Vardenafil with dapoxetine: the combination nobody randomised

A tablet containing both a PDE5 inhibitor and a short-acting SSRI is one of the most widely sold dosage forms in this category, and it rests on a surprisingly thin research file. Both halves are well studied on their own: the 2015 Sheffield health technology assessment for premature ejaculation screened 103 studies, 102 of them randomised controlled trials, and found significant improvements in intravaginal ejaculatory latency time (IELT) versus placebo for dapoxetine at 30 mg and 60 mg, for the PDE5 inhibitors vardenafil and tadalafil, and for several SSRIs. What that review could not do is tell you what happens when the two are in the same tablet, because no trial in its pool tested that combination against placebo. The product discussed here is Super Vilitra, the vardenafil and dapoxetine combination, sitting in this catalogue between standalone vardenafil and standalone dapoxetine.

What the systematic reviews actually pooled

The Sheffield assessment’s list of interventions that beat placebo on IELT is worth reading as a list of single agents: topical anaesthetics, SSRIs including citalopram, escitalopram, fluoxetine, paroxetine, sertraline and dapoxetine at 30 mg and 60 mg, duloxetine, inhaled clomipramine 4 mg, vardenafil, tadalafil, and tramadol. It also records that improvements in sexual satisfaction and other outcomes were evident for SSRIs, PDE5 inhibitors and tramadol, and that treatment-related adverse events were evident with most pharmacological interventions.

The 2018 network meta-analysis by Sridharan and colleagues pooled 44 studies and ranked the drugs by their likelihood of being the best available option. Dapoxetine 30 mg had the highest likelihood in the interventional pool, which is why it is used as a first-line reference point in the discussion. Look closely at what the network contained, though: among the combinations that significantly increased IELT it lists dapoxetine 30 mg with mirodenafil, paroxetine with sildenafil, topical lidocaine with tadalafil, paroxetine with tadalafil, and combined fluoxetine with tadalafil. Vardenafil with dapoxetine is not in that list. The network can only rank what was randomised, and this pairing was not.

The one human study of the pair, and what it measured

There is a direct human study of vardenafil hydrochloride with dapoxetine hydrochloride, and it is a pharmaceutics paper rather than an efficacy trial. El-Refai and colleagues in Drug Development and Industrial Pharmacy developed vardenafil orodispersible tablets by freeze-drying, added dapoxetine to the best three formulations, and evaluated them for weight variation, friability, drug content, disintegration time, wetting time and dissolution. Gelatin as matrix former with N-methylpyrrolidone as solubiliser released 100 % of both drugs within 15 minutes.

The in vivo part is the part usually quoted, and it needs its denominators. The study enrolled six healthy male volunteers. From the combination orodispersible tablet it reports a vardenafil Tmax of 0.583 ± 0.129 h and a dapoxetine Tmax of 0.625 ± 0.137 h, AUC0-12 of 39.234 ± 10.932 ng·h/ml for vardenafil and 531.681 ± 129.544 ng·h/ml for dapoxetine, and relative bioavailability of 100.9 % and 85 % compared with Levitra and Priligy.

So: six people, a pharmacokinetic comparison against the reference products, and a formulation that dissolves faster than a conventional tablet. No IELT, no partner-reported outcome, no comparison against placebo, no control arm on either monotherapy. That is what a randomised trial of this combination would need, and what does not exist in the indexed literature.

What the guidelines say, and at what evidence level

The 2013 ISSM standards of care for erectile dysfunction, from a committee that includes the authors of the major PDE5 trials, sets out how it grades evidence. It assigns level 1 evidence to PDE5 inhibitor monotherapy and to injectable or intraurethral prostaglandin E1; level 2 to oral L-arginine and topical PGE1 in selected populations; level 3 to oral yohimbine; level 3 to combinations of PDE5 inhibitors with injection therapy, which “generate better efficacy rates than either monotherapy alone”.

The PDE5 inhibitor plus dapoxetine combination appears in that document at level 5, described as expert opinion: there is level 5 evidence showing that adding either PDE5 inhibitors or intraurethral PGE1 may improve outcomes in specific surgical settings, and that the combination of a PDE5 inhibitor with dapoxetine “is effective and safe in patients suffering from both ED and premature ejaculation”. The document’s own level 5 is expert opinion — the weakest grade on its scale, and the level assigned when the evidence is clinical experience rather than trials.

That is not a criticism of the combination. It is a description of its file.

The other half of the indexed literature is analytical

Search this pairing by name and most of what comes back is not clinical at all. The 2021 RSC Advances paper by Abdelshakour and colleagues developed HPLC-UV and UPLC-MS/MS methods for the simultaneous determination of sildenafil, vardenafil and tadalafil together with the compounds commonly found in counterfeit “aphrodisiac” products — dapoxetine, paroxetine, citalopram, tramadol and yohimbine — and applied the method to 50 commercial products, including honey sachets and instant coffee marketed as aphrodisiacs and suspected of containing PDE5 inhibitors.

Why that paper matters here: the products it had to build a screen for are the same two molecules, sold together in unregistered combinations. The methods paper tells you how reliably you can detect what is in one; it tells you nothing about what such a combination does to a latency time.

The 2015 thermal-analysis paper by Attia and colleagues belongs to the same genre: it characterises dapoxetine and vardenafil hydrochlorides by thermogravimetry and differential scanning calorimetry and reports purity values of 99.97 % and 99.95 %. Quality-control chemistry, useful for manufacturing, silent on clinical effect.

What the data do not show

• No placebo-controlled trial of vardenafil plus dapoxetine reports an IELT. Not in the 2015 assessment of 103 studies, not in the 2018 network meta-analysis of 44.
• No trial shows the combination beats either monotherapy. The dose-finding logic people quote is transferred from the sildenafil and tadalafil combination studies, not measured for this pair.
• The six-volunteer study is pharmacokinetics. Tmax, AUC and relative bioavailability describe how fast and how much reaches circulation. They are not efficacy endpoints and should never be read as one.
• The guideline support is level 5, i.e. expert opinion, and it says “effective and safe” without a trial attached to either word for this pairing.
• Nothing here is advice. These are research materials sold as such; the milligrammes in these papers are the regimens those studies ran, not a recommendation for any person.