Tretinoin and Tadalafil Interaction: What Patients and Clinicians Need to Know

Does topical tretinoin interact with tadalafil?

Neither label lists the other drug. The Cialis label's drug interactions section covers nitrates, alpha-blockers, antihypertensives, alcohol, antacids, H2 antagonists, drugs that inhibit or induce CYP3A4, and a group of CYP substrates that includes warfarin, midazolam, lovastatin, theophylline and digoxin; tretinoin is not among them [1]. The Renova label, a 0.02% cream for fine facial wrinkles, covers other topical products that irritate skin and drugs known to be photosensitizers such as thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides; tadalafil is not among them [2].

A label that does not list a drug is not the same as a study that tested the pair. The sections below cover how much tretinoin reaches the blood and what tadalafil does react with.

How much tretinoin gets into the blood

The Renova label gives absorption figures for topical tretinoin. Across topical formulations, transdermal absorption ranged from 1% to 31% of the applied dose depending on whether the skin was healthy or inflamed [2]. No percutaneous absorption study was run with Renova 0.02% itself. For a 0.05% cream, radiolabeled and applied to healthy men, absorption was less than 2% of the dose after a single application (n=7) and after 28 days of daily application (n=7), and the extent of bioavailability was lower after repeated use [2]. The label also reports no significant difference in endogenous tretinoin concentrations between single and repeated daily applications [2].

Tretinoin activates three retinoic acid receptors (RAR alpha, RAR beta and RAR gamma), and the label states it has not been established whether the clinical effects come from that receptor activation, from irritation, or both [2].

What tadalafil actually reacts with

Tadalafil is a PDE5 inhibitor approved as Cialis for erectile dysfunction, for benign prostatic hyperplasia, and for the two together, and as Adcirca 20 mg tablets for pulmonary arterial hypertension at a 40 mg daily dose [1][4]. The Cialis label's interaction profile includes:

• Organic nitrates in any form, regular or intermittent, are contraindicated [1]. In a life-threatening situation where a nitrate is medically necessary, the label says at least 48 hours should pass after the last Cialis dose and the nitrate should be given only under close medical supervision with hemodynamic monitoring [1]. That is an emergency rule, not permission to combine them. In a crossover study of 150 men given tadalafil 20 mg daily for 7 days and then sublingual nitroglycerin 0.4 mg, standing systolic pressure fell below 85 mm Hg in more tadalafil-treated men at 4, 8 and 24 hours, with no difference from placebo at 48, 72 and 96 hours [3].
• Guanylate cyclase stimulators such as riociguat are contraindicated, because PDE5 inhibitors may potentiate their blood pressure-lowering effect [1].
• Alpha-blockers are additive on blood pressure. With doxazosin 8 mg daily, tadalafil 20 mg produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg [1]. For erectile dysfunction the label says to be stable on the alpha-blocker first and start tadalafil at the lowest dose; for BPH it does not recommend the combination [1].
• CYP3A4 inhibitors raise tadalafil exposure. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22% [1]. With these drugs the Cialis limits are no more than 10 mg every 72 hours as needed, and no more than 2.5 mg once daily [1].
• CYP3A4 inducers lower tadalafil exposure. Rifampin 600 mg daily cut tadalafil 10 mg exposure by 88% and peak concentration by 46%; the label calls for no dose adjustment but notes that once-daily efficacy may fall by an unknown amount [1].
• Alcohol at 5 units or more can add to tadalafil's vasodilation and produce orthostatic symptoms such as dizziness, a higher heart rate and lower standing blood pressure [1].

The Adcirca label has the same three contraindications and adds that potent CYP3A inhibitors such as ketoconazole and itraconazole should be avoided [4]. Tretinoin appears in none of these categories.

What each label says to watch for

The Renova label calls tretinoin cream a dermal irritant. In double-blind, vehicle-controlled studies of 339 patients, almost all reported one or more local reactions such as peeling, dry skin, burning, stinging, redness and itching; in 32% irritation was severe, led to temporary discontinuation or led to a mild topical corticosteroid, and about 4% discontinued because of adverse reactions [2]. The label also warns about sun sensitivity, says sun and sunlamp exposure should be avoided or minimized, advises a sunscreen of at least SPF 15 with protective clothing, and says the product should not be given to patients taking drugs known to be photosensitizers [2].

The Cialis label says to stop the drug and seek medical attention for a sudden loss of vision in one or both eyes, which may be non-arteritic anterior ischemic optic neuropathy, and for a sudden decrease or loss of hearing, and to seek emergency care for an erection lasting more than 4 hours [1].