Erectile dysfunction: avanafil

Drug action

Avanafil (Spedra, A. Menarini Farmaceutica Internazionale) is a reversible inhibitor of cyclic guanosine monophosphate (cGMP) ‑specific PDE5 inhibitor. When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by avanafil produces increased levels of cGMP in the corpus cavernosum of the penis. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Avanafil has no effect in the absence of sexual stimulation (summary of product characteristics for avanafil, 2014).

Licensed therapeutic indication

Avanafil (Spedra) 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 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.

According to the summary of product characteristics, avanafil has similar contraindications, cautions and interactions to other PDE5 inhibitors. It is contraindicated in men:

Special warnings and precautions for use include cardiovascular disease; priapism; visual, bleeding and hearing disorders; and concomitant use of alpha‑blockers, antihypertensive drugs, alcohol, and other treatments for erectile dysfunction. Co‑administration of avanafil with potent inhibitors of CYP3A4, such as ketoconazole, clarithromycin or ritonavir, is contraindicated. See the summary of product characteristics for avanafil for full details.

Course and cost

Avanafil is available as 50 mg, 100 mg or 200 mg tablets. The recommended dose is 100 mg as needed approximately 30 minutes before sexual activity. If it is taken with food, the onset of activity may be delayed. Based on individual efficacy and tolerability, the dose may be increased to a maximum dose of 200 mg or decreased to 50 mg. The maximum recommended dosing frequency is once daily. Sexual stimulation is required for a response to treatment.

According to MIMS (June 2014; costs excluding VAT):

Clinical effectiveness

Overall, in the 3 RCTs, (Goldstein et al. 2012a, Goldstein et al. 2012b and Mulhall et al. 2013), 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 IIEF erectile function domain scores compared with placebo. In Goldstein et al. (2012a), avanafil 100 mg and 200 mg were statistically significantly better than avanafil 50 mg. In Goldstein et al. 2012a and Goldstein et al. 2012b, there were no significant differences between avanafil 100 mg and 200 mg (comparison not reported in Mulhall et al. 2013).

Higher response rates were generally seen with avanafil in the general population with erectile dysfunction (Goldstein et al. 2012a), than in men with diabetes (89.5% type 2; Goldstein et al. 2012b) or in men who had undergone bilateral nerve‑sparing radical prostatectomy (Mulhall et al. 2013). 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.

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 experienced a response to avanafil 100 mg and, of those who did not, a further two‑thirds experienced a response 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).

General population with erectile dysfunction ( Goldstein et al. 2012a )

In this study, from baseline, placebo and avanafil 50 mg, 100 mg and 200 mg statistically significantly improved:

Clinically important improvements from baseline are reported to be 23% for successful intercourse, 21% for vaginal penetration and 4 points for IIEF (European public assessment report for avanafil).

The mean percentage of sexual attempts resulting in successful intercourse was 41.3%, 57.1%, and 57.0% for avanafil 50 mg, 100 mg, and 200 mg respectively, compared with 27.0% for placebo. All doses of avanafil were statistically significantly more effective than placebo (all p≤0.0002 for successful intercourse, p≤0.0009 for vaginal penetration, and p≤0.0014 for IIEF erectile function domain score). Avanafil 100 mg and 200 mg were statistically significantly better than avanafil 50 mg (both p<0.0001 for successful intercourse, p=0.0004 and p=0.0064 respectively for vaginal penetration, and p<0.0001 and p=0.0003 respectively for IIEF erectile function domain score). However, there were no statistically significant differences between avanafil 100 mg and 200 mg. See table 1 for more details.

Type 1 or type 2 diabetes mellitus ( Goldstein et al. 2012b )

In this study, in which 89.5% of men had type 2 diabetes, from baseline, placebo and avanafil 100 mg and 200 mg statistically significantly improved:

The mean percentage of sexual attempts resulting in successful intercourse was 34.4% and 40.0% for avanafil 100 mg and 200 mg respectively, compared with 20.5% for placebo. Both doses of avanafil were statistically significantly more effective than placebo (both p<0.0001 for successful intercourse, p≤0.0004 for vaginal penetration, and p≤0.0017 for IIEF erectile function domain score). However, there were no statistically significant differences between avanafil 100 mg and 200 mg. See table 1 for more details.

Bilateral nerve‑sparing radical prostatectomy ( Mulhall et al. 2013 )

In this study, from baseline, placebo and avanafil 100 mg and 200 mg statistically significantly improved:

The mean percentage of sexual attempts resulting in successful intercourse was 23.4% and 26.4% for avanafil 100 mg and 200 mg respectively, compared with 8.9% for placebo. Both doses of avanafil were statistically significantly more effective than placebo (both p≤0.0004 for successful intercourse, p≤0.0003 for vaginal penetration, and p≤0.0001 for IIEF erectile function domain score). Avanafil 100 mg and 200 mg were not compared in this study. See table 1 for more details.

Open‑label long‑term extension study ( Belkoff et al. 2013 )

Overall, during the 52‑week treatment period (mean treatment duration 35.3 weeks), the mean percentage of sexual attempts resulting in successful intercourse was:

Overall, the mean percentage of sexual attempts resulting in successful vaginal penetration was 80.2% during the 52‑week treatment period (mean change from baseline 36.9%) and the mean IIEF erectile function domain score was 22.6 at the end of treatment (mean change in score from baseline 10.3). The data suggest that increasing the dose of avanafil to 200 mg may improve efficacy in some men who do not experience a response to 100 mg. See table 2 for more information.

Safety and tolerability

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).

General population with erectile dysfunction ( Goldstein et al. 2012a )

Avanafil was generally well tolerated. In total, 37.9% (183/483) of men who received avanafil treatment and 26.1% (42/161) of men who received placebo experienced an adverse event (statistical analysis not reported). The most frequently reported adverse events, occurring in more than 2% of men in any treatment group, included headache, flushing, nasal congestion, back pain, nasopharyngitis and bronchitis. No treatment‑related serious adverse events were seen.

A total of 96 (14.9%) men discontinued the study, primarily due to lack of compliance with the protocol (8.2%) or loss to follow‑up (3.4%). In the placebo, avanafil 50 mg, 100 mg and 200 mg groups respectively, 5, 3, 6 and 2 men discontinued treatment due to adverse events (statistical analyses not reported).

Type 1 or type 2 diabetes mellitus ( Goldstein et al. 2012b )

Avanafil was generally well tolerated. Overall, 33.3% (86/258) of men who received avanafil and 23.8% (31/130) men who received placebo reported 1 or more adverse event (statistical analysis not reported). Events that occurred in at least 2% of men in any treatment group included headache, nasopharyngitis, flushing, sinus congestion, back pain, sinusitis, dyspepsia, and influenza. All drug‑related adverse events were reported to be mild to moderate in severity. None of the serious adverse events reported were considered treatment‑related.

Of the 57 (14.6%) men who discontinued the study, 4 (0.1%; 2 taking avanafil 100 mg and 2 taking avanafil 200 mg) discontinued because of adverse events, 36 (9.2%) discontinued because of protocol noncompliance, and 15 (3.8%) were lost to follow‑up.

Bilateral nerve‑sparing radical prostatectomy ( Mulhall et al. 2013 )

Avanafil was generally well tolerated. Adverse events were reported in 41.9% (83/198) of men who received avanafil and 23.0% (23/100) men who received placebo (statistical analysis not reported). The most frequently reported adverse events were headache, flushing and nasopharyngitis. No serious adverse events were reported during the study.

Overall, 46 (15.4%) men discontinued the study, primarily due to withdrawal of consent (23 [7.7%]) and loss to follow‑up (10 [3.4%]). Five (1.7%) men discontinued due to an adverse event (1 in the placebo group, 2 in the avanafil 100 mg group and 2 in the avanafil 200 mg group).

Open‑label long‑term extension study ( Belkoff et al. 2013 )

Avanafil was generally well tolerated. In this 52‑week study (mean treatment duration 35.3 weeks), 38.7% (275/711) of men reported adverse events. In 11.1% of men, these were considered to be drug‑related. None of the serious adverse events reported were considered treatment‑related. The most frequently reported adverse events, seen in at least 2% of men, were headache, flushing and nasopharyngitis and nasal congestion.

The overall discontinuation rate was 30.6% (220/712) and discontinuations due to adverse events occurred in 2.8% (20/712) of men. Other key reasons for discontinuation were loss to follow‑up, protocol noncompliance, and withdrawal of consent. The percentage of men who discontinued the study was lower among those who received avanafil 100 mg and 200 mg (25.9%) than among those who received avanafil 100 mg only (46.2%; statistical analysis not reported). Discontinuations due to adverse events were also lower among men who received both doses (1.5%) than among those who received avanafil 100 mg only (6.4%; statistical analysis not reported).

Summary of product characteristics ( Spedra )

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). Overall, adverse events were more frequent in men with a normal body mass index (BMI; less than 25 kg/m²). In the long‑term clinical study, the percentage of men who experienced adverse events decreased with increasing length of exposure.

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).

Evidence strengths and limitations

The 3 double‑blind RCTs evaluating the safety and efficacy of 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) were generally well designed. However, all of the studies are placebo‑controlled and it is not known how avanafil compares to other PDE5 inhibitors. In addition, some data for the primary outcomes are missing in Mulhall et al. (2013) and no confidence intervals are provided for the data in any of the RCTs.

No p values or confidence intervals are reported in the long‑term extension study (Belkoff et al. 2013). Other limitations of this study include the lack of a comparator and blinding, and the possibility that men who experienced a response to avanafil in the qualifying studies may have been more likely to enrol than men who did not, potentially over estimating the benefits of avanafil. Dropout rates were around 15% in the 3 RCTs and 30% in the long‑term extension study. However, analyses were by intention-to-treat and few discontinuations were due to adverse events.

The majority of men included in the 4 studies were white (80−86%), which limits the generalisability of the results to other races. Also, the average age of participants was about 56−58 years: limited data are available in older men aged 70 years or above (see the summary of product characteristics). Men with mild, moderate and severe erectile function domain scores were well represented in the studies undertaken in the general and diabetic populations: 71.5% of men in the post‑prostatectomy study (Mulhall et al. 2013) had severe erectile dysfunction.

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, avanafil 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. Only 10.5% of participants in Goldstein et al. (2012b) had type 1 diabetes, which limits the study's applicability to men with this condition.

In the European public assessment report for avanafil, the CHMP notes that the average weight, height and BMI of participants in the studies, which were carried out in the US, are not generalisable to many regions in Europe. An increased frequency of adverse events was seen in men with a normal BMI (18.5−25kg/m²) compared with overweight and/or obese men.

In the RCTs, about three‑quarters of men had previously used PDE5 inhibitors. However, it is not known whether avanafil is effective in men whose erectile dysfunction has consistently failed to respond to other PDE5 inhibitors, or whether it is tolerated by men who have experienced dose‑limiting adverse effects with another of these drugs, because these populations were excluded from the studies. The CHMP questioned whether the study population was an enriched population, favouring the observed efficacy results, but the company argued that by defining treatment failure as 'the failure to respond to 2 or more specific PDE5 inhibitors, with each used on multiple attempts', the company tried to identify men unresponsive to PDE5 inhibitor therapy as a class, rather than to a single agent (European public assessment report for avanafil, 2013).

During their assessment of avanafil, the CHMP questioned the lack of a pre‑planned definition of 'responders' and 'clinically significant' change from baseline for the 3 co‑primary endpoints. In response to this, a post‑hoc analysis was provided, which defined the minimum thresholds for clinically relevant changes from baseline for successful intercourse, vaginal penetration and IIEF as improvements of 23%, 21% and more than 4 points respectively (European public assessment report for avanafil, 2013).

All studies were funded by the companies involved in the development of avanafil, Vivus and Mitsubishi Tanabe Pharma Corporation. (Menarini has been granted the rights to market avanafil in Europe).

Alternative treatments

First‑line therapy for erectile dysfunction is usually an oral selective phosphodiesterase type 5 (PDE5) inhibitor. Alternatives to avanafil are sildenafil, tadalafil and vardenafil. All are used as required: tadalafil can also be used daily at lower doses. 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 (European Association of Urology guidelines on male sexual dysfunction, 2014), as well as efficacy, safety and cost.

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).

Other treatment options include vacuum erection devices, and intracavernous, intraurethral and topical alprostadil. Surgical implantation of a penile prosthesis may be considered in men who fail pharmacotherapy or who want a permanent solution (European Association of Urology guidelines on male sexual dysfunction, 2014).

Costs of alternative treatments

Table 3 Costs of PDE5 inhibitors

Likely place in therapy

Avanafil 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 compared with placebo. The majority of improvements were of clinical importance and avanafil was well tolerated. However, it is not known how the efficacy and safety of avanafil compare with the other PDE5 inhibitors, 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 Association of Urology guidelines on male sexual dysfunction, sildenafil is effective 30−60 minutes after administration and efficacy may be maintained for up to 12 hours. Efficacy rates (erection rigidity sufficient for vaginal penetration) are 56%, 77% and 84% in men taking 25 mg, 50 mg and 100 mg of sildenafil, respectively. The efficacy of sildenafil has been well established in most subgroups of men with erectile dysfunction and there is more cumulative experience with sildenafil than with the other PDE5 inhibitors (NICE Clinical knowledge summary: erectile dysfunction).

Tadalafil is effective from 30 minutes after administration but its peak efficacy occurs after about 2 hours and efficacy is maintained for up to 36 hours. Efficacy rates are 67% and 81% in men taking 10 mg and 20 mg of tadalafil, respectively. Although PDE5 inhibitors were introduced as on‑demand treatment, tadalafil has also been approved for continuous, everyday use at 2.5 mg and 5 mg doses (European Association of Urology guidelines on male sexual dysfunction, 2014).

Vardenafil is effective 30 minutes after administration. Efficacy rates are 66%, 76% and 80% in men taking 5 mg, 10 mg and 20 mg of vardenafil, respectively (European Association of Urology guidelines on male sexual dysfunction, 2014).

A systematic review and meta-analysis (Yuan J et al. 2013: 118 RCTs, n=31,195) has compared the efficacy and safety of PDE5 inhibitors for erectile dysfunction. It found that, compared with sildenafil, tadalafil and vardenafil, avanafil was statistically significantly less effective on Global Assessment Questionnaire question 1 ('Has the treatment you are taking improved your erectile function?') and there were no major differences in safety between PDE5 inhibitors. However, the systematic review included only 2 RCTs of avanafil (Goldstein et al. 2012a and Zhao et al. 2012) and inadequate data were available to include avanafil in the meta‑analysis for any other outcomes. Therefore, limited information is available about the relative efficacy and safety of avanafil.

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 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.

The European guidelines on male sexual dysfunction advise 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. 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 (10 mg and 20 mg) and vardenafil should be taken 25−30 minutes before sexual activity.

Although the summary of product characteristics currently states that avanafil should be taken approximately 30 minutes before sexual activity, 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 and a decision is expected later in 2014 (Menarini; personal communication, June 2014).

According to a secondary analysis in Goldstein et al. (2012a), 300 sexual attempts were made within 15 minutes of dosing and, of these, 64−71% attempts were reported to be successful in the avanafil groups compared with 27% in the placebo group. However, the European public assessment report for avanafil states that the time from drug intake to the start of the sexual activity was not well defined during the studies. Based on the men's diary responses, the percentages of success at different time periods are very similar (from earliest times up to 4‑6 hours post‑dose), which precluded the Committee for Medicinal Products for Human Use from reaching any definitive conclusions about the onset of action. If the license extension is approved, any new evidence on a 15 minute effectiveness window will need to be assessed before any recommendations can be made in this regard.

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 avanafil for erectile dysfunction. 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 usage

A Department of Health impact assessment for the proposed changes to the NHS availability of treatment for erectile dysfunction estimated that the total prevalence of drug therapy for erectile dysfunction is about 184,000 and the number of men being prescribed a PDE5 inhibitor within UK primary care at any one time is about 177,000. This figure is likely to increase if prescribing restrictions are removed.

It has been suggested that about 40% of men discontinue their first‑line PDE5 inhibitor therapy because of lack of efficacy (Carvalheira et al. 2012). Assuming that there are 177,000 men receiving treatment at any one time, this suggests that an estimated 70,800 men might be considered for a second‑line alternative. Assuming a market penetration for avanafil that is the same as the third to market (vardenafil, 7.7%), about 5000 men might be prescribed avanafil second‑line in the UK at any one time. This is around 3% of the 177,000 men receiving treatment with a PDE5 inhibitor. The manufacturer notes that this is an appropriate market share for a fourth to market drug (Menarini; personal communication, March 2014). However, specialists involved in the production of this evidence summary have advised that it might be an overestimation, primarily due to the increasing impact of generic sildenafil.

Expert advisers

Prof Michael Cummings, Consultant Diabetologist and Endrocrinologist, Portsmouth NHS Trust

Mr Ian Pearce, Consultant Urological Surgeon, Manchester Royal Infirmary

Declarations of interest

No relevant interests declared.

Copyright

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ISBN 978-1-4731-0683-3