Tretinoin Side Effects: Incidence Rates Across Clinical Trials

What rates does the Renova label report?

The Renova 0.02% cream label reports adverse reactions from double-blind, vehicle-controlled studies involving 339 patients who applied the cream to their faces [1]. Almost all patients reported one or more local reactions: peeling, dry skin, burning, stinging, erythema, and pruritus [1].

In 32% of all study patients, skin irritation was reported that was severe, led to temporary discontinuation of Renova, or led to use of a mild topical corticosteroid [1]. About 7% of patients using Renova, compared with less than 1% of control patients, had sufficiently severe local irritation to warrant short-term use of mild topical corticosteroids [1]. About 4% of patients had to discontinue Renova because of adverse reactions [1].

What did the Retin-A Micro trials report?

The Retin-A Micro label lists skin irritation, burning, erythema, peeling, dryness, itching and dermatitis as the most common reactions [5]. In two 12-week vehicle-controlled trials of the 0.1% gel (172 treated vs 175 vehicle, mean age 19), irritation scores peaked in the first two weeks and then declined; no more than 3% of subjects treated with the 0.1% gel had scores indicating severe irritation, and 6% discontinued for cutaneous irritation (the label prints this as 14/224, although 172 subjects are listed for that arm) [5].

With the 0.04% gel (Studies 3 and 4: 225 treated vs 226 vehicle), about half of the treated subjects had irritation at week 2, fewer than 10% had moderate irritation, and none had severe irritation at that point; over the 12 weeks, 1% (2/225) had scores indicating severe irritation and 1.3% (3/225) discontinued for cutaneous irritation [5]. These figures describe the Retin-A Micro gels in acne; the Renova figures above describe 0.02% cream used in a fine-wrinkle program [1].

Why the rates do not apply to every tretinoin product

Renova 0.02% cream is indicated only as an adjunct, with a comprehensive skin care and sunlight avoidance program, for mitigation of fine facial wrinkles [1]. Its label states that it does not eliminate wrinkles, repair sun-damaged skin, reverse photoaging or restore a more youthful skin structure [1]. The 339-patient adverse-reaction set therefore comes from a fine-wrinkle population using a structured skin care and sun avoidance program, not from an acne trial of a gel or a higher-strength cream [1].

What did a head-to-head irritation study show?

A single-center, investigator-blinded, randomized, split-face phase 4 study compared tretinoin gel microsphere 0.04% in a pump dispenser with adapalene 0.1% plus benzoyl peroxide 2.5% gel in 170 subjects [3]. Participants used each product on a randomly assigned side of the face daily for three consecutive weeks [3].

Tretinoin gel microsphere 0.04% had significantly less cumulative erythema, dryness, burning/stinging and itching than the adapalene plus benzoyl peroxide gel, with P<0.0001 for each comparison [3]. The study reports a tolerability comparison, not incidence rates for each reaction [3].

Does tretinoin cause photosensitivity, and how often?

The Renova label warns that exposure to sunlight, including sunlamps, should be avoided or minimized because of heightened sunburn susceptibility [1]. It advises sunscreens with a minimum SPF of 15 and protective clothing, and says patients with sunburn should not use Renova until fully recovered [1]. It also says Renova should not be used with drugs known to be photosensitizers, such as thiazides, tetracyclines, fluoroquinolones, phenothiazines or sulfonamides, because of possible augmented phototoxicity [1].

The label gives no incidence rate for photosensitivity [1].

What can FAERS reports tell you about incidence?

The FDA's adverse event dashboard states that reports cannot be used to estimate the incidence of events [2]. Reports may be duplicate or incomplete, and the existence of a report does not establish that the drug caused the event [2].