Cialis and Diphenhydramine Interaction: What You Need to Know

Do tadalafil and diphenhydramine affect each other's blood levels?

Tadalafil is broken down mainly by CYP3A4. Ketoconazole 400 mg daily raised exposure (AUC) to a single 20 mg tadalafil dose by 312%, and rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% [2]. Diphenhydramine's documented enzyme effect is on a different enzyme: it is a potent competitive inhibitor of CYP2D6, and in a randomized study of 16 healthy men it roughly halved metoprolol's oral clearance in extensive metabolizers, with no change in poor metabolizers [4]. Diphenhydramine is not named among the CYP3A4 inhibitors discussed in the Cialis label [2].

In the other direction, the Cialis label says tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1, and is not expected to cause clinically significant changes in the clearance of drugs handled by those enzymes [2]. Whether tadalafil changes diphenhydramine blood levels has not been established.

What the labeled effects are

Drowsiness from diphenhydramine. The Benadryl Drug Facts warn that marked drowsiness may occur, that alcohol, sedatives and tranquilizers may increase drowsiness, and advise care when driving or operating machinery [1]. In a randomized four-way crossover in the Iowa Driving Simulator, 40 licensed drivers with seasonal allergic rhinitis took a single dose of diphenhydramine 50 mg, fexofenadine 60 mg, alcohol at about 0.1% blood alcohol, or placebo. Diphenhydramine produced poorer coherence (the ability to match the speed of a vehicle ahead) than alcohol; lane keeping was impaired after both diphenhydramine and alcohol; and response time to a blocking vehicle was slowest after alcohol. Fexofenadine performed like placebo, and self-reported drowsiness did not predict impairment [3].

Dizziness and blood pressure from tadalafil. In healthy volunteers, tadalafil 20 mg lowered mean maximal supine blood pressure by 1.6/0.8 mm Hg compared with placebo [2]. In the 12-week once-daily trials for BPH and for ED with BPH, dizziness was reported by 1.0% of men on tadalafil 5 mg versus 0.5% on placebo [2]. The Cialis label warns that alpha-blockers, antihypertensives or substantial alcohol (5 units or more) may lead to hypotension [2].

The prescription diphenhydramine injection label lists dizziness and hypotension among reported reactions and notes that patients about 60 and older are more likely to have dizziness, sedation and hypotension [7].

Men taking tadalafil for BPH

Cialis (tadalafil) 5 mg once daily is FDA-approved for the signs and symptoms of BPH and for ED with BPH [2]. In a 12-week trial of men aged 45 and older with lower urinary tract symptoms from BPH, tadalafil 5 mg once daily (161 men) lowered the IPSS by 5.6 points versus 3.6 with placebo (164 men; P=0.004), an effect apparent at week 1 and significant by week 4; it did not significantly improve peak urine flow or post-void residual volume [8].

The Benadryl label's warnings name trouble urinating due to an enlarged prostate [1]. The prescription diphenhydramine injection label lists difficulty urinating and urinary retention among adverse reactions and advises considerable caution in symptomatic prostatic hypertrophy and bladder-neck obstruction [7]. Diphenhydramine is an H1 antihistamine with anticholinergic (drying) and sedative effects, and it reaches the central nervous system, which is why it causes drowsiness [7][4].

Older adults

The 2023 AGS Beers Criteria recommend avoiding first-generation antihistamines, including oral diphenhydramine, in adults 65 and older (moderate quality of evidence, strong recommendation). The panel cites high anticholinergic burden, falling clearance with age, tolerance when the drugs are used as a hypnotic, and risks of confusion, dry mouth, constipation and other anticholinergic effects [5][6]. The same criteria advise avoiding anticholinergics in dementia, in delirium or high risk of delirium, and in people with a history of falls or fractures [5].

Age also changes tadalafil handling: exposure is about 25% higher in healthy men aged 65 or older [2].

What the labels say to watch for

Benadryl (diphenhydramine HCl 25 mg tablets). The tablet label lists 25 to 50 mg (1 to 2 tablets) every 4 to 6 hours for adults and children 12 and older, with no more than 6 doses in 24 hours [1]. Its warnings also name glaucoma and breathing problems such as emphysema or chronic bronchitis, and warn against use to make a child sleepy or with any other product containing diphenhydramine, even one used on the skin [1].

Overdose. An FDA safety communication in September 2020 warned that taking more than the recommended dose of OTC diphenhydramine can cause serious heart problems, seizures, coma or death, and said the drug is safe and effective when used as directed [9].

Cialis. The label contraindicates any form of organic nitrate with tadalafil, and says combining it with other PDE5 inhibitors or other ED treatments has not been studied [2]. For BPH, the label does not recommend combining tadalafil with an alpha-blocker. For ED, it advises caution in men taking alpha-blockers, and says to be stable on the alpha-blocker first and start Cialis at the lowest dose [2].