Article Author:
Leila Tolaymat
Article Editor:
Patrick Zito
2/2/2019 8:36:56 AM
PubMed Link:


Adapalene is a topical retinoid which is FDA-approved for the treatment of acne vulgaris. Retinoids are used to treat a wide variety of skin disorders. Adapalene can be used for several non-FDA-approved indications including the treatment of verruca, molluscum contagiosum, Darier disease, Fox-Fordyce disease, Dowling-Degos disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.[1][2][3]

Adapalene was initially FDA-approved in 1996 for acne in patients 12 years of age or older. Adapalene is supplied as a 0.1% cream, gel, and lotion and 0.3% gel. Adapalene 0.1% gel was FDA-approved in 2016 as an over-the-counter acne treatment in patients 12 years of age or older.  Adapalene 0.1% lotion and cream and adapalene 0.3% gel are available by prescription only.

Retinoids are vitamin A derivatives. Topical retinoids used in the treatment of acne vulgaris include adapalene, tretinoin, and tazarotene.  Topical retinoids are recommended as first-line therapy for the treatment of acne vulgaris, either alone or in combination with other acne medications. Topical retinoids target 2 pathogenic mechanisms of acne vulgaris: microcomedone formation, which is the precursor of all forms of acne lesions, and the inflammatory response.

Conventional teaching indicates that the retinoids used to treat acne have varying degrees of efficacy and tolerability. Adapalene is perceived to be the least efficacious, but the best tolerated. Tretinoin is perceived to have moderate efficacy and tolerability. Tazarotene is perceived to be the most efficacious, but the least tolerated due to patient skin irritation.

Studies support that adapalene is efficacious in the treatment of acne vulgaris. Five randomized controlled trials were included in a meta-analysis that suggested that adapalene 0.1% gel has similar efficacy, but enhanced tolerability, in the treatment of acne as compared to tretinoin 0.025% gel.

A vehicle formulation of microsphere gel was developed for tretinoin which allows for the medication to be delivered primarily to the epidermis. This allows for decreased irritation and better tolerability.  A randomized controlled trial of tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin 0.1% microsphere gel revealed that the efficacy was comparable in terms of total, non-inflammatory and inflammatory lesions. However, the cutaneous tolerability was significantly enhanced in the adapalene group of patients.

Adapalene also performs well when compared to tazarotene. In a 12-week randomized, evaluator-blinded study comparing adapalene 0.3% gel and tazarotene 0.1% gel, each group had a clinically significant reduction in total lesion counts. A 61% reduction in acne lesions was seen with the use of adapalene, and a 57% reduction was seen with the use of tazarotene. Adapalene 0.3% gel was found to have equivalent efficacy as tazarotene 0.1% gel. However, patients using adapalene experienced less irritation than patients in the tazarotene treated group.

Adapalene has additional advantages when compared to other retinoids. Adapalene is a more stable molecule. This leads to less concern for photodegradation of the molecule, allowing for use during daylight hours. This is in contrast to both tretinoin and tazarotene which are photolabile. Adapalene also exhibits less chemical instability, allowing for use in combination with benzoyl peroxide.

Mechanism of Action

Adapalene is a naphthoic acid derivative. Adapalene is an active metabolite and therefore requires no metabolic conversion. Adapalene, when applied topically, penetrates into the hair follicles due to its lipophilic nature. Follicular absorption occurs 5 minutes after topical application. The medication binds the nuclear retinoic acid receptors (RAR), RAR-beta and RAR-gamma. This complex then binds DNA through retinoic acid response elements and induces gene transcription, leading to downstream keratinocyte proliferation and differentiation. As a result, adapalene decreases microcomedone formations, exfoliates mature comedones and has anti-inflammatory effects.[4][5]

The pathogenesis of acne vulgaris is multifactorial. The main factors associated with acneiform lesion development are follicular hyperkeratinization, sebum production by sebaceous glands, and inflammation. In acne-prone patients, keratinocytes accumulate in the lumen of the hair follicle due to increased keratinocyte proliferation and cohesiveness. This leads to the formation of a keratotic plug, which results in the microcomedone. The microcomedone is the precursor to all visible acne lesions like open comedones, closed comedones, inflammatory papules, pustules, and nodulocystic lesions. Adapalene normalizes differentiation of follicular epithelial cells to prevent microcomedone formation.

In addition to follicular hyperkeratinization, acne is also a disorder associated with inflammation. Propionibacterium acnes is a gram-positive, anaerobic rod found in the sebaceous follicle. P. acnes is present in both acne-prone individuals and those without acne. It is hypothesized that there may be differences in the strains of P. acnes or in the host response to P. acnes, which leads to its varying degrees of pathogenicity. P. acnes release mediators that contribute to comedone rupture and stimulate inflammatory cells. P. acnes stimulates the toll-like receptor II (TLR-2) pathway which induces the release of pro-inflammatory modulators. This leads to neutrophil recruitment and release of enzymes that result in follicular epithelium rupture. One mediator, IL-12, promotes a TH1 immune response. Adapalene is thought to suppress polymorphonuclear lymphocyte chemotaxis and down-regulate15-lipoxygenase and TLR-2 which contributes to its anti-inflammatory effects.


Adapalene is applied once daily, either in the morning or at bedtime to a clean face. The patient should be advised to wash the face with a gentle cleanser and allow the face to dry thoroughly. A pea-sized amount of adapalene should be applied as a thin layer to the whole face. Care should be taken to avoid application to eyelids, lips and mucous membranes. An oil-free moisturizer can be applied over adapalene to help decrease the risk of irritation. As there is a risk of photosensitivity with topical retinoids, an oil-free sunscreen should also be recommended, and excessive sun exposure should be avoided.

Adverse Effects

Adverse reactions reported from adapalene include photosensitivity, irritation, redness, dryness, itching, and burning. These are usually mild adverse events.[6][7]

Adapalene is less irritating compared to other topical retinoids. In an investigator-masked, randomized, controlled, parallel group study of 591 acne patients, a combined safety analysis conducted in the United States and Europe compared adapalene 0.1% gel and tretinoin 0.025% gel. The number of patients discontinuing the study due to adverse events was about twice as high in those using tretinoin (2.4%) compared to adapalene (1.3%). There were no systemic adverse reactions noted in the study. Most of the adverse reactions noted were related to skin irritation.

The enhanced tolerability of adapalene has been attributed, in part, to the selective affinity of adapalene to the nuclear RAR-beta and RAR-gamma receptors, as opposed to RAR-alpha. The decreased risk of skin irritation may contribute to better long-term compliance.

Rare, severe allergic reactions may be characterized by pruritus, facial edema, lip swelling and/or eyelid swelling. If a patient experiences anaphylactic reactions with symptoms including facial swelling, hives, chest pain or shortness of breath, then adapalene should be discontinued, and the patient should seek immediate medical evaluation.


Contraindications include a history of hypersensitivity to adapalene or other retinoids. Relative contraindications include patients with a photosensitive disorder, eczema, sunburn, or concomitant use of other potentially irritating skin care products.


The patient should be reassessed for efficacy in 12 weeks; sooner if adverse effects occur.

Adapalene is pregnancy category C and should be avoided in pregnant patients as systemic retinoids are teratogenic. It is unknown whether adapalene is excreted in breast milk and thus should be used with caution in breastfeeding patients.

Enhancing Healthcare Team Outcomes

Adapalene is a topical retinoid which is FDA-approved for the treatment of acne vulgaris and several non-FDA-approved indications including the treatment of verruca, molluscum contagiosum, Darier disease, Fox-Fordyce disease, Dowling-Degos disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata. Nurse practitioners and primary care physicians who prescribe this agent, as well as pharmacist interacting with patients, must be fully aware of its side effects and contraindications. Because the drug is teratogenic, it should not be prescribed to women of childbearing age or women who are breast feeding.[8][9][10]


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