Tretinoin Cream Side Effects: Rare but Serious Risks

What are the rare but serious risks of tretinoin cream?

In the Renova trials, adverse reactions were limited primarily to the skin: peeling, dry skin, burning, stinging, redness and itching, with pigmentation change in about 2% of spontaneous postmarketing reports for the 0.05% cream [1]. The Renova label warns about severe local irritation and increased susceptibility to sunburn. It also lists ingredient hypersensitivity as a contraindication and says the cream should not be used during pregnancy [1].

Does tretinoin cream carry a boxed warning?

No. Renova 0.02% cream has no boxed warning [1]. Oral isotretinoin is a different drug product, a capsule that has a boxed warning and a REMS program; topical tretinoin is not the same drug.

How severe can the skin reaction get?

The Renova label's trials enrolled 339 patients who applied the 0.02% cream to the face. In 32% of all study patients, skin irritation was severe, led to temporary discontinuation, or led to use of a mild topical corticosteroid; about 7% needed short-term topical corticosteroids, against less than 1% of vehicle-treated patients; about 4% discontinued because of adverse reactions [1].

The label also describes the cream as a dermal irritant and states that the results of continued irritation of the skin for longer than 52 weeks of chronic use are not known [1].

The Renova label describes severe local erythema, pruritus, burning, stinging and peeling at the application site [1]. Tretinoin has also been reported to cause severe irritation on eczematous skin [1], and the Renova label says not to use the cream on sunburned skin or on skin with eczema or other chronic facial conditions [1].

The Renova label says concomitant topical medicines, medicated or abrasive soaps, strong drying products, high-alcohol products, astringents, spices or lime, permanent wave solutions, electrolysis, depilatories and waxes may increase irritation [1].

Photosensitivity: sun exposure as a labeled risk

The Renova label warns of increased susceptibility to sunburn and says exposure to sunlight, including sunlamps, should be avoided or minimized during use, with sunscreen of at least SPF 15 and protective clothing; it says patients with sunburn should not use the cream until fully recovered, and that patients with considerable occupational sun exposure or inherent sun sensitivity should exercise caution [1].

The Renova label also says the cream should not be administered to patients taking known photosensitizers, such as thiazides, tetracyclines, fluoroquinolones, phenothiazines or sulfonamides, because of possible augmented phototoxicity [1].

Allergic reaction

The Renova label's only contraindication is a history of sensitivity reactions to any of its components, and the label says to discontinue if hypersensitivity to any ingredient is noted [1].

Pregnancy: what the Renova label says

The Renova label's dosing instructions say not to use the 0.02% cream in a patient who is pregnant, attempting to become pregnant or at high risk of pregnancy [1]. Its teratogenicity section notes that oral tretinoin is teratogenic in several animal species, that topical tretinoin in animal tests has given equivocal results, and that 30 human cases of temporally associated congenital malformations were reported during two decades of clinical use of another topical tretinoin formulation (Retin-A), including five cases of holoprosencephaly, with no definite pattern of teratogenicity and no causal association established [1].

The same section notes that with widespread use of any drug a small number of birth defect reports would be expected by chance alone, and that the significance of these spontaneous reports for fetal risk is not known [1]. The label also reports that dermal tretinoin was fetotoxic in rabbits at 0.5 mg/kg/day, 42 times the maximum human systemic dose normalized for total body surface area [1].

Systemic absorption

The Renova label states that no percutaneous absorption study was conducted with Renova 0.02% in human volunteers, and that transdermal absorption of tretinoin from various topical formulations ranged from 1% to 31% of the applied dose, depending on whether it was applied to healthy skin or dermatitic skin [1]. In a study of a radiolabeled 0.05% oil-in-water emulsion in healthy men, absorption was less than 2% after a single application (n=7) and after repeated daily applications for 28 days (n=7), bioavailability was less after repeated application, and no significant difference in endogenous tretinoin concentrations was observed between single and repeated daily applications [1].

How to read reports of rare events

FDA's adverse event database is a reporting system. A report does not establish that the drug caused the event, reports are not medically verified, duplicates exist, and the data cannot be used to estimate how often an event occurs [3].