Avanafil (Spedra)

What avanafil is

Avanafil is a prescription-only phosphodiesterase-5 inhibitor, approved in the EU as Spedra since June 21, 2013.

What is rated is the state of knowledge. For avanafil there are several phase 3 trials, including in diabetes and after prostate removal, and meta-analyses. The data base and post-marketing surveillance are smaller than for the older PDE5 inhibitors.

How it works

Like the other PDE5 inhibitors, avanafil inhibits the breakdown of the messenger cGMP and thus amplifies the nitric oxide signal that relaxes the vascular muscle in the erectile tissue during sexual arousal. Without sexual stimulation it has no effect. According to the summary of product characteristics, it inhibits PDE5 more than 100 times more strongly than PDE6, which occurs in the retina.

Avanafil is absorbed rapidly: the peak blood concentration is reached after a median of 30 to 45 minutes, and the half-life is about 6 to 17 hours. A high-fat meal delays absorption by an average of 1.25 hours and lowers the peak concentration by 39 percent.

What the studies show

The pivotal trial

Goldstein 2012 (J Sex Med) randomized 646 men with mild to severe erectile dysfunction to 50, 100 or 200 mg avanafil or placebo over 12 weeks, taken 30 minutes before intercourse, without restrictions on food or alcohol. All three doses were better than placebo for successful penetration, successful intercourse and erectile function. Of 300 attempts within 15 minutes of dosing, 64 to 71 percent succeeded on avanafil and 27 percent on placebo; of 80 attempts after more than 6 hours, 59 to 83 versus 25 percent. The most common side effects were headache, facial flushing and nasal congestion.

Onset of action after 15 minutes

Hellstrom 2015 (J Urol) randomized 440 men to 100 mg, 200 mg or placebo and measured with a stopwatch whether an erection sufficient for completed intercourse was achieved within about 15 minutes of dosing. This was the case in 25.9 and 29.1 percent of attempts, compared with 14.9 percent on placebo. A statistically significant difference appeared as early as 10 minutes on 200 mg and 12 minutes on 100 mg. So the majority of early attempts did not succeed, even on avanafil.

After prostate removal

Mulhall 2013 (J Urol) treated 298 men with erectile dysfunction after bilateral nerve-sparing radical prostatectomy for 12 weeks with 100 mg, 200 mg or placebo; 71.5 percent had severe erectile dysfunction. Both doses were better than placebo on all three primary endpoints. Attempts at 15 minutes or earlier succeeded in 36.4 versus 4.5 percent. No serious side effects occurred.

Meta-analysis and comparison with other PDE5 inhibitors

Li 2019 (Am J Mens Health) pooled 8 randomized trials with 3,709 patients. Compared with placebo, successful penetration (RR 3.20) and successful intercourse (RR 2.53) were considerably more frequent, but so were side effects (RR 1.78). 200 mg worked somewhat better than 100 mg for intercourse, with the same side-effect rate. Chen 2015 (Eur Urol) compared the starting doses of all PDE5 inhibitors in a network meta-analysis of 82 studies: avanafil 100 mg had a similar number of side effects to sildenafil 50 mg, but considerably lower overall efficacy. The comparison of the two better-known substances is shown on the page Tadalafil vs. sildenafil.

Where the data stop

• An advantage over sildenafil. The data do not show one. In the network comparison of starting doses, avanafil was less effective than sildenafil 50 mg; head-to-head comparison studies are not available in the sources evaluated here.
• The rapid onset of action in everyday life. Statistically the effect sets in early; in practice, only 26 to 29 percent of attempts succeed after about 15 minutes, compared with 15 percent on placebo.
• Long-term and market data. Avanafil has only been approved in the EU since 2013. Experience from post-marketing surveillance is correspondingly shorter than for sildenafil, tadalafil and vardenafil.
• Products from outside the pharmacy. The studies apply to the approved medicine, not to products from the gray market.

Status, approval and legal

Spedra has been approved in the EU since June 21, 2013; avanafil is prescription-only in Germany. The indication is erectile dysfunction in adult men. According to the summary of product characteristics, the approved dosage is 100 mg as needed about 15 to 30 minutes before intercourse, depending on effect and tolerability 50 mg or at most 200 mg, at most once daily.

The approval does not cover other indications such as pulmonary hypertension or symptoms of benign prostatic enlargement; sildenafil and tadalafil respectively are approved for those.

Safety

The most common side effects are headache, facial flushing and nasal congestion. In the meta-analysis, side effects overall were more frequent than on placebo, relative risk 1.78. Alcohol combined with avanafil can promote a drop in blood pressure with dizziness or fainting.

Contraindications are concomitant use with nitrates or nitric oxide donors, whose blood-pressure-lowering effect avanafil amplifies, and with strong CYP3A4 inhibitors such as ketoconazole, ritonavir or clarithromycin; ritonavir increased the amount of the substance in the blood to about 13 times. Avanafil is also contraindicated in severe kidney or liver impairment. Visual disturbances due to NAION and sudden hearing loss have rarely been reported with other PDE5 inhibitors, not in the avanafil studies.

Sources

• Goldstein I et al., J Sex Med 2012 – phase 3 trial of avanafil, 646 men over 12 weeks
• Hellstrom WJ et al., J Urol 2015 – efficacy 15 minutes after dosing, RCT with 440 men
• Li J et al., Am J Mens Health 2019 – meta-analysis of avanafil, 8 RCTs with 3,709 patients
• Mulhall JP et al., J Urol 2013 – phase 3 trial after nerve-sparing radical prostatectomy, 298 patients
• Chen L et al., Eur Urol 2015 – network meta-analysis of PDE5 inhibitors, 82 studies with 47,626 patients
• EMA – Spedra, European public assessment report (EPAR)
• EMA – Spedra, product information (summary of product characteristics)
• German Prescription Medicines Ordinance (AMVV), Annex 1 (prescription-only substances)