Sildenafil

Sildenafil is an oral therapy for erectile dysfunction of a broad range of causes. By selectively inhibiting phosphodiesterase type 5, it allows corpus cavernosum smooth muscle to relax, potentiating erections during sexual stimulation. Blood pressure is reduced transiently by sildenafil, but more marked hypotension may occur during concurrent administration of sildenafil and organic nitrates; this combination is contraindicated.

Sildenafil is rapidly absorbed, with dose-proportional peak plasma concentrations within 1 hour of administration. The elimination half-life is 3 to 5 hours. Dosages usually begin at 50mg taken when needed ≈1 hour before sexual activity no more than once daily. The maximum dose is 100mg when needed once daily and lower doses (e.g. 25mg) may be used in elderly patients and those with hepatic or renal impairment or receiving cytochrome P450 enzyme CYP3A4 inhibitors, such as ritonavir, saquinavir, ketoconazole, erythromycin or cimetidine.

More than 3000 patients with erectile dysfunction of organic (e.g. diabetes or spinal cord injury), psychogenic or mixed origin received sildenafil 5 to 100mg or placebo in fixed- or titrated-dose trials. Sildenafil was associated with dose-related improvements in the frequency, hardness and duration of erections and in patients’ abilities to achieve and maintain erections adequate for successful sexual intercourse. In titrated-dose trials, the most commonly effective doses were 50 or 100mg, although lower doses were effective in some patients. Sildenafil was significantly more effective than placebo in erectile dysfunction of all tested causes.

The efficacy of sildenafil was not affected by patient age (> or ≤65 years) or by antihypertensive or antidepressant medications. The drug was effective in patients with severe erectile dysfunction. Efficacy was maintained in long term (1-year) studies. Sildenafil also appears to improve the quality of life of both patients and their sexual partners.

Common adverse events associated with sildenafil were transient and mild or moderate and included headache, flushing, dyspepsia, nasal congestion and abnormal vision. Tolerability was maintained in long term (≤1 year) studies. No serious sildenafil-related adverse events occurred in clinical trials; cardiovascular events seen in postmarketing surveillance generally occurred in patients with other known risk factors.

Conclusions: Sildenafil is an effective oral treatment in men with erectile dysfunction. It was significantly superior to placebo in improving erections and allowing successful penetrative sexual intercourse. Although its place in disease management is still emerging and there are contraindications to its use, if preliminary positive reports are confirmed, sildenafil will be the pre-eminent first-line therapy for erectile dysfunction.

Background to the Evaluation of Sildenafil

Erectile dysfunction is the inability of a male to achieve and maintain an erect penis as a part of overall male sexual function. The most common organic causes of erectile dysfunction are vascular, neurological and pharmacological. The incidence of erectile dysfunction generally increases with advancing age.

The pharmacological effects of agents such as sildenafil can be measured objectively, but because of the personal and interpersonal nature of erectile function, clinical assessment of the drug must rely on subjective reports from patients. Objective pharmacodynamic measurement of the response of erectile function to sildenafil in humans is primarily performed by determining penile rigidity in response to visual sexual stimulation. Clinical assessments are made using a detailed sexual questionnaire surveying patients on general issues such as whether they thought their erections had improved, supplemented by diary data and partner surveys.

Pharmacological Properties

Sildenafil promotes erections in response to sexual stimulation by inducing smooth muscle relaxation in the corpus cavernosum through selective inhibition of phosphodiesterase type 5 (PDE5). By reducing the inactivation of cyclic guanosine monophosphate (cGMP) rather than promoting its production, sildenafil promotes penile erection only in response to sexual stimulation, but has no effects in the absence of sexual stimulation. Indeed, the effects of sildenafil on cGMP were enhanced by sodium nitroprusside in rabbit corpus cavernosum in vitro, indicating that sildenafil augments nitric oxide-mediated activity in this tissue. The activity of sildenafil is highly selective, being 80- to >8500-fold greater against human PDE5 than against several other human PDEs and 7.7- to 16.6-fold greater against human PDE5 than PDE6.

In well controlled studies in patients with erectile dysfunction of a variety of causes, single doses of sildenafil enabled more men to achieve an erection than placebo, and erections were maintained for longer with sildenafil than placebo. More patients achieved >60% rigidity of the base of the penis, and this rigidity lasted for longer, with sildenafil than placebo. Single doses of sildenafil appear to produce dose-related rigidity at the base and tip of the penis in response to visual sexual stimulation. Daily sildenafil improved erections in more patients than placebo and was associated with an increased rate of erections (6.1 vs 1.3 erections in 7 days, p = 0.005).

Blood pressure was transiently reduced by sildenafil 100mg, and larger blood pressure reductions may occur when sildenafil is given with nitrates; the ECG, however, did not change. Dose-related effects of sildenafil on retinal PDE6 may cause the impairment of colour (blue/green) discrimination seen with sildenafil, but the drug had no major effects on vision in healthy volunteers. Sildenafil alone or with aspirin has no effects on bleeding time, but sodium nitroprusside-induced inhibition of platelet aggregation was increased in vitro by sildenafil.

Oral sildenafil is rapidly absorbed, with peak plasma concentrations (C_max) occurring within 1 hour. Absolute bioavailability was 41%. Food slows absorption but does not affect the area under the plasma sildenafil concentration-time curve (AUC). AUC and C_max were dose-proportional over single sildenafil doses from 1.25 to 200mg. The steady-state volume of distribution was 105L, indicating wide distribution. Plasma protein binding was ≈96%. The elimination half-life was 3 to 5 hours. ≈80% of a dose was found in the faeces and ≈13% in the urine as metabolites; <2% was excreted unchanged. N-demethylation by CYP3A4 is the major route of metabolism. Clearance of sildenafil is reduced in healthy elderly patients, patients with renal insufficiency (creatinine clearance <1.8 L/h or <30 ml/min) and those with hepatic cirrhosis.

Clinical Efficacy

The clinical effects of sildenafil have been studied in patients with erectile dysfunction of a broad range of causes (organic, psychological or mixed origin), including those with clear organic causes such as spinal cord injury or diabetes. Three major end-points of clinical trials were whether treatment improved erections or affected the patient’s ability to achieve penetration or maintain an erection after penetration. All trials were well designed, with suitable controls for bias (e.g. randomised, placebo-controlled, double-blind), and most enrolled large numbers of patients or used crossover design. Fixed-dose and dose-titration studies were performed, testing doses from 5 to 100mg. In all studies, sildenafil was administered when needed no more than once a day ≈1 hour before sexual activity. In all trials, the ability of sildenafil to improve erections was superior to that of placebo and exhibited a dose-response effect.

In patients with broad spectrum erectile dysfunction, 2 major trials found sildenafil to be effective in improving erectile function and enabling successful sexual intercourse. Patients were more likely to require sildenafil doses of 50 or 100mg for efficacy. Patients receiving sildenafil were more likely to have erections adequate for sexual intercourse and to be able to maintain their erections for longer periods than those receiving placebo in both fixed- and titrated-dose studies. Erectile function, orgasmic function, intercourse satisfaction and overall satisfaction with treatment improved with sildenafil to a greater extent than with placebo (p < 0.001). Mean scores for sexual desire were unaffected by therapy. The number of successful attempts at sexual intercourse also increased in the final weeks of treatment with sildenafil relative to placebo (5.9 over 4 weeks vs 1.5 attempts with placebo, p < 0.001) and 69% of attempts at sexual intercourse were successful in sildenafil recipients (vs 22% with placebo, p < 0.001). A 200mg sildenafil dose did not provide additional efficacy over that seen with a 100mg dose, but tended to produce more adverse events.

Early trials of sildenafil in patients with erectile dysfunction of no known organic cause found 3-fold more frequent erections and more patients reporting improvements in erections with sildenafil (65 to 93%) than placebo (20 and 27%). Dose-response effects of sildenafil 10, 25 and 50mg were reported on hardness, frequency and duration of erections and frequency of sexual intercourse in 1 trial, but the drug did not alter the number of attempts at intercourse. After a single dose of sildenafil 50mg, 86% of patients subsequently randomised to placebo reported their erections were ‘worse’ during placebo than they had been during sildenafil treatment; patients also reported more frequent erections in the sildenafil than placebo groups. 87% of sildenafil recipients had doses titrated to 50 or 100mg.

Significant improvements in ability to achieve and maintain erections were seen in diabetic patients receiving sildenafil 25 to 100mg compared with placebo in a 12-week dose-titration study in 268 patients. At the end of the study, 93% of sildenafil recipients required 100mg doses for efficacy. Data from subgroup analysis of 692 patients with diabetes in both dose-titration and fixed-dose therapeutic trials lasting 6 to 26 weeks showed similar improvements in erections and the ability to achieve and maintain erections.

Whether or not patients had residual erectile function, sildenafil was significantly more effective than placebo for erectile dysfunction caused by spinal cord injuries, with improvements in erections seen in 64% of sildenafil recipients with no residual erectile function and 75 and 78% of those with erectile function. Subgroup analysis from the major clinical trials suggests that men with severe erectile dysfunction respond better to sildenafil than to placebo and that sildenafil is similarly effective in broader patient populations and in patients undergoing antihypertensive therapy, aged ≥65 years or those experiencing depression. Trials in small numbers of patients with heart transplants or receiving maintenance haemodialysis for end-stage renal disease suggest that sildenafil can be effective, although effects of the drug were prolonged in the dialysis patients. The efficacy of sildenafil appears to be maintained after long term treatment.

There are reports of significant positive effects of sildenafil on patients’ quality of life and on female partners’ satisfaction and perceptions of treatment. Significant improvements (p < 0.05) were seen on 7 of 11 quality of life end-points after 12 weeks ’ treatment with sildenafil compared with placebo in a pooled population of 940 patients with broad spectrum erectile dysfunction. In a dose-titration study, partner ratings significantly favouring sildenafil were reported. Female partners of patients with spinal cord injury reported greater personal satisfaction with sexual intercourse and improvements in their partners’ erections after the 178 patients received sildenafil than after placebo.

Tolerability and Drug Interactions

Sildenafil was very well tolerated in clinical trials, with the most commonly reported adverse events being headache, flushing, dyspepsia and nasal congestion. Adverse events were generally transient and mild to moderate and occurred in similar proportions of patients receiving sildenafil and placebo. The incidence of commonly reported adverse events or discontinuations from therapy was dose-related. Vision changes were mild and transient, and included a colour tinge to vision, increased sensitivity to light or blurred vision. In clinical trials, the tolerability of sildenafil in patients receiving antihypertensive medications was similar to that seen in general study populations. There are isolated reports of painful, prolonged erections. In long term studies, sildenafil was well tolerated and headache (10%), flushing (9%), dyspepsia (6%) and respiratory tract infection (6%) were the most common adverse events. Abnormal vision occurred in 2% of patients and no long term vision problems were noted. Good tolerability and low withdrawal rates were seen during 2 years’ treatment.

In clinical trials, no serious adverse events were judged to be related to sildenafil therapy. The incidence of serious cardiovascular events in patients receiving sildenafil was similar to that in patients receiving placebo. After >6 million sildenafil prescriptions were dispensed, most of the 130 deaths associated with sildenafil appear to have occurred in patients with known risk factors or contraindications to the use of the drug (e.g. known or suspected myocardial infarction, cardiac arrest, cardiac symptoms, coronary artery disease, concomitant nitrate use). Symptoms leading to death occurred most often within 4 to 5 hours after administration. 70% of patients had risk factors for cardiovascular disease.

The interaction between sildenafil and organic nitrates contraindicates the concomitant use of these drugs. The potential exists for interactions between sildenafil and inhibitors or inducers of CYP3A4 and CYP2C9; however, only CYP3A4-related interactions have been documented (e.g. with erythromycin, ritonavir, saquinavir, ketoconazole, itraconazole or cimetidine). Rifampicin (rifampin), a CYP3A4 inducer, is expected to decrease sildenafil plasma concentrations. Sildenafil does not appear to interact with magnesium hydroxide/aluminium hydroxide antacids, thiazide diuretics, ACE inhibitors, calcium antagonists, alcohol, amlodipine, the CYP2C9 inhibitors tolbutamide and warfarin or CYP2D6 inhibitors such as selective serotonin reuptake inhibitors or tricyclic antidepressants.

Dosage and Administration

Sildenafil is indicated as an oral therapy for male patients with erectile dysfunction. In the US, sildenafil is contraindicated in patients taking organic nitrates or nitric oxide donors and in those for whom sexual activity carries a major cardiovascular risk; it should be used with caution in patients with recent heart attack, stroke, life-threatening arrhythmia, significant hypo- or hypertension, unstable angina, heart disease that could be affected by reductions in blood pressure, or retinitis pigmentosa. In Europe, contraindications to the use of sildenafil include the use of nitrates or nitric oxide donors and patients in whom sexual activity is not advised (e.g. patients with severe cardiac illness such as unstable angina or severe heart failure), those with hypotension, severe hepatic impairment, retinitis pigmentosa, or a recent history of stroke or myocardial infarction.

The usual dosage of sildenafil is a single 50mg dose taken when needed ≈1 hour before sexual activity, but the drug may be taken from 0.5 to 4 hours before sexual activity. No more than 1 dose should be taken in any given day. Depending on effectiveness and tolerability, single doses may be increased to a maximum of 100mg or reduced to 25mg.

A lower (25mg) initial dose may be considered in patients aged >65 years, or those with hepatic impairment or moderate to severe renal impairment (creatinine clearance <1.8 L/h or <30 ml/min), or those receiving concomitant CYP3A4 inhibitors (e.g. ritonavir, saquinavir, erythromycin, ketoconazole, itraconazole).

Authors and Affiliations

1. Adis International Limited, Auckland, New Zealand

   Heather D. Langtry & Anthony Markham

Corresponding author

Correspondence to Anthony Markham.

Various sections of the manuscript reviewed by: W.W. Dinsmore, Department of Genito-Urinary Medicine, The Royal Group of Hospitals and Dental Hospital, Health and Social Services Trust, Belfast, Northern Ireland; I. Eardley, Pyrah Department of Urology, St James’s University Hospital, Leeds, England; J.C. Gingell, Department of Urology, Southmead Hospital, Bristol, England; C.A. Glass, Southport & Formby NHS Trust, Regional Spinal Injuries Centre, District General Hospital, Merseyside, England; M. Godschalk, Department of Veteran Affairs, McGuire VA Medical Center, Richmond, Virginia, USA; A.T. Guay, Center for Sexual Function, Lahey Clinic, Peabody, Massachusetts, USA; Y. Kimoto, Department of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan; J.Y. Jeremy, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, England; D.W. Lording, Cabrini Medical Centre, Malvern, New South Wales, Australia; T.F. Lue, USCF Urology Group, Mount Zion Medical Center, University of California, San Francisco, California, USA; F. Montorsi, Responsabile Centro di Andrologia, Aiuto Divisione di Urologia, Istituto Scientifico H. San Raffaele, Milan, Italy; A. Morales, Queen’s University, Department of Urology, Kingston General Hospital, Kingston, Ontario, Canada; B.M. Soni, Southport & Formby NHS Trust, Regional Spinal Injuries Centre, District General Hospital, Merseyside, England.

Data Selection

Sources: Medical literature published in any language since 1966 on sildenafil, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. 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: AdisBase search terms were ‘sildenafil’, ‘UK-92480’, ‘Viagra’, ‘impotence’ and ‘phosphodiesterase inhibitors’. Medline and EMBASE search terms were ‘sildenafil’, ‘UK-92480’, ‘Viagra’, ‘therapeutic use’, ‘pharmacokinetics’ and ‘pharmacology’. Searches were last updated 3 May 1999.

Selection: Studies in men with erectile dysfunction 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, erectile dysfunction, impotence, pharmacokinetics, pharmacodynamics, therapeutic use.

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