Safe Use of Adapalene 0.1 % Gel in a non-Prescription Environment

December 2021 | Volume 20 | Issue 12 | Original Article | 1330 | Copyright © December 2021

Published online November 10, 2021

Jonathan S. Weiss MD,a Sreenadh Mallavalli PharmD,b Matthew H. Meckfessel PhD,b Sean Griffin MBA,b Nathalie Wagnerb

aGeorgia Dermatology Partners and Gwinnett Clinical Research Center, Inc., Snellville, GA
bGalderma Research & Development, LCC, Fort Worth, TX

Background: Topical retinoids are the mainstay of acne therapy and, until 2016, were only available by prescription. The margin of safety (MOS) of adapalene for potential teratogenic effects, and its use in pregnancy were investigated as part of the OTC switch.
Objective: To determine MOS using a maximal usage trial (MUsT) and animal embryo-fetal development studies. To conduct a thorough review of safety data with respect to use of Adapalene 0.1% Gel during pregnancy.
Methods: The MUsT was multicenter, open-label pharmacokinetic study which enrolled adolescents and adult subjects with mainly severe acne vulgaris. The no observable adverse event level (NOAEL) for adapalene teratogenicity was established in rat and rabbit embryo-fetal development studies. An exhaustive review of pregnancy data from multiple safety databases was conducted.
Results: The calculated MOS for teratogenicity was 70 for Adapalene 0.1% Gel. For the pregnancy safety review, no pregnancy malformations were attributable to topical adapalene use.
Limitations: Animal studies do not always predict effects in human development. Additionally, safety data is voluntarily reported and intrinsically incomplete.
Conclusion: Adapalene has a large and reassuring MOS making it suitable for OTC use. No teratogenic risk was identified in a MUsT and Pregnancy Safety Review. Adapalene 0.1% Gel is a safe and effective medication for the treatment of acne in a non-prescription environment. Based on available evidence, use of adapalene during pregnancy does not pose harm to the fetus.

J Drugs Dermatol. 2021;20(12):1330-1335. doi:10.36849/JDD.6527


Acne vulgaris is a condition that affects up to 87% of adolescents and over 50% of adults.1 Acne sufferers commonly self-treat with well-established over the counter (OTC) products approved by the FDA under the OTC monograph. As a multi-factorial disease, acne is characterized by abnormal follicular keratinocyte desquamation, anaerobic Propionibacterium acnes proliferation, inflammation, and excess sebum production.2

Acne affects all races and ethnicities and is one of the most commonly diagnosed dermatological conditions. The prevalence of acne for women of childbearing age (19 to 45 years) is 32.5%, indicating potential for women who are pregnant to seek treatment.3 Until 2016, there were five non-prescription active ingredients available on the market: benzoyl peroxide (BPO), salicylic acid, sulfur, resorcinol and resorcinol monoacetate. Topical retinoids have long been considered first line therapy for the treatment of acne.4 The paradox is that some retinoids have a black box warning stating that women who are pregnant should not use these vitamin A receptor agonists.5

Excess systemic retinoid exposure during pregnancy can disrupt normal embryonic development in a wide range of experimental animals, targeting cardiovascular, CNS (central nervous system), craniofacial and skeletal development.6 In humans, administration of systemic therapeutic retinoids has been associated with developmental abnormalities including CNS (hydrocephalus, hypoplastic or malformed cerebellar or cerebral cortices), craniofacial region (cleft palate, external ear defects), heart, thymus and limbs.6 These abnormalities are associated specifically with oral retinoids. Although systemic exposure to topical retinoids is lower, the risk during pregnancy is inadequately studied.

Adapalene 0.1% Gel was originally approved as a prescription medication for the treatment of acne vulgaris in the United States in May 1996 (NDA 20380). Topical adapalene-containing products, formulated at various strengths between 0.1% and 0.3%, and in combination with BPO, were all approved Pregnancy Category C drugs before the FDA removed pregnancy categories from prescription medications.7 This