Key points from the evidence

Summary

In 2 randomised controlled trials (RCTs) alprostadil 300 microgram cream statistically significantly improved erectile function and intercourse ability compared with placebo but the average absolute benefit was modest and only 31%–40% of men (depending on outcome considered) obtained a clinically relevant response. Most reported adverse events were mild to moderate, transient and localised. There are no long term safety data for the use of alprostadil cream and its excipients in treating erectile dysfunction and there are no published comparisons with other drug treatments.

Regulatory status: Alprostadil cream (Vitaros) received a European marketing authorisation in August 2013 and was launched in the UK in June 2014.

Effectiveness

  • In 2 RCTs (n=1732) and compared with baseline, alprostadil 300 microgram (410 men) produced a mean:

    • 2.5 point increase in the 30‑point International Index of Erectile Function erectile function (IIEF‑EF) domain score.

    • 15.1% relative increase in proportion of intercourse attempts with successful penetration (7.6 percentage points absolute increase).

    • 34.1% relative increase in proportion of attempts at intercourse successful to ejaculation (9.8 percentage points absolute increase).

All outcomes were statistically significantly different from placebo but only the last one met the criteria for clinical relevance.

  • A post‑hoc analysis reported that close to 40% of men had a clinically significant increase in IIEF‑EF score, 36% had a clinically relevant improvement in penetration ability and 31% had a clinically relevant improvement on ability to have successful intercourse.

  • These response rates are less than those reported with other treatments for erectile dysfunction but there are no direct head‑to‑head comparisons and indirect comparisons are limited by differences in study design and clinical endpoints.

Safety

  • Adverse events were reported in 67% of men using alprostadil cream and 12% of men using placebo, and in 7% and 3% of partners respectively (no statistical analyses reported).

  • The summary of product characteristics states that commonly reported adverse events are transient, localised urogenital effects including penile burning, pain and erythema in men, and vaginal burning and vaginitis in female partners.

  • Treatment discontinuation due to adverse events occurred in around 3–4% of participants in clinical trials

  • Alprostadil cream should not be used in combination with oral selective phosphodiesterase type‑5 (PDE5) inhibitors because an additive increased cardiovascular risk cannot be excluded.

  • The summary of product characteristics advises that the dose may need to be reduced in response to side‑effects or in men with hepatic or renal insufficiency, but only a 300 microgram single‑dose product is available.

  • There are no safety data for use beyond 9 months or for use in anal or oral sex.

User factors

  • European guidelines on erectile dysfunction advise that alprostadil offers an alternative choice for men who cannot tolerate or have contraindications to PDE5 inhibitors or in whom they are ineffective.

  • Alprostadil cream has similar contraindications, cautions and interactions to other alprostadil formulations.

  • The topical application route may be preferred to the intraurethral or intracavernosal route by some men.

  • The licensed maximum frequency of use is no more than 2–3 times per week and only once per 24‑hour period.

Resource implications

  • Alprostadil cream costs £10 per dose, which is significantly more than generic sildenafil but is slightly less costly than other alprostadil products, at usual therapeutic dose.

  • Department of Health amended regulations allow unrestricted prescribing of generic sildenafil for men with erectile dysfunction. Avanafil, branded sildenafil, tadalafil, vardenafil, and alprostadil may be prescribed on the NHS only under certain circumstances.

Introduction and current guidance

NICE has not published a clinical guideline on erectile dysfunction, although erectile dysfunction is referred to in several NICE guidelines (see Relevance to NICE guidance programmes for more information). The European Association of Urology 2014 guidelines on male sexual dysfunction define erectile dysfunction as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Erectile dysfunction (ED) affects physical and psychosocial health and has a significant impact on the quality of life for men and their partners. The European guidelines advise that addressing lifestyle and other possible causes of ED must precede or accompany any pharmacological treatment. According to the guidelines, first‑line pharmacotherapy is usually an oral selective phosphodiesterase type‑5 (PDE5) inhibitor (avanafil, sildenafil, tadalafil or vardenafil). Non‑pharmacological treatment options are also available.

Full text of Introduction and current guidance.

Product overview

This evidence summary considers the efficacy and safety of alprostadil cream, a new topical formulation of a drug already licensed for treating erectile dysfunction. Alprostadil is chemically identical to prostaglandin E1 (PGE1) and causes vasodilation of blood vessels. Alprostadil cream (Vitaros) received a European marketing authorisation for the treatment of erectile dysfunction in adult men in August 2013. It was approved through the European Decentralized Procedure; Netherlands acted as the Reference Member State and it was launched in the UK in June 2014.

The summary of product characteristics states that after application of alprostadil cream to the tip of the penis, the onset of erection is within 5 to 30 minutes. Improvement of erections may last from 1 to 2 hours after dosing. Alprostadil cream has similar contraindications, cautions and interactions to other alprostadil formulations.

Full text of Product overview.

Evidence review

  • This evidence summary is based on 3 phase III studies that evaluated the efficacy and safety of alprostadil cream in men with erectile dysfunction. Two of the studies were randomised controlled trials (RCTs) in a general population, with a 12 week treatment period, using the same protocol, and were published as an integrated analysis (Padma-Nathan et al. 2006).

  • Alprostadil 300 microgram produced a mean 2.5 point increase in the 30‑point International Index of Erectile Function erectile function (IIEF‑EF) domain score, a mean 15.1% relative increase in proportion of intercourse attempts with successful penetration and a mean 34.1% relative increase in proportion of attempts at intercourse successful to ejaculation. All outcomes were statistically significantly different from placebo but only the last met the criteria for clinical relevance.

  • A post‑hoc analysis reported that close to 40% of men had a clinically significant increase in IIEF‑EF score, 36% had a clinically relevant improvement in penetration ability and 31% had a clinically relevant improvement in ability to have successful intercourse.

  • A statistically significantly greater proportion of men in the alprostadil 300 microgram group than in the placebo group reported improved erections (52% compared with 20%, p<0.001).

  • An open‑label long‑term extension study (Rooney et al. 2009) reported on alprostadil cream use over a 9 month period. As this study did not compare alprostadil cream directly with an active treatment or placebo (non‑comparative), it is not discussed in detail in this evidence summary.

  • The summary of product characteristics states that the most common adverse events reported in clinical studies were transient, localised urogenital adverse effects. The majority of adverse events were mild to moderate in severity, resulting in small numbers of discontinuations (2.7% in Padma-Nathan et al. 2006 and 4.3% in Rooney et al. 2009).

  • Most commonly reported partner adverse events were transient local vaginal reactions (3% in the placebo group versus 6.5% in the alprostadil group). Study withdrawals due to partners' treatment‑related adverse events were infrequent (0.4% in Padma-Nathan et al. 2006).

  • There are no safety data for alprostadil cream use longer than 9 months duration or for use in anal or oral sex.

  • The 2 RCTs were placebo‑controlled and it is not known how alprostadil cream compares to other alprostadil products or PDE5 inhibitors.

Full text of Evidence review.

Context

Alprostadil (prostaglandin E1) is currently licensed and available in products for intracavernosal (Caverject, Viridal) or intraurethral (MUSE) treatment of erectile dysfunction. Alprostadil is recommended as an alternative therapeutic option for men who cannot tolerate or have contraindications to oral treatment with PDE5 inhibitors or in whom PDE5 inhibitors are ineffective. Non‑pharmacological treatment options for erectile dysfunction, such as vacuum erection devices, are also available.

Full text of Context.

Estimated impact for the NHS

Alprostadil cream is an alternative route of administration that may be preferred to intracavernosal (Caverject, Viridal) or intraurethral (MUSE) administration by some men with ED. Although direct comparison studies have not been reported, indirect comparisons suggest that alprostadil is generally less effective than PDE5 inhibitors and is recommended in European guidelines as a second‑line treatment option. The summary of product characteristics advises that the dose may need to be reduced in response to side effects or in men with hepatic or renal insufficiency, but only a 300 microgram single dose product is available.

As well as efficacy, safety and individual user factors, local decision makers will need to take cost into account when considering the likely place in therapy of alprostadil cream for erectile dysfunction. Alprostadil cream is slightly less costly than alprostadil for intracavernosal injection or intraurethral application, at usual therapeutic dose, but costs substantially more than generic sildenafil (£10 per dose compared with £0.28 to £0.31 per dose for 25 mg to 100 mg tablets respectively).

The Department of Health has amended regulations to allow unrestricted prescribing of generic sildenafil for men with erectile dysfunction. Avanafil tadalafil, vardenafil, branded sildenafil and alprostadil may be prescribed on the NHS only under certain circumstances (see individual preparations in the British National Formulary).

Full text of Estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.