Erectile dysfunction: Alprostadil cream

Drug action

Alprostadil is chemically identical to prostaglandin E₁ (PGE1) and causes vasodilation of blood vessels in the erectile tissue of the corpora cavernosa and an increase in intracavernosal artery blood flow, resulting in an erection. The excipient dodecyl‑2‑N, N‑dimethylaminopropionate hydrochloride (DDAIP) is added to the formulation of the cream to optimise the absorption of alprostadil (see the summary of product characteristics).

Licensed therapeutic indication

Alprostadil cream (Vitaros) received a European marketing authorisation for the treatment of ED in men aged 18 years and older in August 2013. It was approved through the European Decentralized Procedure; Netherlands acted as the Reference Member State. It was launched in the UK in June 2014.

The summary of product characteristics states that the onset of erection is within 5 to 30 minutes. Improvement of erections will last approximately 1 to 2 hours, but will vary from person to person. Alprostadil cream has similar contraindications, cautions and interactions to other alprostadil formulations. For example, it is not recommended in men with unstable cardiovascular disease, previous myocardial infarction, orthostatic hypotension or predisposition to priapism. It is also contraindicated in men with abnormal penile anatomy. Concomitant administration with other erectile dysfunction agents is not recommended and no interaction studies have been performed for its use with sympathomimetics, antihypertensives, vasodilators, anticoagulants and antiplatelets. See the summary of product characteristics for alprostadil cream for full details.

Alprostadil cream has not been studied in men with renal or hepatic impairment and the summary of product characteristics states that the dose may need to be lowered in these men or in response to side effects, although only one formulation strength is available in the UK.

Course and cost

Alprostadil 300 micrograms in 100 mg of cream is available in single dose containers. The cream is applied to the tip of the penis (meatus) 5–30 minutes before attempting intercourse. The maximum frequency of use is 2–3 times per week and only once per 24 hour period. Alprostadil cream costs £40 per pack of 4 doses (MIMS October 2014, cost excluding VAT).

Clinical effectiveness

The comparative phase III studies (Padma-Nathan et al. 2006) included 100 microgram and 200 microgram strengths of alprostadil cream, but these are not available in the UK, so only the results for the 300 microgram and placebo treatment groups are discussed in this evidence summary (except where only total combined results are reported, for example participant withdrawals). The mean improvements in the 3 primary efficacy measures with 300 microgram alprostadil cream were statistically significant compared with placebo (table 1). However, the degree of improvement from baseline in IIEF‑EF score and in penetration success (SEP question 2) were less than that accepted as being clinically relevant. Only the improvement in percentage of sexual intercourse attempts leading to ejaculation (SEP question 3) was clinically relevant.

Selected secondary endpoints showed a statistically significant improvement compared to placebo. For example the percentage of men reporting improved erections (table 1) and patient satisfaction scores, as measured by the GAQ (data not reported, p<0.001).

During their assessment of topical alprostadil, the Netherlands Medicines Evaluation Board requested a post‑hoc responder analysis, which was reported briefly in the PAR. This states that close to 40% of men treated with the 300 microgram dose obtained a clinically relevant improvement in IIEF‑EF score, 36% had a clinically relevant improvement in vaginal penetration ability and 31% had a clinically relevant improvement in ability to have successful intercourse to ejaculation. The public assessment report states that similar results to those of all men were generally observed within subpopulations (men who had previously obtained limited benefit from PDE5 inhibitors and men with diabetes, heart disease, hypertension or who had undergone a prostatectomy).

Safety and tolerability

The PAR states that in the 2 comparative phase III trials (Padma-Nathan et al. 2006), 1732 men were treated, of whom 434 received placebo and 1298 received active treatment with alprostadil in doses of 100 microgram, 200 microgram and 300 microgram. Men received treatment for a 12 week duration with a mean of 17–18 applications per person. The phase III open‑label extension study (Rooney et al. 2009) yielded data on 300 men exposed for more than 6 months, and 148 men exposed for up to 9 months. In addition, 120 men had exposure for up to 10 months to the excipient DDAIP in both the drug and placebo. Twelve month safety data are absent because the study was stopped prematurely by the study sponsor and the US Food and Drug Administration (FDA), due to concerns about DDAIP arising from results of the Tg.AC mouse carcinogenicity study. This 'clinical hold' was later lifted by the FDA. The PAR states that no events have been reported in alprostadil cream phase III studies that would indicate local carcinogenicity at the application site.

In the phase III studies a small number of serious ischaemic cardiac events were reported in the placebo and 300 microgram group (0.5% and 1.4% respectively). All the affected men had underlying cardiovascular disease at baseline or risk factors and the PAR states that none of the events were considered product‑related. The PAR concludes that although there is no clear indication that topical alprostadil cream increases the risk of cardiovascular events, it cannot be excluded that people with underlying disease or risk factors are at increased risk in combination with increased sexual or physical activity.

Most reported side effects were localised to the application site, showed a dose effect and were mild to moderate in severity. In the comparative phase III studies (Padma-Nathan et al. 2006) the most frequently reported treatment‑related adverse events included penile burning, genital pain and penile erythema (23.0%, 17.5%, 11.3% respectively, table 1). Most of these adverse events resolved within 2 hours. In the longer term study (Rooney et al. 2009) application site reactions (penile burning or erythema) occurred in 12.2% of men using the 300 microgram dose, application site pain was reported by 4.4% of men and 1.3% men reported penis disorders (prolonged or painful erections).

In the comparative phase III studies (Padma-Nathan et al. 2006), partner treatment‑related adverse events were reported in 6.5% (28/434) of women but all were transient and resolved within 2 hours. The most common partner treatment‑related adverse event was vaginal burning (4.3%, table 1). Five men (0.4%) withdrew from the phase III studies due to their partners' treatment‑related adverse events.

Systemic vasodilation symptoms were reported infrequently. Small numbers of men in the 300 microgram alprostadil cream treatment group experienced dizziness, hypotension or syncope (0.4% in Padma-Nathan et al. 2006).

Evidence strengths and limitations

The phase III studies (Padma-Nathan et al. 2006) were double‑blind randomised RCTs in a large general population of men with erectile dysfunction in the US. However, specialists involved in the production of this evidence summary have advised that this study may not reflect the patient cohort seen within the UK. Only 41% of men receiving alprostadil 300 micrograms were over the age of 65. The specialists advise that erectile dysfunction severity increases with increasing age, and it is not clear if the response to alprostadil cream is dependent upon the man's initial IIEF‑EF score.

The results reported in the comparative phase III studies (Padma-Nathan et al. 2006) for the 410 men that used the 300 microgram dose of alprostadil cream available in the UK, demonstrate a modest, but statistically significant effect over placebo. The primary endpoints used in the studies are commonly used in erectile dysfunction literature. However the study design had some limitations. During their assessment of topical alprostadil, the Netherlands Medicines Evaluation Board questioned the lack of a pre‑planned definition of 'responders' and 'clinically relevant' change from baseline for the 3 co‑primary endpoints.

The published report of the phase III studies (Padma-Nathan et al. 2006) provides limited detail on inclusion and exclusion criteria and it is unclear if treatment allocation was concealed. No confidence intervals are reported for the data in the RCTs. The study authors note that the baseline mean scores for SEP question 2 were very high in this study (50% in the alprostadil 300 microgram group) indicating a relatively high level of erectile function before drug treatment. The authors go onto state that this may have been due to limitations with inclusion criteria methodology and could have contributed to the relatively low increases in the primary efficacy results.

The limitations of the open‑label extension study (Rooney et al. 2009) include the lack of a comparator, and the possibility that men who experienced a response to topical alprostadil in the qualifying studies may have been more likely to enrol than men who did not, potentially over‑estimating the benefits of alprostadil. Dropout rates were around 3% in the combined RCTs and 5% in the long‑term extension study. However, analyses were by intention-to-treat and few discontinuations were due to adverse events.

The Medicines Evaluation Board acknowledged in the PAR that lack of 12 month safety data is not in line with current European licensing recommendations. The Board decided that data for 6 months were acceptable because alprostadil is a known active substance with an established safety profile. The report concluded that in addition, given the intermittent dosing of alprostadil cream and its short half‑life and duration of action, long‑term safety issues are not likely to occur. Data on the long‑term safety information of DDAIP are limited. For example, the PAR states that there is insufficient evidence to conclude that the effect of degeneration of seminiferous tubules in the testis of rabbits due to local treatment with DDAIP is not relevant for humans.

The numerous exclusion criteria of the studies are reflected in the contraindications and special warnings and precautions for use in the summary of product characteristics. For example, topical alprostadil has not been evaluated in men with erectile dysfunction due to spinal cord injury or other neurological disorders, or in men with severe renal or hepatic impairment or for use in oral or anal sex.

The main studies were placebo‑controlled or non‑comparative. It is not known how topical alprostadil cream compares to other erectile dysfunction therapies. Extrapolation of data from different populations using different interventions may not be valid. According the European guidelines, efficacy (erection rigidity sufficient for vaginal penetration, SEP question 2) is seen in 56%–84% with PDE5 inhibitors (depending on drug and dose), up to 90% of men using vacuum erection devices, more than 70% of men using intracavernosal alprostadil and 30–66% of men using intraurethral alprostadil.

Alternative treatments

The European Association of Urology guidelines on male sexual dysfunction (2014) advise that first‑line treatment of erectile dysfunction is usually with an oral selective PDE5 inhibitor, assuming there are no contraindications or drug interactions. The choice of PDE5 inhibitor depends on the frequency of intercourse and the man's personal experience of these drugs, as well as efficacy, safety and cost.

Vacuum erection devices are also recommended as an alternative first‑line treatment option for ED in the European guidelines, with high response rates reported but a wide range of user satisfaction rates (27% to 94%).

Alprostadil (prostaglandin E₁) is currently licensed and available in products for intracavernosal (Caverject, Viridal) or intraurethral (MUSE) treatment of erectile dysfunction. Alprostadil is recommended in the European guidelines as an alternative pharmacological therapeutic option for men who cannot tolerate or have contraindications to oral treatment with PDE5 inhibitors or in whom PDE5 inhibitors are ineffective. The guidelines state that intracavernosal alprostadil is associated with high drop‑out rates (41–68% reported) and limited compliance. The guidelines advise that intraurethral alprostadil provides an alternative choice for men who may prefer a less‑invasive but less‑efficacious treatment to intracavernous injection.

Costs of erectile dysfunction treatments

Vacuum pumps (manually or battery operated devices) and constrictor rings (to maintain erection) are also available as a treatment option for ED. Prices range from £89.50 to £191.58 for single pumps and £4.00 to £17.53 per constrictor ring.
(Drug Tariff, October 2014, excluding VAT).

Likely place in therapy

European guidelines advise that any pharmacological treatment should be part of a package of care for the management of ED. This should include identifying and addressing any underlying cause, providing lifestyle advice and discussion of available treatments. The NICE Clinical knowledge summary on erectile dysfunction advises that all men who cannot be adequately managed in primary care should be referred to a specialist. The European guidelines recommend alprostadil as a second‑line therapeutic option for men with ED. Alprostadil cream is an alternative route of administration to intracavernosal or intraurethral formulations. Some men may prefer this less‑invasive option, but the fixed single dose may be a limitation in practice. Although direct comparison studies have not been reported, indirect comparisons suggest that alprostadil cream is generally less effective than PDE5 inhibitors and vacuum erection devices.

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.

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).

Estimated usage

The NHS prescription cost analysis for England 2013 reports that approximately 84,000 community prescriptions for alprostadil were dispensed in 2012 at a cost of approximately £5 million (net ingredient cost). The manufacturer of alprostadil cream estimates that by Year 5 after launch approximately 40% men who are currently prescribed intracavernosal and intraurethral alprostadil in the UK may alternatively receive topical alprostadil cream (Takeda UK Ltd. Personal communication, August 2014). Specialists involved in the production of this evidence summary advise is that this is likely to be an overestimate because of the efficacy and side‑effect profile of topical alprostadil cream and wider availability of generic sildenafil as a treatment option.

Expert advisers

Prof Christopher Chapple
Consultant Urological Surgeon, Royal Hallamshire Hospital. Honorary Professor, University of Sheffield. Visiting Professor, Sheffield Hallam University. Secretary General Elect, European Association of Urology

Mr Michael Foster
Consultant Urologist, Heart of England NHS Foundation Trust

Mr Ian Pearce
Associate Clinical Head of Division, Consultant Urological Surgeon, Manchester Royal Infirmary. Honorary Senior Lecturer, University of Manchester

Declarations of interest

Chris Chapple has acted as a paid consultant for AMS, Allergan, Astellas, Lilly, ONO, Pfizer and Recordati and as a researcher, trial participant and spoken on behalf of Allergan, Astellas, Pfizer and Recordati.

Mike Foster had no relevant interests to declare.

Ian Pearce had no relevant interests to declare.

Copyright

© National Institute for Health and Care Excellence, 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.

ISBN 978-1-4731-0868-4