Continuing Education Activity
Adapalene is a topical retinoid with FDA-approval for the treatment of acne vulgaris. Clinicians use retinoids are used to treat a wide variety of skin disorders. Adapalene also has therapeutic application in 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. This activity outlines the indications, contraindications, interactions, monitoring, and other therapeutic information pertinent to members of an interprofessional team in the care of patients on adapalene therapy.
- Identify the approved indications for adapalene.
- Describe the mechanism of action and pharmacology of adapalene.
- Summarize the adverse effect profile of adapalene.
- Review interprofessional team strategies for improving care coordination and communication to improve outcomes for patients using adapalene.
Adapalene is a topical retinoid that is FDA-approved for the treatment of acne vulgaris. Retinoids have utility in the treatment of a wide variety of skin disorders. Adapalene is also useful 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.
Adapalene was initially FDA-approved in 1996 for acne in patients 12 years of age or older. Adapalene is available 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 two 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 effective, but the best tolerated. Tretinoin is understood 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. A meta-analysis included five randomized controlled trials and 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 provides 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 adapalene patient group exhibited significantly enhanced cutaneous tolerability.
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 occurred with the use of adapalene, with a 57% reduction in the tazarotene group. 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, which leads to less concern for molecular photodegradation, allowing for use during daylight hours. This stability 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 the hair follicles due to its lipophilic nature. Follicular absorption occurs 5 minutes after topical application. The medication binds to 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.
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, leading 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 the 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. The hypothesis is 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 action leads to neutrophil recruitment and the 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.
Patients apply adapalene once daily, either in the morning or at bedtime, to a clean face. The patient should wash their face with a gentle cleanser and allow the face to dry thoroughly. Then they should apply a pea-sized amount of adapalene as a thin layer to the whole face. Care is necessary 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, the clinician should also recommend an oil-free sunscreen, and warn the patient against excessive sun exposure.
Adverse reactions reported from adapalene include photosensitivity, irritation, redness, dryness, itching, and burning. These are usually mild adverse events.
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 observed 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 characteristically demonstrate 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 skincare products.
The patient should have a reassessment for efficacy in 12 weeks, or sooner if adverse effects occur.
Adapalene was pregnancy category C under the prior FDA pregnancy classification system and should be avoided in pregnant patients as systemic retinoids are teratogenic. It is unknown whether adapalene is excreted in breast milk and thus requires caution in breastfeeding patients.
Enhancing Healthcare Team Outcomes
Adapalene is a topical retinoid that 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 pharmacists interacting with patients, must be fully aware of its side effects and contraindications. Pharmacists will also perform through medication reconciliation. Because the drug is teratogenic, clinicians should not prescribe adapalene to women of childbearing age or women who are breastfeeding. Dermatology specialty-trained nursing staff should be on hand to counsel and followup with patients on adapalene therapy. Nursing should assess patient compliance, answer questions regarding dosing/administration, and monitor for adverse events and alert the prescriber promptly if present. Collaboration between all these disciplines in an interprofessional team can optimize adapalene therapy while minimizing adverse effects. [Level V]