4PLAY sublingual

Our assessment

We reviewed this product before without a single milligram figure to work from, and said so. That gap is now closed: the dispensing pharmacy’s patient information sheet lists every strength, and the criticism we made no longer applies. What it is replaced by is more interesting.

Run the arithmetic against the approved ceilings. Sildenafil 40 mg against a 100 mg maximum is 40 per cent of it. Tadalafil 4 mg against 20 mg on demand is 20 per cent. Vardenafil 7.5 mg against 20 mg is 37.5 per cent. Add those fractions and the total PDE5 load comes to roughly 97.5 per cent of one full maximum dose.

That is not three drugs stacked. That is one maximum dose deliberately divided across three molecules with different onset and duration curves — fast sildenafil, slower and much longer tadalafil, potent vardenafil in between. Whoever formulated this was thinking about total exposure rather than piling on, and after the products we have taken apart on this site, that deserves saying plainly.

It also changes what our objection is. It is no longer the dosing. Every PDE5 component sits well inside its own envelope, and the combined load is about what a man would get from a single approved tablet at maximum strength.

That leaves apomorphine, and here we have to correct something we wrote about it — not only in this review, but in several others.

We had been treating apomorphine as an unexplained addition. It is not. Sublingual apomorphine was licensed in Europe specifically for erectile dysfunction, sold as Uprima and Ixense, at 2 to 3mg under the tongue — which is exactly the route and dose used here. It has published trial data: pooled results put erections firm enough for penetration at around 54 per cent of attempts against roughly 34 per cent on placebo. It left the market in the mid-2000s because it could not compete commercially with PDE5 inhibitors, not because of a safety finding.

It has never been approved in the United States for this indication — Abbott withdrew the application — and it is approved here for Parkinson’s disease instead. So an American prescriber is using it off-label, which is worth knowing. But “off-label, with a European licence at this dose and trial data behind it” is a very different sentence from the one we had been writing.

There is a further point in the formulation’s favour that we had missed. The criticism we make of combination products is that they stack drugs from the same class — three PDE5 inhibitors hitting one enzyme, tripling the side-effect profile to reach the same target. Apomorphine is not in that class at all. It works centrally, on dopamine pathways involved in arousal, rather than on penile blood flow. Pairing a central agent with a peripheral one is combining two mechanisms rather than doubling one, and that is the defensible kind of combination.

The fractional-sum arithmetic above is also a heuristic rather than a law. These three molecules differ in potency, half-life and selectivity, so adding percentages is a reasonable way to see that nobody has been reckless — not a demonstration that the combination behaves like a single 100 mg tablet. Nobody has run that trial.

The patient literature deserves specific credit, because it is markedly better than the marketing that sells the product. It lists nitrates and riociguat as absolute contraindications, names CYP3A4 inhibitors individually — the interaction class most online questionnaires never ask about — flags grapefruit, alpha blockers and alcohol, and states without hedging that compounded medicines are not FDA-reviewed for safety, effectiveness or quality.

It also catches something most sellers of apomorphine combinations do not: the 5-HT3 anti-nausea drugs. Ondansetron and its relatives with apomorphine can produce severe hypotension, and since nausea is apomorphine’s characteristic side effect, a man reaching for an anti-sickness tablet is a realistic scenario rather than a theoretical one. Flagging that pairing is the mark of someone who has thought about how the drug is actually used.

So the honest summary is this. The PDE5 dosing is deliberately conservative. The fourth ingredient has a European licence at this route and dose, trial data behind it, and a mechanism that complements the others rather than duplicating them. The dispensing literature is better than most of what we read. What is still missing is a trial of this specific combination — nobody has run one, and until somebody does, the case for four actives over one rests on reasoning rather than evidence.

That is a genuinely different position from most of the compounded products on this site, and it is worth being clear about the distinction. Our objection to the rest of this category is that it stacks doses or hides them. Neither applies here.