Tretinoin Side Effects: Delayed-Onset Adverse Events You Need to Know

Renova (tretinoin cream 0.02%) is labeled as an adjunct for fine facial wrinkles. Retin-A, Retin-A Micro and other tretinoin products carry their own labels with their own trial data, so this page names the product behind each figure.

Do tretinoin side effects arrive early or late?

The Renova adverse-reaction section covers 339 patients who applied the 0.02% cream to the face in double-blind, vehicle-controlled studies. Almost all reported one or more local reactions: peeling, dry skin, burning, stinging, erythema and pruritus. 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% of patients using the cream, compared with less than 1% of controls, had irritation severe enough to warrant short-term use of a mild topical corticosteroid, and about 4% discontinued because of adverse reactions [1]. The Renova label does not break these reactions down by week.

Other sources give the timing. A review of topical retinoids in acne says erythema, dryness, itching and stinging occur frequently during the early treatment phase, with impact varying by vehicle, skin type, frequency and mode of application, moisturizer use, and environmental factors such as sun exposure or temperature [2]. In the Retin-A Micro label, irritation scores in the 12-week vehicle-controlled trials of the 0.1% gel peaked during the initial two weeks of therapy and decreased thereafter [5].

What does the label say about pigment change?

The Renova label states that approximately 2% of spontaneous postmarketing adverse event reporting for Renova 0.05% were for skin hypo- or hyperpigmentation, and that other spontaneously reported events for that strength appear to be local reactions similar to those seen in trials [1]. The label does not give a time of onset for these reports.

The 2% figure is a share of reports, not a share of users. Spontaneous reports cannot be used to estimate how often an event occurs: they are often duplicated or incomplete, and a report does not establish that the drug caused the event [3].

Sun sensitivity

The Renova label warns that exposure to sunlight, including sunlamps, should be avoided or minimized during use because of heightened sunburn susceptibility, and that patients should be warned to use sunscreens with a minimum SPF of 15 and protective clothing. It says patients with sunburn should be advised not to use the cream until fully recovered, and that patients with considerable sun exposure, for example from their occupation, and those with inherent sensitivity to sunlight should exercise caution [1].

The Renova label also says the cream should not be administered to patients also taking drugs known to be photosensitizers (thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of possible augmented phototoxicity [1]. The Renova label does not state how long heightened sensitivity lasts after the last application.

What long-term use shows

The Renova label states that neither the safety nor the efficacy of daily use for more than 52 weeks has been established, and that daily use beyond 52 weeks has not been systematically and histologically investigated in adequate, well-controlled trials. Its warnings section says there is evidence of atypical changes in melanocytes and keratinocytes and of increased dermal elastosis in some patients treated with Renova 0.05% for longer than 48 weeks, that the significance of these findings and their relevance to the 0.02% cream are unknown, and that the results of continued irritation of the skin beyond 52 weeks are not known [1].

A separate product gave a different histology result. A two-year, randomized, placebo-controlled trial of tretinoin emollient cream 0.05% in 204 subjects with moderate to severe facial photodamage found no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on the stratum corneum compared with placebo [4]. That is a different formulation studied for a different indication.

What the Renova label says about irritation that persists

The Renova label states that topical use may cause severe local erythema, pruritus, burning, stinging and peeling at the application site, and that if the degree of local irritation warrants, patients should be directed to use less medication, decrease the frequency of application, discontinue use temporarily, or discontinue use altogether and consider additional appropriate therapy [1]. It also states that applying larger amounts than recommended has not been shown to lead to more rapid or better results, and that marked redness, peeling or discomfort may occur [1]. The label describes tretinoin as reported to cause severe irritation on eczematous skin, to be used only with caution there [1].