Brand name: Revatio
Legal category: POM.
Active ingredient: Sildenafil (as citrate) 20 mg.
Description: Film-coated white round tablet marked with company name on one side and code and strength on the reverse.
Presentation: 90, £373.50.
Indication: Treatment of patients with pulmonary arterial hypertension classified as WHO functional class III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
Pharmacology: Sildenafil is a potent selective PDE5 inhibitor that is currently licensed for the treatment of erectile dysfunction. However, the presence of PDE5 in the pulmonary vasculature has led to its recent development as a treatment of pulmonary arterial hypertension, a disease characterized by progressive increase in pulmonary vascular resistance. In patients with this condition, sildenafil is thought to act on smooth muscle cells in the pulmonary vasculature. By increasing cGMP within these cells, sildenafil brings about smooth muscle relaxation causing vasodilatation of the pulmonary vascular bed and thereby alleviating pulmonary arterial hypertension.
Following oral administration sildenafil is rapidly absorbed from the GI tract with maximum plasma concentration observed within 30 - 120 minutes of dosing and it has a mean absolute bioavailability of 41%. Sildenafil undergoes hepatic metabolism predominantly via the microsomal isoenzymes CYP 3A4 and CYP2C9 and it has a terminal phase half-life of 3-5 hours. It is primarily excreted in the faeces and to a lesser extent in the urine.
Sildenafil was evaluated in a randomised double-blind placebo-controlled study involving 278 patients with primary pulmonary hypertension, pulmonary arterial hypertension associated with connective tissue disease and pulmonary arterial hypertension following surgical repair of congenital heart lesions. Sildenafil (20mg, 40mg or 80mg) or placebo was added to patient's background therapy.
At the start of the study, a 6-minute walk test was conducted to establish a baseline for the primary efficacy endpoint. A statistically significant increase in 6-minute walk distance was observed in the sildenafil groups compared with those on placebo and at a dose of 20 mg three times daily the placebo corrected increase at week 12 was 45 metres. An improvement in walk distance was noted after 4 weeks treatment and was maintained throughout the 12-week study period.
The reduction in mean pulmonary arterial pressure compared with those given placebo was also statistically significant. The placebo corrected reduction was -2.7 mm Hg for sildenafil 20 mg and the mean change from baseline in pulmonary vascular resistance was -122 dyne.sec/cm5. The percentage reduction at 12 weeks was 11.2% and was proportionally greater than the reduction in systemic vascular resistance of 7.2%.
Adult Dose: 20 mg three times daily with or without food.
Child Dose: Not recommended.
Contraindications: Severe hepatic impairment, recent stroke or MI, severe hypotension. Degenerative retinal disorders. Pregnancy, lactation. Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption. Combination with nitrates, nitric oxide donors or potent CYP3A4 inhibitors.
Special precautions: Severe pulmonary arterial hypertension (class IV). Co-administration with medium/intermediate potency CYP3A4 inhibitors. Hypotension, fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction. Withdraw gradually. Pre-existing cardiovascular risk factors. Anatomical deformation of the penis or predisposition to priapism. Advise patients on postural hypotension. Bleeding disorders, active peptic ulceration. Pulmonary oedema - consider veno-occlusive disease.
Interactions: Other pulmonary hypertension treatments. Other PDE5 inhibitors (these 2 are not specifically in interactions section, but no controlled studies so concomitant use can't be recommended). Nitrates or nitric oxide donors eg amyl nitrite (contraindicated). CYP3A4 or CYP2C9 inhibitors, substrates or inducers. Alpha blockers. Vitamin K antagonists. Beta blockers, nicorandil.
Adverse reactions: Headache, flushing, limb pain, myalgia, dyspepsia, diarrhoea, cough, epistaxis, insomnia, pyrexia, influenza, visual disturbance. Anaemia, vertigo, eye disorders, GI disturbance, reflux, haemorrhoids, sinusitis, cellulitus, weight gain, fluid retention, nervous system disorders, anxiety, bronchitis, rhinitis, gynaecomastia, alopecia, erythema. Rare reports of non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vein occlusion and visual field defect.
? Report any adverse reactions to CSM.
Further information: Pfizer Ltd, Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS. Tel: (01304) 616161.
Brand name: Revatio