The Nonprescription Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted unanimously April 15 to recommend over-the-counter marketing (OTC) of adapalene gel 0.1% (Differin Gel, Galderma Laboratories) for persons aged 12 years or older with acne.
"I think the data that [have] been presented indicate that the product is safe and I think it would be a big boon to adolescents with acne. I think it's a very severe disease and that this would really help in the treatment. I think the benefits greatly outweigh any minimal…risk. I don't think the teratogenicity is a risk," said voting committee member Lorraine J. Gudas, PhD, professor of pharmacology, medicine, and urology, Weill Cornell Medical College, New York City.
Adapalene is a third-generation topical retinoid that inhibits comedone formation and inflammation.
The FDA approved adapalene gel 0.1% in 1996 as a prescription product, and it is available in 83 countries including Russia. It is available without a prescription in Russia. The 0.1% gel formulation is the most widely prescribed; it is also available in a 0.1% cream and lotion, a 0.3% gel, and in two combination products: 0.1% and 0.3% in combination with benzoyl peroxide 2.5%.
Other topical retinoids used for acne treatment include tretinoin and tazarotene. Isotretinoin is an oral retinoid. Retinoids are recommended as first-line treatment for all severities of acne either alone or in combination with other topical or oral medications.
All retinoids are teratogenic in animals; the FDA has assigned tazarotene and oral isotretinoin to pregnancy category X. Oral isotretinoin is only available with a Risk Evaluation and Mitigation Strategy that includes a pregnancy prevention program and registry. The FDA has assigned tretinoin and adapalene 0.1% gel to pregnancy category C.
The formulation discussed Friday was the single-ingredient product containing adapalene 0.1% gel, the lowest dose of the medication. Because the FDA has already approved adapalene, the panel did not discuss efficacy.
Label Comprehension Study
The label comprehension study (study 100544) included 586 adults and adolescents aged 12 to 70 years, divided into a general population group and an augmented low-literacy group. The primary and secondary endpoints were whether or not patients understood label instructions to use the product daily and to not use it on damaged skin. The study did not test participants on avoiding sunlight or talking with a healthcare provider before using during pregnancy.
For the instruction to use once daily, most participants of normal literacy (96.5%; lower bound of the confidence interval [LBC], 94.4%) and low literacy (86.9%; LBC, 79.9%) responded correctly. For the instruction to not use on damaged skin, 97.4% (LBC, 95.5%) of patients with normal literacy and 99.2% (LBC, 95.8%) of patients with low literacy responded correctly. Results were similar for adults and adolescents.
The self-selection study (study 103439) was a single-visit, targeted, self-selection study in 293 pregnant and breastfeeding women aged 13 to 54 years. The study included a low literacy cohort of 51 (17%) participants. Only two participants were adolescents.
The primary objective was to determine whether or not pregnant or breastfeeding women with acne would talk with a healthcare professional before using adapalene, as instructed on the label.
In the group of women who were pregnant only, 70% (LBC, 58.7%) responded that they would consult a doctor before use. Reasons given indicate that women believe topical medications will not hurt a developing fetus, and that it is safe to use OTC products during pregnancy. Fifteen women said they did not see the warning on the label.
The company conducted two trials to study safety, the actual-use and maximum-use trials. In both studies, adverse events were similar to those already listed on the product's label.
The actual-use trial (Juno trial, study 13049) was a 6-week, open label, multicenter trial in 947 adolescents (aged 12 to 17 years; N = 203) and adults with self-reported acne, 13.2% of whom were of low literacy. Women underwent testing for pregnancy before they were allowed to purchase the study drug and also at the end of the study period.
The trial's primary objectives were to determine the frequency of use and off-label use for conditions other than acne. A secondary objective was to determine whether participants used the medication inappropriately near the eyes, mouth, lips, or on damaged skin.
Fourteen participants chose to use the medication while they were pregnant (N = 4) or breastfeeding (N = 10), stating that they believed there was a low risk because the product was topical, they didn't believe the warning was serious, or they did not see the warning.
Most participants (89.1%; LBC, 87.1%) used the product once daily and results were comparable in adolescents and participants with low literacy.
Almost all participants (99.3%; LBC, 98.5%) used the product only for acne and used it on the correct body area (97.5%; LBC, 96.2%).
Nine participants discontinued the trial, eight of whom did so because of adverse events. The most frequent adverse events were headache, dry skin, and erythema. No patients reported serious adverse events.
The maximum-use trial (RD.06.SRE.18254) was a multicenter, open-label trial that studied the systemic exposure to adapalene 0.1% topical gel in 24 adolescents (n = 10) and adults (n = 6) with moderate-to-severe acne under maximal-use conditions during 4 weeks. Participants applied a thin layer to the face, shoulders, upper chest, and upper back, and 24-hour pharmacokinetic profiles were performed on day 1, day 15, and day 29.
In this trial, 33% of patients experienced one or more adverse events, the most frequent of which were skin irritation, pruritis, and headache. There were no reports of serious adverse events.
The sponsor submitted postmarketing safety data related to carcinogenic and teratogenic potential in humans from the sponsor's pharmacovigilance database, the FDA's Adverse Event Reporting System, the World Health Organization (WHO VigiBase), and the published literature.
The committee said the warning about breastfeeding should be removed from the label, but had mixed opinions about whether to keep the label warning about seeing a healthcare provider before using the medication during pregnancy. Several committee members said that if the committee truly believes there is no risk for pregnant women, keeping that warning would send mixed messages, and some voiced concern that the warning might unnecessarily alarm women. Others felt the labeling should remain but be worded differently.
"We either say it's safe or we say it's not safe. If we voted that it's safe, then I don't like giving our pregnant moms misinformation...I want to be very, very clear to my patients," said temporary voting committee member Sarah Gloria Obican, MD, assistant professor of maternal fetal medicine in the department of obstetrics and gynecology, University of South Florida, Tampa.
"If we think that it's really safe like the data suggest that it is, I think we need to take that labeling off," said voting committee member Paul Pisarik, MD, MPH, from St. John Health System Urgent Care, Tulsa, Oklahoma.
Several panel members said that instead of saying to use once daily, the label should instruct consumers to use once every 24 hours and be more specific about how much product to apply. The label currently instructs to wash the affected skin with a "mild cleanser," and some committee members said the label should be more specific about what constitutes a mild cleanser.
Some committee members also said that the warning about sun exposure is too vague.
Several committee members said instructions for adolescents should be clearer, and voiced concern that adolescents might apply more than the recommended amount of the medication thinking that, "if some is good, more is better."
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Cite this: FDA Advisory Panel Backs OTC Adapalene Gel 0.1% for Acne - Medscape - Apr 18, 2016.