Enclomiphene Citrate and Diphenhydramine Interaction: What Patients and Clinicians Need to Know

Does diphenhydramine interact with enclomiphene?

No published study has measured the combination, so there is no measured change in blood levels or effect to report. Compounded enclomiphene products are not FDA-approved and have not been reviewed by FDA for safety, effectiveness or quality [9].

The diphenhydramine side is easier to describe. It is an H1 antihistamine with anticholinergic (drying) and sedative effects, it distributes into the brain, and it inhibits the enzyme CYP2D6 [3][4]. Sedation and anticholinergic effects matter most for someone who is older or already taking other sedating drugs.

What enclomiphene does in the body

Enclomiphene is an oral selective estrogen receptor modulator (SERM). It blocks estrogen receptors in the pituitary, which normally suppress the pituitary-testis axis, so the pituitary releases more LH and FSH and the testes make more testosterone while sperm production is maintained [2][21]. It is absorbed quickly, with peak levels about 2 to 3 hours after a dose and a half-life of roughly 10 hours; the main metabolite is 4-hydroxy enclomiphene and excretion is mainly in feces [2].

It is not approved by FDA or by the European Medicines Agency; FDA issued a complete response letter to the sponsor in 2015, and EMA's committee recommended refusing authorisation for EnCyzix in January 2018 [2][6].

In the phase 3 program the most frequent side effects were headache, hot flushes, nausea and muscle spasm, and the reasons men stopped treatment included blurred vision, muscle spasm, headache and aggression [7]. Drowsiness is not among those reported most often.

What diphenhydramine does that matters here

The oral Benadryl label says marked drowsiness may occur, to be careful when driving a motor vehicle or operating machinery, and that alcohol, sedatives and tranquilizers may increase drowsiness [10].

In the Iowa Driving Simulator study, 40 licensed drivers with seasonal allergic rhinitis drove for an hour after a single dose of diphenhydramine 50 mg, fexofenadine 60 mg, alcohol at about 0.1% blood alcohol, or placebo. Diphenhydramine produced the poorest overall driving performance of the four treatments, and lane keeping was impaired after both alcohol and diphenhydramine. Self-reported drowsiness did not predict impairment [1].

In a study of 21 people given a single oral dose of diphenhydramine syrup, mean elimination half-life was 9.2 hours in young adults and 13.5 hours in adults with a mean age of 69 [5].

The CYP2D6 inhibition has been measured with another drug. In 16 healthy men, steady-state diphenhydramine cut metoprolol clearance about twofold and its alpha-hydroxylation clearance 2.5-fold in extensive CYP2D6 metabolizers, with stronger and longer-lasting heart-rate and blood-pressure effects from metoprolol [4]. Other CYP2D6 drugs were not tested.

FDA also warned in 2020 that taking more than the recommended dose of OTC diphenhydramine can cause serious heart problems, seizures, coma or death [11].

Who should be most careful

Adults 65 and older. The 2023 AGS Beers Criteria recommend avoiding first-generation antihistamines such as diphenhydramine in adults 65 and older because they are highly anticholinergic and carry risks including confusion, dry mouth and constipation (moderate-quality evidence, strong recommendation) [8]. The criteria also note that cumulative anticholinergic exposure is associated with falls, delirium and dementia [8]. In a prospective cohort of 3,434 adults 65 and older followed for a mean of 7.3 years, more than 1,095 cumulative standardized daily doses of strong anticholinergic drugs over 10 years was associated with an adjusted hazard ratio for dementia of 1.54 (95% CI 1.21-1.96) [12]. A separate nested case-control study of 58,769 people with dementia found rising odds with cumulative anticholinergic exposure, but antihistamines were not among the classes its abstract lists as significantly increased [13]. Both are observational.

Men with prostate enlargement or glaucoma. The oral Benadryl label says to ask a doctor before use with glaucoma or trouble urinating due to an enlarged prostate gland [10].

Anyone stacking sedatives. The oral label says to avoid alcoholic drinks and that alcohol, sedatives and tranquilizers may increase drowsiness [10]; the prescription injection label describes additive effects with alcohol and other CNS depressants [3]. Beers advises avoiding any combination of three or more CNS-active drugs in older adults because of falls and fracture risk [14].

What the label says about dosing

The Benadryl Allergy tablet label lists 25 to 50 mg (1 to 2 tablets) for adults and children 12 and older every 4 to 6 hours, with no more than 6 doses in 24 hours; other products and formulations can differ. The label also says not to use the product with any other product containing diphenhydramine, even one used on the skin [10].

If you need an antihistamine or a sleep aid

On driving measures, fexofenadine 60 mg performed like placebo in the simulator study, while diphenhydramine did not [1]. Beers advises avoiding and minimizing the number of anticholinergic drugs [14].

Tolerance to diphenhydramine's sedation develops fast. In a randomized crossover trial, 15 healthy men aged 18 to 50 took diphenhydramine 50 mg or placebo twice daily for 4 days; sleepiness and psychomotor performance were significantly worse on diphenhydramine on day 1 but indistinguishable from placebo by day 4 [15]. That trial measured sleepiness and performance, not the drying or urinary effects.