Egrifta (Tesamorelin) and Diphenhydramine Interaction: What You Need to Know

What the Egrifta labels say about other drugs

Egrifta SV is tesamorelin 1.4 mg injected subcutaneously into the abdomen once daily; Egrifta WR is 1.28 mg once daily, and the labels state the two formulations are not substitutable [1][2]. Tesamorelin is approved only for reducing excess abdominal fat in HIV-infected adults with lipodystrophy [1].

Both labels have a Drug Interactions section with two subsections [1][2].

The first subsection covers glucocorticoid replacement. Growth hormone inhibits 11-beta-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, so people taking glucocorticoid replacement for hypoadrenalism may need higher maintenance or stress doses after starting tesamorelin. Cortisone acetate and prednisone may be affected more than other steroids [1].

The second covers drugs cleared by CYP450 liver enzymes. Published data suggest growth hormone can change CYP450-mediated clearance, with corticosteroids, sex steroids, anticonvulsants and cyclosporine named as examples, and the label says to monitor for interactions with such drugs [1]. In healthy subjects, tesamorelin changed simvastatin exposure by about -8% (AUC; simvastatin acid -15%) and ritonavir exposure by about -9%, which the label calls no significant impact [1].

Is diphenhydramine's CYP2D6 inhibition relevant here?

Diphenhydramine is an H1 antihistamine with anticholinergic and sedative effects, and it also inhibits the enzyme CYP2D6 [3][4]. The clearest human demonstration is a randomized study of 16 healthy men given metoprolol 100 mg with steady-state diphenhydramine or placebo. Diphenhydramine cut metoprolol oral and nonrenal clearance about twofold and its alpha-hydroxylation clearance 2.5-fold in CYP2D6 extensive metabolizers, but not in poor metabolizers, and metoprolol's heart-rate and blood-pressure effects were stronger and longer-lasting [4]. In this study, diphenhydramine changed how the body cleared metoprolol. It does not show what happens when diphenhydramine is taken with tesamorelin [4].

That result concerns a drug cleared through CYP2D6. Tesamorelin is a 44-amino-acid peptide with no formal human metabolism studies. After a 1.4 mg Egrifta SV dose, the mean elimination half-life is about 8 minutes, and absolute bioavailability was under 4% after a 2 mg dose of the original Egrifta formulation [1]. The label's CYP450 subsection describes growth hormone changing how the body clears other drugs, not tesamorelin being cleared by CYP enzymes [1].

The antihistamine's own label warnings

Benadryl Allergy tablets contain diphenhydramine. For adults and children 12 and older, the label allows 1 to 2 tablets every 4 to 6 hours, no more than 6 times in 24 hours [5]. The Drug Facts label says marked drowsiness may occur, to avoid alcoholic drinks because alcohol, sedatives and tranquilizers may increase drowsiness, and to be careful when driving or operating machinery [5].

In a randomized four-way crossover study of 40 licensed drivers with seasonal allergic rhinitis in the Iowa Driving Simulator, a single 50 mg dose of diphenhydramine produced the poorest driving performance of the four treatments. Lane keeping was impaired after both alcohol (about 0.1% blood alcohol) and diphenhydramine, while fexofenadine 60 mg performed like placebo. Self-reported drowsiness did not predict impairment [6]. FDA warned in 2020 that doses above the label can cause serious heart problems, seizures, coma or death [7].

Older adults on tesamorelin

The 2023 AGS Beers Criteria advise avoiding first-generation antihistamines, oral diphenhydramine among them, in adults 65 and older (moderate-quality evidence, strong recommendation). The criteria cite their strong anticholinergic effects, with risks of confusion, dry mouth and constipation, and note that cumulative anticholinergic exposure is associated with falls, delirium and dementia [8][9]. The Egrifta SV and Egrifta WR labels state there is no information on use in patients older than 65 [1][2]. These are two separate facts; neither label addresses the other drug.

What the Egrifta labels monitor

The labeled safety program for tesamorelin concerns growth hormone effects, not antihistamines. Among patients treated for 26 weeks, 47% had IGF-1 above 2 standard deviation scores and 36% above 3, and the label says to monitor IGF-1 [1]. HbA1c of 6.5% or higher developed in 5% of tesamorelin patients versus 1% on placebo by week 26, a hazard ratio of 3.3 (95% CI 1.4 to 9.6), and the label says to evaluate glucose before and during treatment [1]. Fluid retention, hypersensitivity reactions (4% in trials) and injection-site reactions (25% versus 14% on placebo over the first 26 weeks) are also labeled warnings [1].