metabolite of sildenafil has an in vitro potency approximately half that of the parent compound.

Therapeutic Efficacy

The Efficacy of sildenafil in adults with idiopathic PAH was demonstrated in a large, well designed, 12-week trial (SUPER-1). Dosages included 20 (the approved dosage), 40 and 80 mg three times daily. At baseline, most patients were in WHO functional class II or III and had a mean 6-minute walking distance of 344 m. All dosages of sildenafil significantly increased the placebo-corrected 6-minute walking distance (the primary endpoint) by 45—50 m after 12 weeks, but there was no significant difference in efficacy between the three dosages. At the approved dosage, sildenafil also led to significant increases in the proportion of patients improving by at least one functional class and exhibiting significant improvements in haemodynamic parameters, including mean PAP and PVR. Health-related quality of life (all dosages combined) significantly improved with sildenafil compared with placebo for domains addressing the physical impact of PAH and general health. In an open-label extension study of SUPER-1 (SUPER-2) in which all patients received sildenafil 80 mg three times daily (higher than the approved dosage), efficacy was maintained to 1 year and, among 141 patients with idiopathic PAH, 1-year survival was 96% compared with a predicted survival of 71%.

Studies comparing sildenafil with other specific PAH therapies, or evaluating combination therapy, all used dosages higher than the approved dosage. In a small, 16-week study in patients with PAH (functional class III), there was no significant difference between sildenafil and bosentan for change in right ventricular mass (primary endpoint) or 6-minute walking distance. The combination of sildenafil with intravenous epoprostenol was evaluated in a large, well designed, 16-week trial in patients with PAH. The addition of sildenafil to epoprostenol significantly increased 6-minute walking distance (placebo-corrected increase of 26 m; p = 0.0009) and improved most haemodynamic parameters compared with placebo.

Tolerability

Sildenafil was generally well tolerated by patients with PAH. Based on placebo-subtracted incidences, the most common adverse events with sildenafil 20 mg three times daily in SUPER-1 were epistaxis, headache, dyspepsia, flushing, insomnia and erythema. Retinal haemorrhage occurred in 1.4% of the sildenafil 20 mg three times daily group (vs 0% for placebo); most patients had risk factors for bleeding. Epistaxis was more common among patients with connective tissue disorders than in those with idiopathic PAH, and concomitant use of vitamin K antagonists also increased the risk of epistaxis.

Adverse events reported during combination therapy with sildenafil and epoprostenol were consistent with events reported during SUPER-1.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Author information

Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand

    Katherine F. Croom & Monique P. Curran

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Katherine F. Croom & Monique P. Curran

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  1. Katherine F. Croom
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  2. Monique P. Curran
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Correspondence to Monique P. Curran.

Additional information

Various sections of the manuscript reviewed by: S.H. Abman, Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, Colorado, USA; R.N. Channick, University of California San Diego Medical Center, La Jolla, California, USA; G.A. Heresi, Department of Pulmonary, Allergy and Critical Care Medicine, The Cleveland Clinic, Cleveland, Ohio, USA; L.J. Rubin, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, La Jolla, California, USA; A. Torbicki, Department of Chest Medicine, National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘sildenafil’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘sildenafil’ and (‘PAH’ or ‘pulmonary arterial hypertension’ or ‘hypertension pulmonary’). Searches were last updated 29 January 2008.

Selection: Studies in patients with pulmonary arterial hypertension who received sildenafil. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Sildenafil, pulmonary arterial hypertension, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Croom, K.F., Curran, M.P. Sildenafil. Drugs 68, 383–397 (2008). https://doi.org/10.2165/00003495-200868030-00009

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