Avanafil (Stendra, Spedra)

Avanafil is the youngest of the four approved PDE-5 inhibitors and was designed as a refinement of the class: the same target as sildenafil, tadalafil and vardenafil, but a faster onset and an overall sharper selectivity for that target. The molecule, a pyrimidine-5-carboxamide, was discovered at Mitsubishi Tanabe in Japan. It has been approved in the US as Stendra since 2012 and in the EU as Spedra since 2013.

It is taken as a tablet on demand, about 15 to 30 minutes before planned activity according to the EU prescribing information. The US label allows as little as 15 minutes, which makes avanafil the member of the class with the shortest lead time. Its window extends beyond six hours in the trials, well short of the roughly 36 hours of tadalafil. You can get avanafil as tablets of 100mg or 200mg, 4 tablets per blister.

This information is for research and educational purposes only. No medical advice.

During sexual arousal, nerve endings in the erectile tissue release nitric oxide. That raises the messenger cGMP inside the smooth muscle cells, the muscle relaxes, the feeding arteries widen and the tissue fills with blood. The enzyme phosphodiesterase type 5 (PDE5) breaks cGMP down again and so ends the signal. Avanafil blocks PDE5 and the messenger persists longer. An erection forms more easily and holds more reliably. Without arousal the chain never starts, which is why nothing happens without stimulation.

What sets avanafil apart from the older agents is selectivity. Kotera and colleagues (Journal of Urology 2012) tested it against eleven phosphodiesterase isozymes: PDE5 is inhibited with an IC50 of 5.2 nM, selectivity over PDE6 is 121-fold (sildenafil and vardenafil 16- to 21-fold), over PDE1 more than 10,000-fold (sildenafil 375-fold) and over PDE11 more than 19,000-fold (tadalafil 25-fold). PDE6 sits in the retina and is behind the blue tinge seen with sildenafil, PDE1 in heart and vessels, PDE11 among other places in skeletal muscle, where the back pain under tadalafil is thought to originate. Less binding to those off-targets should in theory mean fewer side effects beyond the intended one. The trial data fit that expectation.

Taken fasted, avanafil reaches its peak level after a median of 30 to 45 minutes, per the prescribing information. A high-fat meal pushes the peak back by about 1.1 to 1.25 hours and lowers it by roughly 39 percent while total absorption barely changes (minus 3.8 percent). That is why it may be taken with or without food, but anyone who wants the fast window should not take it straight after a heavy meal. The registration trial placed no restrictions on food or alcohol. Efficacy held up regardless.

The US prescribing information gives a terminal half-life of about 5 hours, the EU SmPC 6 to 17 hours, depending on how long sampling continued after the dose. What matters in practice is the quick fall after the peak: far shorter than tadalafil (17.5 hours) and in the range of sildenafil. Avanafil is around 99 percent bound to plasma proteins and is cleared mainly through CYP3A4, with the metabolites leaving the body about 62 percent via the faeces and 21 percent via the urine. With daily dosing the accumulation ratio is about 1.2, so practically nothing builds up.

CYP3A4 clearance is where interactions arise. Ketoconazole raised the exposure of a 50mg dose 13-fold and stretched the half-life to about 9 hours; erythromycin, a moderate inhibitor, tripled exposure and extended the half-life to around 8 hours. In older men (65 to 80 years) exposure was only about 7 percent higher. The prescribing information sees no need for a dose adjustment on age alone.

The three differ less in potency than in time course and side effect profile:

• Avanafil: lead time about 15 minutes, peak after 30 to 45 minutes, half-life about 5 hours (US figure), window beyond 6 hours. High selectivity over PDE1, PDE6 and PDE11 at once, a single participant with a colour vision change across all trials up to 200mg. Food matters little.
• Sildenafil: lead time 30 to 60 minutes, duration about 4 to 6 hours. Sensitive to fatty food, a blue tinge to vision is possible (PDE6). The longest-established agent with the most data.
• Tadalafil: window up to 36 hours, can also be dosed low daily. Back and muscle pain as its class-specific effect (PDE11), food barely matters.

In short: avanafil for spontaneity with a short lead time and a clean side effect profile, tadalafil for a long window or daily dosing, sildenafil as the classic with the broadest evidence base. Avanafil is not approved for daily low-dose use and there are no registration data for it.

Registration trial (Goldstein, Journal of Sexual Medicine 2012): 646 men with mild to severe erectile dysfunction received 50, 100 or 200mg avanafil or placebo for 12 weeks, taken 30 minutes before activity with no restrictions on food or alcohol. All three doses improved the success rate for intercourse (SEP3), penetration (SEP2) and the IIEF erectile function score significantly versus placebo. Of 300 attempts within 15 minutes of dosing, 64 to 71 percent succeeded on avanafil versus 27 percent on placebo. Of 80 attempts more than six hours after dosing, 59 to 83 percent succeeded versus 25 percent.

Stopwatch trial (Hellstrom, Journal of Urology 2015): 440 men, 100 or 200mg or placebo, with success timed by stopwatch to 15 minutes after dosing. Within that limit 25.9 percent of attempts succeeded on 100mg and 29.1 percent on 200mg, versus 14.9 percent on placebo. The difference was statistically significant from 10 minutes (200mg) and 12 minutes (100mg). That is the evidence for the short lead time, even though absolute rates within such a tight window are naturally lower than across a whole evening.

Hard populations: in 390 men with diabetes (Goldstein, Mayo Clinic Proceedings 2012), 100 and 200mg improved all three co-primary endpoints significantly, with the same window from 15 minutes to beyond six hours. After bilateral nerve-sparing radical prostatectomy (Mulhall, Journal of Urology 2013), 71.5 percent of the 298 participants had severe dysfunction, yet both doses met all three endpoints. Of the attempts within 15 minutes, 36.4 percent succeeded versus 4.5 percent on placebo.

Long term (Belkoff, International Journal of Clinical Practice 2013): 712 men from two of the phase 3 trials continued avanafil open-label for 52 weeks, initially on 100mg with the option of 200 or 50mg. The SEP3 success rate rose from 13 to 68 percent and the IIEF erectile function score from 13.6 to 22.2. Fewer than 3 percent discontinued because of adverse events. What is missing: data on daily low-dose use and head-to-head trials against sildenafil or tadalafil. The short lead time is well established; the claim of better tolerability rests on selectivity data and indirect comparisons.

• Headache: the most common side effect and clearly dose-dependent: 5.1 percent on 50mg, 6.9 on 100mg, 10.5 on 200mg, versus 1.7 percent on placebo (pooled registration trials, prescribing information).
• Flushing: facial redness in 3 to 4 percent, in nobody on placebo.
• Nasal congestion and nasopharyngitis: 1 to 3 percent, with nasopharyngitis barely above placebo (2.9 percent). The stuffy nose is mechanism-driven as in the whole class.
• Back pain: 1 to 3 percent, without a clear dose relationship.
• Less common (1 to 2 percent): dyspepsia, nausea, constipation, rash, raised blood pressure, upper respiratory infections.
• Vision and hearing: across all avanafil trials only a single participant reported a change in colour vision, per the US prescribing information, but the class warnings still apply: a sudden loss of vision (NAION) or a sudden loss of hearing is a reason to stop at once and seek medical help.
• Priapism: rare, but any erection lasting more than four hours is an emergency.

The discontinuation rate for adverse events in the registration trials was 1.4 to 2.0 percent, on a par with placebo (1.7 percent). Over 52 weeks it was 2.8 percent.

The one rule that applies to the whole class and leaves even less room with avanafil because of its fast onset: never combine with nitrates. That includes nitroglycerin, isosorbide dinitrate and mononitrate as well as the alkyl nitrites sold as poppers. Both act on the same signalling chain. Together they can drop blood pressure to life-threatening levels. The prescribing information also lists guanylate cyclase stimulators such as riociguat (the US label adds vericiguat) as contraindications and requires at least 12 hours between the last avanafil dose and a nitrate in an emergency.

Blood pressure: alpha-blockers (tamsulosin, alfuzosin, doxazosin), other antihypertensives and more than three units of alcohol add to the blood pressure drop. The prescribing information advises against avanafil after a heart attack, stroke or revascularisation within the last six months, with resting blood pressure below 90/50 or above 170/100 mmHg, with unstable angina and with heart failure of NYHA class II or worse, simply because those groups were not in the trials. Sexual activity is physical exertion. Anyone with a cardiovascular history should clear this with a doctor first.

CYP3A4: strong inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir and other HIV protease inhibitors) raise exposure up to 13-fold and rule avanafil out. Moderate inhibitors (erythromycin, diltiazem, verapamil, fluconazole, aprepitant) cap the dose at 50mg in 24 hours. Grapefruit juice also inhibits CYP3A4. The EU SmPC advises avoiding it in the 24 hours before a dose.

Store dry, at room temperature and protected from light. Leave the tablets in the blister until you need them. Use a split 100mg tablet promptly rather than keeping the half around for weeks. Keep out of reach of children and mind the expiry date.