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

What the interaction actually is

Tadalafil is a PDE5 inhibitor approved for erectile dysfunction (ED), the signs and symptoms of benign prostatic hyperplasia (BPH), and both together [2]. Cialis tablets come in 5, 10 and 20 mg strengths, and the 2.5 mg Cialis tablet is listed as discontinued [7]. Generic tadalafil 2.5, 5, 10 and 20 mg tablets follow the Cialis indications [7][8]. Dosing and contraindications below are from the Cialis label. Some 20 mg tadalafil tablets, such as Alyq, are labeled for pulmonary arterial hypertension instead and follow the Adcirca label [10][8].

Diphenhydramine is a first-generation antihistamine sold as Benadryl and as store brands and generics for temporary relief of allergy and common-cold symptoms [5][3][9].

Diphenhydramine is not one of the drugs the tadalafil label rules out. The Cialis label's contraindications are any organic nitrate, guanylate cyclase stimulators such as riociguat, and a history of serious hypersensitivity to tadalafil [2]. What the two drugs share is a set of effects that can land at the same time: sedation and dizziness from diphenhydramine, mild blood-pressure lowering from tadalafil, and anticholinergic action on the bladder from diphenhydramine [3][4][2].

Do they change each other's blood levels?

Diphenhydramine's documented enzyme interaction is with CYP2D6, which is not the main route that clears tadalafil. In vitro, diphenhydramine is a potent competitive CYP2D6 inhibitor with an inhibitory constant of 2 micromol/L. In a randomized study of 16 healthy men, steady-state diphenhydramine roughly halved metoprolol's oral and nonrenal clearance in CYP2D6 extensive metabolizers and cut its alpha-hydroxylation clearance 2.5-fold, with stronger and longer-lasting heart-rate and blood-pressure effects from metoprolol [1].

Tadalafil is metabolized mainly by CYP3A4, and potent CYP3A4 inhibitors raise its exposure sharply: ketoconazole 400 mg daily increased tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22% [2]. The Cialis label caps as-needed dosing at 10 mg every 72 hours and once-daily dosing at 2.5 mg when a potent CYP3A4 inhibitor is used [2].

In the other direction, the Cialis label states that tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 [2]. Diphenhydramine blocks CYP2D6 while tadalafil depends mainly on CYP3A4. That difference makes the metoprolol finding hard to apply directly to tadalafil, but it does not prove the two drugs cannot interact [1][2].

Drowsiness, dizziness and driving

The diphenhydramine injection label lists sedation, sleepiness, dizziness and disturbed coordination among its most frequent reactions [4]. The over-the-counter Benadryl Drug Facts label warns that marked drowsiness may occur, says to avoid alcoholic drinks and to be careful when driving a motor vehicle or operating machinery, and notes that alcohol, sedatives and tranquilizers may increase drowsiness [3].

In a randomized, double-blind, four-way crossover study of 40 licensed drivers aged 25 to 44 with seasonal allergic rhinitis, a single 50 mg dose of diphenhydramine produced the poorest driving performance of the four treatments, which included alcohol at about 0.1% blood alcohol. Self-reported drowsiness did not predict the impairment [11]. In the same study, fexofenadine 60 mg performed like placebo on the driving measures [11].

For tadalafil, healthy volunteers given 20 mg had a mean maximal fall in supine blood pressure of 1.6/0.8 mm Hg compared with placebo [2]. In three 12-week trials of once-daily tadalafil 5 mg for BPH or for ED with BPH, dizziness was reported by 1.0% of men on tadalafil versus 0.5% on placebo [2]. The Cialis label says alpha-blockers, antihypertensives and substantial alcohol (5 units or more) can add to its blood-pressure-lowering effect; with heavy alcohol it describes a faster heart rate, lower standing blood pressure, dizziness and headache [2].

The FDA also 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].

Men taking tadalafil for BPH

Tadalafil 5 mg once daily is FDA-approved for the signs and symptoms of BPH and for ED with BPH [2]. The urinary concern comes from diphenhydramine, not from a studied tadalafil interaction. The diphenhydramine injection label lists difficulty urinating and urinary retention among possible reactions and says to use it with considerable caution in symptomatic prostatic hypertrophy and bladder-neck obstruction [4]. The over-the-counter Benadryl label says to ask a doctor before use with trouble urinating due to an enlarged prostate gland, and also lists glaucoma and breathing problems such as emphysema or chronic bronchitis [3].

Adults 65 and older

The 2023 AGS Beers Criteria list first-generation antihistamines, including oral diphenhydramine, as potentially inappropriate for adults 65 and older: avoid, based on moderate-quality evidence with a strong recommendation. The stated reasons are high anticholinergic burden, falling clearance with age and tolerance when the drugs are used as hypnotics, with risks of confusion, dry mouth, constipation and other anticholinergic effects [5][6]. The criteria also advise avoiding anticholinergics in people with dementia or cognitive impairment, in delirium or at high risk of delirium, and in those with a history of falls or fractures [5][6].

The diphenhydramine injection label notes that patients about 60 and older are more likely to have dizziness, sedation and hypotension [4]. Tadalafil exposure (AUC) is about 25% higher in healthy men aged 65 or older than in younger men [2].

Dose and product facts

Per the Cialis label: as-needed use for ED starts at 10 mg before sexual activity and can be raised to 20 mg or lowered to 5 mg, never more than once a day; once-daily use for ED starts at 2.5 mg and may go to 5 mg; BPH and ED with BPH use 5 mg once daily at about the same time each day [2]. For product information, see tadalafil.