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Vardenafil

A Review of its Use in Erectile Dysfunction

Summary

Abstract

Vardenafil (Levitra®) is a potent and highly selective oral phosphodiesterase type 5 (PDE5) inhibitor.

Vardenafil improved erectile function in men with mild to severe erectile dysfunction (ED) of varying aetiology in two randomised, double-blind, multicentre, fixed-dose studies of 12 or 26 weeks’ duration. Men receiving vardenafil 10 or 20mg had significantly greater improvements in International Index of Erectile Function (IIEF) questionnaire erectile function domain scores than placebo recipients. Moreover, improvements in penetration and maintenance of erection (assessed using IIEF or Sexual Encounter Profile [SEP] questions) were significantly greater with vardenafil 5–20mg than with placebo. Improvements in IIEF intercourse satisfaction and orgasmic function domain scores were significantly greater with vardenafil 10 or 20mg than with placebo and the proportion of patients with a positive response to a Global Assessment Question (GAQ) concerning improvement in erections after 12 or 26 weeks’ therapy was significantly higher with vardenafil 5–20mg than with placebo.

Vardenafil improved erectile function in men with ED associated with diabetes mellitus or ED following unilateral or bilateral nerve-sparing radical retropubic prostatectomy in two randomised, double-blind, multicentre, fixed-dose, 3-month studies. In both studies, improvements from baseline in the erectile function domain score of the IIEF and in positive responses to SEP questions were significantly greater with vardenafil 10 or 20mg than with placebo. In addition, a significantly higher proportion of vardenafil 10 or 20mg recipients than placebo recipients had positive GAQ responses.

Vardenafil was generally well tolerated in men with ED; treatment-emergent adverse events were of mild to moderate intensity and transient in nature. The most commonly reported adverse events (typical of those seen with PDE5 inhibitors) in vardenafil 5–20mg recipients included headache, flushing, rhinitis, dyspepsia and sinusitis. There were no reports of abnormal colour vision in men with ED taking vardenafil at clinically recommended doses (5–20mg).

Conclusion: Vardenafil is a potent and highly selective oral PDE5 inhibitor. It is effective and generally well tolerated in men with mild to severe ED of varying aetiology, as well as in men with ED associated with diabetes mellitus or ED after radical prostatectomy. Vardenafil should be considered a first-line treatment option in men with ED who are suitable candidates for oral PDE5 inhibitor therapy.

Pharmacodynamic Profile

Vardenafil is a potent and highly selective inhibitor of phosphodiesterase type 5 (PDE5). The vardenafil concentration required to inhibit 50% of the activity (IC50) of PDE5 ranged from 0.11–0.7 nmol/L, depending on the assay used. Vardenafil, like sildenafil and tadalafil, showed highly selective inhibition of PDE5, with limited or no activity against other known PDE isoenzymes. Relative to PDE5, vardenafil (4-to 25-fold selectivity) and sildenafil (≈ 10-fold) demonstrated some selectivity for PDE6, whereas tadalafil (5-fold) had some activity against PDE11 A.

Both vardenafil and sildenafil inhibited cyclic guanosine monophosphate (cGMP) hydrolysis in a competitive manner in human corpus cavernosum smooth muscle cell extracts; IC50 values were ≈5-fold lower for vardenafil than for sildenafil. The accumulation of cGMP in human corpus cavernosum tissue induced by the nitric oxide donor sodium nitroprusside (SNP) was significantly augmented by vardenafil 3 nmol/L. This effect was also seen with sildenafil 30 nmol/L, but not with lower concentrations. Vardenafil significantly enhanced relaxation in human trabecular smooth muscle induced by SNP, acetylcholine or transmural electrical stimulation.

Oral vardenafil successfully induced penile erections in a conscious rabbit model; a dose-dependent erectile response was seen with oral vardenafil 1–10 mg/ kg. It has been suggested that the duration of effect of vardenafil may be much longer than its measured elimination half-life (t1/2). In a conscious rabbit model, a significant erectile response was obtained with SNP 7 hours after oral vardenafil administration (vardenafil t1/2 of 1.2 hours in rabbits).

Single-dose oral vardenafil 10–40mg significantly increased penile rigidity and tumescence during visual sexual stimulation in men with erectile dysfunction (ED) in two double-blind, randomised, placebo-controlled crossover studies. The mean total duration of erections with >60% rigidity was significantly longer with vardenafil 10–40mg than with placebo, and the mean total duration of erections with >80% rigidity was significantly longer with vardenafil 20 or 40mg than with placebo. Rigidity activity units and tumescence activity units were significantly higher with vardenafil 10–40mg than with placebo. The mean time to onset of the first erection was 26.8, 26.2 and 34.9 minutes with vardenafil 20 or 40mg or placebo.

Administering oral vardenafil 10mg 1–24 hours before sublingual nitroglycerin (glyceryl trinitrate) 0.4mg in healthy men did not potentiate the blood pressure (BP)-lowering effect of the latter drug (the coadministration of vardenafil and nitrates in men with ED is contraindicated). Some healthy men who received concomitant administration of vardenafil 10 or 20mg and α-blockers experienced hypotension.

Oral vardenafil 10 or 20mg did not impair the ability of men with stable coronary artery disease to exercise to a level similar to or greater than that associated with sexual intercourse in two randomised, double-blind, placebo-controlled, crossover studies. In one study, the time to ST-segment depression of ≥1mm was significantly longer with vardenafil 10mg than with placebo (381 vs 341 seconds). Coadministration of oral vardenafil 20mg in men with essential hypertension did not alter the antihypertensive effect of extended-release nifedipine 30 or 60 mg/day to a clinically significantly extent. In men with ED, small decreases in mean BP occurred with oral vardenafil 5–20mg between 11 minutes and 5 hours after treatment (reduction in mean systolic and diastolic BP of −1.4 to −6.6mm Hg and −2.0 to −4.8mm Hg). Changes in systolic and diastolic BP were −0.4 to +0.6mm Hg and −1.3 to +1.5mm Hg with placebo.

Pharmacokinetic Profile

Plasma concentrations rose rapidly after oral administration of single-dose vardenafil 10–40mg in men with ED. The mean maximum plasma vardenafil concentration (Cmax) increased in an almost dose-proportional manner and the median time to Cmax (tmax) was slightly longer with vardenafil 10mg (≈0.9 hours) than with vardenafil 20 or 40mg (≈0.7 hours). Vardenafil has a mean absolute bioavailability of 15% and a mean volume of distribution at steady state of 208L. Both vardenafil and its major circulating metabolite (M1) are highly protein bound. In healthy men, the median tmax was prolonged by 1 hour after consumption of a high-fat meal, compared with the fasting state.

Vardenafil is predominantly metabolised by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP3A5 and CYP2C. The Ml metabolite is pharmacologically active with an estimated efficacy contribution of ≈7%. In men with ED, the mean t1/2 of single-dose vardenafil 10–40mg ranged from 3.94 to 4.79 hours. Vardenafil has a total body clearance of 56 L/h and the mean renal clearance of vardenafil was 2.3 L/h. Approximately 91–95% of the administered vardenafil dose is excreted as metabolites in faeces and ≈2–6% is excreted as metabolites in the urine.

Elderly volunteers (aged >65 years) had higher Cmax and area under the plasma concentration-time curve (AUC) values (by 34% and 52%) and reduced hepatic clearance compared with younger volunteers (aged 18–45 years) after receiving single-dose vardenafil 40mg; t1/2 was slightly longer in elderly than in young volunteers (6.0 vs 4.8 hours). Renal clearance was ≈50% lower in men with mild to severe renal impairment than in healthy volunteers. In addition, the Cmax was lower (18.4 vs 31.8 μg/L) and the tmax (1.4 vs 0.8 hours) and t1/2 (56.1 vs 4.7 hours) were prolonged in men with severe renal impairment compared with healthy volunteers. Vardenafil clearance was reduced in men with mild to moderate hepatic impairment in proportion to the degree of impairment.

Alterations in the pharmacokinetics of vardenafil were seen with concomitant administration of potent CYP3A4 inhibitors such as ritonavir, indinavir and ketoconazole, and the bioavailability of a single dose of vardenafil 20mg was increased by 12% when it was coadministered with cimetidine (a nonspecific inhibitor of CYP isoenzymes). Concomitant administration of vardenafil 5mg and the CYP3A4 inhibitor erythromycin increased the AUC of vardenafil 4-fold and the Cmax of vardenafil 3-fold.

Therapeutic Efficacy

Oral vardenafil improved erectile function in men with mild to severe ED of varying aetiology in two randomised, double-blind, multicentre, fixed-dose studies of 12 or 26 weeks’ duration (n = 580–895 [intent-to-treat]). Men receiving vardenafil 10 or 20mg had significantly greater improvements in International Index of Erectile Function (IIEF) questionnaire erectile function domain scores than placebo recipients after 12 or 26 weeks’ therapy. In addition, in the 26-week study, the proportion of patients responding ‘yes’ to two Sexual Encounter Profile (SEP) questions (‘Were you able to insert your penis into your partner’s vagina’ [SEP-2] and ‘Did your erection last long enough for you to have successful intercourse’ [SEP-3]) was significantly greater with vardenafil 5–20mg than with placebo at both weeks 12 and 26. In the 12-week study, the improvement from baseline in IIEF question 3 (‘When you attempted sexual intercourse how often were you able to penetrate your partner?’) and IIEF question 4 (‘During sexual intercourse how often were you able to maintain your erection after you had penetrated your partner?’) was significantly greater with vardenafil 5–20mg than with placebo.

In both studies, improvements in IIEF intercourse satisfaction and orgasmic function domain scores were significantly greater with vardenafil 10 or 20mg than with placebo. Moreover, the proportion of patients with a positive response to the Global Assessment Question (GAQ) [‘Has the treatment you have taken over the past 4 weeks improved your erections?’] was significantly higher with vardenafil 5–20mg than with placebo after 12 and 26 weeks’ therapy (65–85% vs 28–39%). With regards to health-related quality of life (assessed using the Fugl-Meyer questionnaire), improvements from baseline in mean scores for the question relating to sex life satisfaction were significantly greater with vardenafil 5–20mg than with placebo. A dose-response was seen for improvement in IIEF domain scores and for GAQ.

In a randomised, double-blind, multicentre, fixed-dose, 52-week study in men with mild to severe ED of varying aetiology (n = 1000) who received vardenafil 10 or 20mg, the mean IIEF erectile function domain score increased from ≈13 at baseline to ≈23 after 52 weeks’ therapy; at 104 weeks the erectile function domain score was ≈25. Improvements in positive responses to SEP-2 and SEP-3 were also seen at week 104.

Pooled analyses of randomised, double-blind studies in men with ED who received vardenafil 5–20mg or placebo revealed that compared with placebo, vardenafil significantly improved erectile function irrespective of age, aetiology, baseline ED severity, the presence of comorbidities or whether or not patients were receiving concomitant antihypertensive therapy.

In a 12-week flexible-dose study in men with moderate to severe ED who had not responded to prior sildenafil therapy, the improvement from baseline in the IIEF erectile function domain score and SEP-2 and SEP-3 response rates were significantly greater with vardenafil than with placebo.

Vardenafil improved erectile function in men with ED associated with diabetes mellitus in a randomised, double-blind, multicentre, fixed-dose study (452 randomised patients). The improvements from baseline in the erectile function domain score of the IIEF and the proportion of positive SEP-2 and SEP-3 responses were significantly greater with vardenafil 10 or 20mg than with placebo. Significantly more vardenafil 10 or 20mg than placebo recipients had a positive GAQ response (57% and 72% vs 13%). Improvement with vardenafil occurred irrespective of glycaemic control at baseline. Following study completion, 340 men continued in a 3-month extension study in which placebo recipients switched to receive vardenafil 10 or 20mg. Erectile function domain scores improved in both men who had received vardenafil 10 or 20mg for the entire 6 months and in patients initially randomised to placebo who switched to vardenafil. Improvements were also seen in the percentage of patients able to maintain an erection during intercourse and the percentage of patients responding ‘yes’ to the GAQ

Vardenafil improved erectile function in men with ED following unilateral or bilateral nerve-sparing radical retropubic prostatectomy in a randomised, double-blind, multicentre, fixed-dose study (442 randomised patients). The improvements from baseline in the erectile function domain score of the IIEF and the proportion of positive SEP-2 and SEP-3 responses were significantly greater with vardenafil 10 or 20mg than with placebo. Positive GAQ response rates were significantly higher with vardenafil 10 or 20mg than with placebo (59% and 65% vs 13%).

Tolerability

Vardenafil was generally well tolerated in men with ED. Treatment-emergent adverse events were generally of mild to moderate intensity and transient in nature.

Across three large, well designed, placebo-controlled trials, the most commonly reported adverse events (typical of those seen with oral PDE5 inhibitors) in vardenafil 5–20mg recipients included headache (6.8–22%), flushing (5–13%) and rhinitis (2.8–17%). Dyspepsia (0.7–6.7%) and sinusitis (1–6%) were also reported. Serious adverse events occurred infrequently and were reported in 1–5% of vardenafil 5–20mg recipients and in 3–5% of placebo recipients. Adverse events resulting in treatment discontinuation occurred in 1–5% of vardenafil 5–20mg recipients and in 1% of placebo recipients.

Small decreases in mean BP occurred with vardenafil. In a pooled analysis of five randomised, double-blind trials, ECG abnormalities, oedema, syncope, angina pectoris, hypotension and myocardial ischaemia occurred with an incidence of 0% to <0.6% and were not dose related. Myocardial infarction occurred in one vardenafil and one placebo recipient. Another placebo recipient experienced a cerebrovascular accident and a third required cardiovascular surgery.

There were no reports of abnormal colour vision in men with ED taking vardenafil at clinically recommended doses (5–20mg). Transient vision changes such as mild haziness or an increase in the perceived brightness of light were reported infrequently (incidence of 1% in vardenafil and placebo recipients combined in one study).

Dosage and Administration

Vardenafil is approved in the US and the EU for the treatment of ED. The recommended dose of vardenafil in adult men is 10mg; however, the dose may be increased to the maximum recommended dose (20mg) or decreased to 5mg according to efficacy and tolerability. It is recommended that vardenafil not be taken more than once daily. Vardenafil should be taken orally prior to sexual intercourse. Vardenafil is not indicated for use in women or in individuals aged <18 years.

A starting dose of 5mg should be used in elderly men. EU prescribing information states that a starting dose of 5mg should also be considered in men with mild to moderate hepatic impairment and in men with severe renal impairment, and US prescribing information recommends a starting dose of 5mg in moderate hepatic impairment.

Vardenafil is contraindicated in the EU and not recommended in the US in men with severe hepatic impairment; end-stage renal failure needing dialysis; hypotension; a recent history of stroke or myocardial infarction; unstable angina pectoris; or known hereditary degenerative disorders of the retina (e.g. retinitis pig-mentosa). US prescribing information also states that the use of vardenafil is not recommended in patients with uncontrolled hypertension, a recent history of life-threatening arrhythmia or severe heart failure; vardenafil use should also be avoided in men with QT prolongation. Vardenafil should generally not be prescribed to men with ED for whom sexual activity is inadvisable.

Concomitant administration of vardenafil and nitrates or nitric oxide donors is contraindicated. In the EU, coadministration of vardenafil and potent CYP3A4 inhibitors such as ritonavir, indinavir, oral ketoconazole or oral itraconazole is contraindicated in men aged >75 years and should be avoided in younger men. In the US, reduced doses of vardenafil are recommended when it is administered in combination with ritonavir, indinavir, ketoconazole or itraconazole. Coadministration of vardenafil and grapefruit juice should be avoided and the vardenafil dose should not exceed 5mg when it is coadministered with the CYP3A4 inhibitor erythromycin. Coadministration of vardenafil and α-blockers is not recommended in the EU and contraindicated in the US.

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Notes

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

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Various sections of the manuscript reviewed by: K.-E. Andersson, Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden; J.D. Corbin, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; W.J.G. Hellstrom, Department of Urology, Tulane University Medical Center, New Orleans, Louisiana, USA; M.K. Li, Department of Surgery, National University Hospital, Singapore; C.G. McMahon, Australian Centre for Sexual Health, St Luke’s Hospital, Sydney, New South Wales, Australia; J. Pryor, Lister Hospital, London, UK; D. Ralph, Institute of Urology, London, UK; E. Wespes, Department of Urology, CHU de Charleroi, Belgium; J.M. Young, South Orange County Urological Medical Associates, Laguna Woods, California, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on vardenafil, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). 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 search terms were ‘vardenafil’. EMBASE search terms were ‘vardenafil’. AdisBase search terms were ‘vardenafil’. Searches were last updated 3 November 2003.

Selection: Studies in men with erectile dysfunction who received vardenafil. 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: Vardenafil, erectile dysfunction, pharmacodynamics, pharmacokinetics, therapeutic use.

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Keating, G.M., Scott, L.J. Vardenafil. Drugs 63, 2673–2702 (2003). https://doi.org/10.2165/00003495-200363230-00010

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Keywords

  • Erectile Dysfunction
  • Erectile Function
  • Vardenafil
  • Severe Erectile Dysfunction
  • 20mg Recipient