Advice
Key points from the evidence
Key points from the evidence
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The content of this evidence summary was up-to-date in August 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. |
Summary
Three randomised controlled trials (RCTs; total n=1334) have evaluated the phosphodiesterase type 5 (PDE5) inhibitor, avanafil, in men with erectile dysfunction in the general population (Goldstein et al. 2012a), with diabetes mellitus (Goldstein et al. 2012b), and post‑prostatectomy (Mulhall et al. 2013). Overall, compared with placebo, they found that avanafil 50 mg, 100 mg and 200 mg statistically significantly improved the percentage of sexual attempts in which an erection of sufficient duration was maintained to enable successful intercourse; the percentage of sexual attempts in which vaginal penetration was achieved; and International Index of Erectile Function erectile function domain scores. The majority of adverse events seen in clinical studies were mild‑moderate in severity and resulted in infrequent discontinuations (2.8% with avanafil 100 mg in Goldstein et al. 2012a). However, it is not known how the efficacy, tolerability and safety of avanafil compare with the other PDE5 inhibitors (sildenafil, tadalafil and vardenafil).
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Effectiveness
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Safety
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User factors
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Resource implications
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Introduction and current guidance
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. Although erectile dysfunction is a benign disorder, it affects physical and psychosocial health and has a significant impact on the quality of life of sufferers and their partners.
Erectile dysfunction can generally be treated successfully, although it often cannot be cured. Regardless of the cause, the European guidelines advise that first‑line therapy is usually oral treatment with selective PDE5 inhibitors (sildenafil, tadalafil and vardenafil).
The NICE guidelines on multiple sclerosis (NICE clinical guideline 8), type 1 diabetes (NICE clinical guideline 15), type 2 diabetes (NICE clinical guideline 87) and myocardial infarction (NICE clinical guideline 172) advise that men with erectile dysfunction should be offered PDE5 inhibitors. Men with prostate cancer should have early and ongoing access to specialist erectile dysfunction services (NICE clinical guideline 175) (see Relevance to NICE guidance programmes for more information).
This evidence summary considers the efficacy and safety of avanafil, a new PDE5 inhibitor.
Product overview
Avanafil (Spedra, A. Menarini Farmaceutica Internazionale) received a European marketing authorisation for the treatment of erectile dysfunction in adult men in June 2013 and was launched in the UK in March 2014.
The recommended dose of avanafil is 100 mg as needed approximately 30 minutes before sexual activity. Based on individual efficacy and tolerability, the dose may be increased to a maximum dose of 200 mg or decreased to 50 mg. As with other PDE5 inhibitors, sexual stimulation is required for a response to treatment.
According to the summary of product characteristics, avanafil has similar contraindications, cautions and interactions to other PDE5 inhibitors.
Evidence review
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This evidence summary is based on 4 phase III studies that have evaluated the efficacy and safety of avanafil in men with erectile dysfunction. Three of the studies are double‑blind, RCTs of 12 weeks' duration (1 in a general population with erectile dysfunction [without diabetes or post‑prostatectomy; Goldstein et al. 2012a, n=646]; 1 in men with type 1 or type 2 diabetes [Goldstein et al. 2012b, n=390] and 1 in men with erectile dysfunction following bilateral nerve‑sparing radical prostatectomy [Mulhall et al. 2013, n=298]. Men were instructed to take placebo or avanafil 50 mg (Goldstein et al. 2012a only), 100 mg or 200 mg as needed approximately 30 minutes before initiation of sexual activity.
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In addition, 712 men from 2 of the RCTs (Goldstein et al. 2012a and Goldstein et al. 2012b) enrolled in a 52‑week open‑label extension study (Belkoff et al. 2013). All men were initially assigned to avanafil 100 mg but could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment.
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Overall, in the 3 RCTs, compared with placebo, avanafil 50 mg, 100 mg and 200 mg statistically significantly improved all 3 co‑primary outcomes (percentage of sexual attempts in which an erection of sufficient duration was maintained to enable successful intercourse; percentage of sexual attempts in which vaginal penetration was achieved; and International Index of Erectile Function erectile function domain scores). The mean percentage of attempts resulting in successful intercourse was:
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41.3%, 57.1%, and 57.0% for avanafil 50 mg, 100 mg, and 200 mg respectively in the general population with erectile dysfunction, compared with 27.0% for placebo (all p≤0.0002; Goldstein et al. 2012a)
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34.4% and 40.0% for avanafil 100 mg and 200 mg respectively in men with diabetes (89.5% type 2), compared with 20.5% for placebo (both p<0.0001; Goldstein et al. 2012b)
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23.4% and 26.4% for avanafil 100 mg and 200 mg respectively in men post‑prostatectomy, compared with 8.9% for placebo (both p≤0.0004; Mulhall et al. 2013).
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Avanafil 100 mg and 200 mg were statistically significantly better than avanafil 50 mg (Goldstein et al. 2012a) but there were no significant differences between avanafil 100 mg and 200 mg (Goldstein et al. 2012a and Goldstein et al. 2012b; comparison not reported in Mulhall et al. 2013).
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Higher response rates were generally seen with avanafil in the general population with erectile dysfunction, than in men with diabetes or post‑prostatectomy. In the latter 2 populations, some improvements were of borderline clinical importance only. According to the European public assessment report for avanafil, response rates generally decreased as the severity of erectile dysfunction increased.
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The open‑label long‑term extension study suggests that the effects of avanafil are maintained for up to 52 weeks. In this study, about two‑thirds of men responded to avanafil 100 mg and, of those who did not, a further two‑thirds responded to 200 mg. However, only 24.0% of men remained on the 100 mg dose, with 75.3% of men voluntarily increasing their dose to 200mg (Belkoff et al. 2013).
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From the studies, the overall safety profile of avanafil appears to be similar to that of other PDE5 inhibitors and no new safety concerns have been raised. The majority of adverse events seen in clinical studies were mild‑moderate in severity and resulted in infrequent discontinuations (2.8% with avanafil 100 mg in Goldstein et al. 2012a; European public assessment report for avanafil, 2013).
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The summary of product characteristics states that the most common adverse events reported in clinical studies (n=2144) were headache, flushing, nasal and sinus congestion (all with an incidence of between 1 in 10 and 1 in 100), and back pain (incidence between 1 in 100 and 1 in 1000). Men should be aware of how they react to avanafil before driving or using machines because dizziness, somnolence and altered vision were reported in clinical studies with avanafil (incidence between 1 in 100 and 1 in 1000).
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The 3 RCTs are placebo‑controlled and it is not known how avanafil compares to other PDE5 inhibitors. Limitations of the open‑label extension study include the lack of a comparator and blinding, and the possibility that responders to avanafil in the qualifying studies may have been more likely to enrol than non‑responders, potentially over estimating the benefits of avanafil.
Context
Alternative PDE5 inhibitors to avanafil are sildenafil, tadalafil and vardenafil. The European guidelines on male sexual dysfunction state that the choice of PDE5 inhibitor depends on the frequency of intercourse (occasional or 3−4 times weekly) and the man's personal experience of these drugs. All 4 PDE5 inhibitors are taken on‑demand. At lower doses, tadalafil is also licensed to be taken daily, providing an alternative to on‑demand dosing for couples who prefer spontaneous rather than scheduled sexual activity or who have frequent sexual activity.
When usual starting doses are considered, avanafil costs significantly more than generic sildenafil (£14.08 for 4 x 100 mg tablets compared with £1.08 for 4 x 50 mg tablets) but is competitively priced compared with on‑demand tadalafil (£26.99 for 4 x 10 mg tablets) and vardenafil (£17.88 for 4 x 10 mg tablets).
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 only be prescribed on the NHS under certain circumstances (see individual preparations in the British National Formulary).
Estimated impact for the NHS
Although avanafil was statistically significantly more effective than placebo and well tolerated in the studies, it is not known how its efficacy, safety and tolerability compare with sildenafil, tadalafil and vardenafil. There are no direct head‑to‑head comparisons and indirect comparisons are limited by differences between the studies (for example, study designs, populations, outcomes, rating scales and definitions of success). According the European guidelines on male sexual dysfunction, efficacy rates (erection rigidity sufficient for vaginal penetration) are:
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56%, 77% and 84% in men taking 25 mg, 50 mg and 100 mg of sildenafil, respectively.
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67% and 81% in men taking 10 mg and 20 mg of tadalafil, respectively.
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66%, 76% and 80% in men taking 5 mg, 10 mg and 20 mg of vardenafil, respectively.
It is also not possible to draw conclusions around the efficacy and tolerability of avanafil in men whose erectile dysfunction has consistently not responded to the other PDE5 inhibitors, or whether it is tolerated by men who have experienced dose‑limiting adverse effects with another of these drugs, because these men were excluded from studies.
As well as efficacy, safety and cost, local decision makers will need to take individual user factors into account when considering the likely place in therapy of avanafil for erectile dysfunction. The European guidelines advise that the choice of PDE5 inhibitor depends on the frequency of intercourse and the man's personal experience of these drugs. Onset of action might be important to some men taking PDE5 inhibitors on‑demand. According to the summaries of product characteristics, sildenafil should be taken 1 hour before sexual activity, whereas avanafil, tadalafil and vardenafil should be taken 25−30 minutes before sexual activity.
The current marketing authorisation states that avanafil should be taken approximately 30 minutes before sexual activity. However, the manufacturer, Menarini, has advised that a licence variation to examine the therapeutic effect of avanafil approximately 15 minutes after dosing in men with mild to severe erectile dysfunction has been submitted to the European Medicines Agency. A decision is expected later in 2014 (Menarini; personal communication, June 2014). Any new evidence on a 15 minute effectiveness window will need to be assessed before any recommendations can be made in this regard.
The manufacturer of avanafil estimates that about 5000 men might be prescribed avanafil second‑line in the UK at any one time (Menarini; personal communication, March 2014). However, specialists involved in the production of this evidence summary have advised that this might be an overestimation, primarily due to the increasing impact of generic sildenafil.
Full text of Estimated impact for the NHS.
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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. |