Tretinoin Side Effects: Which Ones Could Be Permanent?

Which tretinoin side effects could be permanent?

The Retin-A cream and gel label states that, to date, all adverse effects of Retin-A have been reversible upon discontinuance of therapy [7].

The Renova 0.02% cream label describes local irritation. In the double-blind, vehicle-controlled studies behind that label, which involved 339 patients who applied the cream to the face, almost all reported one or more local reactions such as peeling, dry skin, burning, stinging, erythema and pruritus [1]. In 32% of all study patients, skin irritation was severe, led to temporary discontinuation, or required a mild topical corticosteroid; about 7% of Renova users versus less than 1% of control patients needed short-term use of a mild topical corticosteroid, and about 4% had to discontinue because of adverse reactions [1]. The warnings section describes severe local erythema, pruritus, burning, stinging and peeling at the application site, and states 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 altogether [1].

The tissue finding the Renova label reports

The Renova label calls the 0.02% cream a dermal irritant and states that the results of continued irritation of the skin for greater than 52 weeks in chronic use are not known. It reports 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, and states that the significance of these findings and their relevance for the 0.02% cream are unknown [1]. The findings come from a different strength than the 0.02% product that label covers.

Dark patches and light patches

The Retin-A label states that temporary hyper- or hypopigmentation has been reported with repeated application of Retin-A [7]. The Renova label reports that approximately 2% of spontaneous postmarketing adverse event reporting for Renova 0.05% were for skin hypo- or hyperpigmentation [1]. That figure is a share of reports received, not a share of users affected. The FDA's dashboard for its adverse event database states that a report does not establish that the drug caused the event, that reports have not been medically verified, and that the information cannot be used to estimate how often an event occurs [2].

In a 24-week trial that randomized 251 people with mild to moderate facial photodamage to tretinoin emollient cream 0.05%, 0.01% or vehicle, histology showed increased epidermal thickness, decreased melanin content and stratum corneum compaction [3].

Does tretinoin thin the skin?

The 24-week trial above reported increased epidermal thickness on histology, not a thinner epidermis, along with stratum corneum compaction, and erythema, peeling and stinging were usually mild and well tolerated [3]. The trial ran 24 weeks, so it does not describe skin after years of use [3].

Sun exposure and the photosensitivity warning

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

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

Pregnancy

The Renova dosage section says not to use the cream if the patient is pregnant, attempting to become pregnant or at high risk of pregnancy [1]. The pregnancy section states that oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters and subhuman primates, that topical tretinoin in animal teratogenicity 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 formulation of topical tretinoin (Retin-A), five of them describing holoprosencephaly, with no definite pattern of teratogenicity and no causal association established. It adds that there are no adequate and well-controlled studies in pregnant women [1].

A 1993 review put the maximal systemic availability reported for transdermal all-trans retinoic acid at 5% to 7% in humans, expected the dose absorbed from daily cosmetic or therapeutic application to be below 0.015 mg/kg, at least 30-fold lower than the lowest teratogenic dose of isotretinoin in humans, and noted that large controlled studies of developmental toxicity in humans are not available [5].