Sildenafil (Generic) and Diphenhydramine Interaction: What You Need to Know

What happens when you take them together?

Sildenafil is a PDE5 inhibitor indicated for erectile dysfunction [1]. Diphenhydramine is an H1 antihistamine with anticholinergic (drying) and sedative effects; it is widely distributed including the central nervous system, and it causes drowsiness and cognitive effects [6].

Sildenafil can lower blood pressure [1], while diphenhydramine can cause marked drowsiness [2]. We found no study that tested the two together.

The Viagra tablet label does not list diphenhydramine among its contraindications or in its drug interaction section, which covers nitrates, alpha-blockers, amlodipine, ritonavir and other CYP3A4 inhibitors, and alcohol [1]. The Benadryl tablet label lists sedatives and tranquilizers as a reason to ask a doctor or pharmacist before use, and says alcohol, sedatives and tranquilizers may increase drowsiness [2].

Does diphenhydramine change sildenafil levels?

Sildenafil is cleared mainly by CYP3A4 and to a lesser extent by CYP2C9 [1]. Diphenhydramine is a potent competitive inhibitor of CYP2D6 in vitro, with an inhibitory constant of 2 micromol/L, and in a randomized study of 16 healthy men it cut metoprolol oral and nonrenal clearance about twofold in extensive metabolizers, with stronger and longer-lasting heart-rate and blood-pressure effects from metoprolol [7]. That study used metoprolol, a CYP2D6 substrate, and did not test sildenafil [7].

Can the combination lower blood pressure too much?

The Viagra tablet label reports that sildenafil 100 mg lowered supine blood pressure in healthy volunteers by a mean maximum of about 8.4/5.5 mm Hg, and the effect was not dose-related between 25 and 100 mg [1]. In hypertensive patients, the Viagra tablet label reports that sildenafil 100 mg added to amlodipine 5 or 10 mg gave an additional mean supine fall of 8 mmHg systolic and 7 mmHg diastolic [1]. With alpha-blockers the Viagra tablet label advises caution and says patients should be stable on the alpha-blocker before sildenafil is started, at a 25 mg dose [1].

In the Viagra fixed-dose erectile dysfunction trials, dizziness was reported by 3% to 4% of men on sildenafil versus 2% on placebo [1]. Syncope and postural hypotension appear among events reported in under 2% of patients in controlled trials, with a causal relationship listed as uncertain [1].

The Viagra tablet label contraindicates nitrates in any form and guanylate cyclase stimulators such as riociguat; sildenafil was shown to potentiate the hypotensive effect of nitrates, and PDE5 inhibitors may potentiate the hypotensive effects of GC stimulators [1].

Drowsiness, driving and anticholinergic effects

The Benadryl Allergy tablet label says marked drowsiness may occur, to be careful when driving a motor vehicle or operating machinery, and to avoid alcoholic drinks [2]. In a randomized, double-blind, four-way crossover study in the Iowa Driving Simulator, 40 licensed drivers aged 25 to 44 with seasonal allergic rhinitis took single doses of fexofenadine 60 mg, diphenhydramine 50 mg, alcohol to about 0.1% blood alcohol, or placebo. Diphenhydramine 50 mg produced the poorest overall driving performance of the four, lane keeping was impaired after both alcohol and diphenhydramine, fexofenadine performed like placebo, and self-reported drowsiness did not predict impairment [5].

The Benadryl tablet label also lists glaucoma, a breathing problem such as emphysema or chronic bronchitis, and trouble urinating due to an enlarged prostate as reasons to ask a doctor before use, and says not to use it with any other product containing diphenhydramine, even one used on skin [2].

Older adults

The 2023 AGS Beers Criteria list oral diphenhydramine among the first-generation antihistamines to avoid in adults 65 and older (moderate-quality evidence, strong recommendation). The criteria note that these drugs are highly anticholinergic, that clearance falls with age, that tolerance develops when one is used as a hypnotic, and that they carry risks of confusion, dry mouth, constipation and other anticholinergic effects [4]. The same criteria say to avoid anticholinergics in dementia or cognitive impairment, in delirium or high risk of delirium, and with a history of falls or fractures unless safer alternatives are unavailable [4]. They also state that more than one anticholinergic drug increases the risk of cognitive decline and advise minimizing the number used [3].

On the sildenafil side, the Viagra tablet label reports AUC about 84% higher in healthy men 65 and older and says to consider a starting dose of 25 mg [1].

Doses and timing

For erectile dysfunction, the Viagra tablet label lists 50 mg about 1 hour before sexual activity as its usual dose, effective from 30 minutes to 4 hours, maximum once per day; the dose may go up to 100 mg or down to 25 mg, and a 25 mg start is suggested for age over 65, hepatic impairment, severe renal impairment, strong CYP3A4 inhibitors, or when starting in a patient stable on an alpha-blocker [1]. The label reports peak sildenafil levels 30 to 120 minutes after a fasting dose, median 60 minutes [1].

The Benadryl tablet label lists 25 mg tablets, taken every 4 to 6 hours and no more than 6 times in 24 hours, with 1 to 2 tablets (25 to 50 mg) for adults and children 12 and over [2].

Sildenafil is prescription-only in the United States [1].

What to watch for

The Viagra tablet label says to seek emergency treatment if an erection lasts more than 4 hours, and says to stop the drug and get medical care for sudden loss of vision in one or both eyes (possible non-arteritic anterior ischemic optic neuropathy) or sudden decrease or loss of hearing [1]. The FDA warned in 2020 that taking more than the recommended dose of over-the-counter diphenhydramine can cause serious heart problems, seizures, coma or death [9].