Catherine Zip, MD, FRCPC
Division of Dermatology, University of Calgary, Calgary, AB, Canada
Conflict of interest:
Catherine Zip has served as a speaker and consultant for Bausch Health and Galderma.
Topical retinoids are recommended as first line therapy for the treatment of acne. Despite this recommendation, topical retinoids are underutilized, in part because of their tendency to cause cutaneous irritation. Tazarotene 0.045% lotion was developed using polymeric emulsion technology to provide an effective, well tolerated topical retinoid for the treatment of acne.
tazarotene, retinoid, acne, topical, facial
Acne is a common chronic inflammatory disease of the pilosebaceous unit. Although its prevalence is highest in adolescence, acne often persists into adulthood, especially in women. In fact, more than 50% of women in their 20s and more than 35% in their 30s experience acne.1 As long-term treatment is frequently required, topical therapy plays a pivotal role in its management. Topical retinoids are recommended as first line therapy for most acne patients by evidence-based guidelines in the US, Europe and Canada.2-4 Although utilization of retinoids has increased over time, a claims-based study of data obtained from a large US database indicated that of all patients seen by a dermatologist for acne, only 59% were prescribed either an oral or topical retinoid. Nondermatologist physicians prescribed a retinoid to 32% of acne patients.5 Novel retinoid formulations may improve tolerability and increase use.
Topical retinoids improve acne by normalizing follicular keratinization and reducing keratinocyte cohesiveness, thereby decreasing follicular occlusion and comedone and microcomedone formation. As well, retinoids have antiinflammatory effects.6 In addition, they may improve acne indirectly by enhancing penetration of other topicals, reducing postinflammatory hyperpigmentation, and improving acne scarring.7
Four topical retinoids have been approved by the United States Food and Drug Administration (FDA) for the treatment of acne: adapalene, tazarotene, tretinoin and trifarotene. Although retinoid effects are likely mediated by multiple pathways, retinoids bind with varying affinity to retinoic acid receptor (RAR) isotypes alpha, beta and gamma. Binding of the retinoid receptor to its agonist leads to modulation of gene transcription. RAR-gamma is the dominant subtype of RAR in the epidermis and hence believed to be a key mediator of retinoid effects in keratinocytes.8
Tazarotene, a third generation synthetic retinoid, is a prodrug which is rapidly converted in the skin to its active form, tazarotenic acid. Tazarotenic acid binds to all 3 RAR isotypes but shows relative selectivity for RAR-beta and RAR-gamma.
Studies comparing the efficacy and tolerability of tretinoin, adapalene and tazarotene have shown mixed results.9-12 Whereas some of these studies have shown comparable efficacy and tolerability, others have demonstrated greater efficacy but lower tolerability with tazarotene 0.1% cream, gel or foam. Studies comparing trifarotene to other topical retinoids have not yet been published.
Tazarotene 0.1% gel, cream and foam are FDA approved for the treatment of acne, initially in 1997. Although effective, cutaneous irritation has limited their clinical use.13 In an effort to improve tolerability and maintain efficacy, tazarotene has been reformulated at a lower concentration into a non-greasy lotion vehicle. Tazarotene 0.045% lotion was approved for the treatment of acne for patients 9 years and older by the FDA in 2019 and by Health Canada for those 10 years and older in 2021. This new formulation utilizes polymeric emulsion technology, which solubilizes tazarotene in an oil-in-water emulsion containing hydrating ingredients that are trapped within a honeycomb matrix. This allows for a uniform distribution of tazarotene and moisturizing excipients on the skin, which should lead to more efficient drug delivery into the epidermis and reduced irritation.14
Phase 2 Data Comparing Different Formulations of Tazarotene
A phase 2 multicenter, double-blind, randomized, vehicle-controlled study compared tazarotene 0.045% lotion and tazarotene 0.1% cream to their respective vehicles.14 A total of 210 patients 12 years and older were enrolled in the 12 week trial. Tazarotene 0.045% lotion showed statistically significant superiority in reducing both inflammatory and noninflammatory lesion counts compared to its vehicle. The mean percentage changes in inflammatory lesion counts from baseline to week 12 were 63.8% with tazarotene lotion versus 51.4% with vehicle, and in noninflammatory lesion counts 56.9% versus 35.2% with vehicle. Tazarotene lotion showed a numerically greater reduction in both inflammatory and noninflammatory lesions than tazarotene cream but the differences were not statistically significant. Both formulations of tazarotene were well tolerated, although more treatmentrelated adverse effects were reported with tazarotene cream (5.6% versus 2.9%). The only treatment-related adverse effect with tazarotene lotion was application site pain, reported in 2 patients.
Phase 3 Data on the Efficacy and Safety of Tazarotene Lotion in Acne Treatment
Two phase 3 multicenter, double-blind, randomized, vehicle-controlled trials studied the efficacy, safety and tolerability of tazarotene 0.045% lotion in the treatment of acne.15 A total of 1614 subjects with moderate to severe facial acne aged 9 years or older were enrolled. Subjects were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle once daily for 12 weeks. The co-primary efficacy endpoints were inflammatory and noninflammatory lesion counts and facial Evaluator Global Severity Score (EGSS). Treatment success was defined as a minimum 2-grade improvement in EGSS and achievement of either clear or almost clear. Demographic data were comparable across the two studies, with a mean age of 20 in both studies. Overall, 66% of subjects were female and 74% were Caucasian.
Tazarotene 0.045% lotion showed statistically significant superiority to vehicle in reducing both inflammatory and noninflammatory lesions in both trials (P<0.001). The mean percent reductions in inflammatory and noninflammatory lesions from baseline were 55.5% and 51.4% with tazarotene lotion in Study 1 (versus 45.7% and 41.5% with vehicle) and 59.5% and 60.0% with tazarotene lotion in Study 2 (versus 49.0% and 41.6% with vehicle). Tazarotene lotion was also significantly more likely than vehicle to achieve treatment success (P<0.001). Treatment success was achieved by 25.5% in Study 1 and 29.6% in Study 2 of subjects treated with tazarotene lotion, compared with 13.0% and 17.3% receiving vehicle in the respective studies.
Treatment-related adverse effects were reported in 11.3% (88/779) of subjects receiving tazarotene lotion. The most common were application site pain (5.3%), dryness (3.6%), exfoliation (2.1%) and erythema (1.8%). Most adverse effects were mild, peaked at week 2 and returned to baseline by week 12. The authors commented that application site reactions were less common than those reported previously with tazarotene 0.1% gel, cream and foam, which may be due to the formulation of the lotion and its lower concentration of tazarotene.
Sensitization and Tolerability Studies
In two phase 1 dermal safety studies of tazarotene lotion conducted in healthy adults, no participants developed dermal sensitization.16 Likewise, no cases of allergic contact dermatitis were reported in tazarotene-treated subjects in the phase 2 and 3 trials. In the phase 1 cumulative irritation patch test study which compared tazarotene 0.045% lotion to vehicle lotion, saline solution, and sodium lauryl sulfate (SLS), tazarotene lotion was deemed to be “slightly irritating”. Although the mean irritation score for tazarotene lotion was statistically greater than that of the SLS positive control, this was felt to be due to the exaggerated dosing conditions employed. The authors commented that the cumulative irritancy score for tazarotene 0.045% lotion was less than half of those reported in previous studies with tazarotene 0.1% cream, gel and foam.
Topical tazarotene is contraindicated in pregnancy. Although pharmacokinetic studies show low systemic exposure with use of topical tazarotene, exposure levels that could lead to teratogenicity in humans are unknown and there is currently very limited data regarding pregnancy outcomes after in utero exposure.17
Based on a small study done with tazarotene 0.1% foam, topical tazarotene has a low potential to cause phototoxicity and has not been reported to cause photoallergic reactions.18 However, as with all retinoids, sun protective measures are recommended with its use. Concomitant application of oxidizing agents such at benzyl peroxide is not recommended to avoid potential degradation of the retinoid.19
When prescribing a topical retinoid, patients should be counselled regarding the use of mild cleansers and emollients, as the large variation in patient usage of topical retinoids may be an important determinant of tolerability.20
Topical retinoids are recommended as first line therapy for most patients with acne. Despite strong data supporting their pivotal role in acne management, they continue to be underutilized. Although comparative studies have shown similar or better efficacy of tazarotene compared to other retinoids, higher rates of irritation have limited use of older formulations of topical tazarotene. Tazarotene 0.045% lotion is a novel formulation which utilizes polymeric emulsion technology to improve tolerability and epidermal penetration. Despite the lower concentration of tazarotene in the lotion formulation, which likely also contributes to improved tolerability, tazarotene 0.045% lotion is at least as effective as tazarotene 0.1% cream. Given its effectiveness and improved tolerability, tazarotene 0.045% lotion is a useful addition to our armamentarium of topical retinoids for the treatment of acne.
- Collier CN, Harper JC, Cantrell WC, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008 Jan;58(1):56-9.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74(5):945-73.
- Nast A, Dreno B, Bettoli V, et al. European evidence-based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol. 2012 Feb;26(Suppl 1):1-29.
- Asai Y, Baibergenova A, Dutil M, et al. Management of acne: Canadian clinical practice guideline. CMAJ. 2016 Feb;188(2):118-26.
- Pena S, Hill D, Feldman SR. Use of topical retinoids by dermatologists and non-dermatologists in the management of acne vulgaris. J Am Acad Dermatol. 2016 June;74(6):1252-4.
- Becherel PA, Mossalayi MD, LeGoff L, et al. Mechanism of anti-inflammatory action of retinoids on keratinocytes. Lancet. 1994 Dec;344(8936):1570-1.
- Leyden J, Stein-Gold L, Weiss J. Why topical retinoids are mainstay of therapy for acne. Dermatol Ther. 2017 Sep;7(3):293-304.
- Fisher GJ, Talwar HS, Xiao JH, et al. Immunological identification and functional quantification of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem. 1994 Aug;269(32):20629-35.
- Webster GF, Guenther L, Poulin YP, et al. A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris. Cutis. 2002 Feb;69(2 Suppl):4-11.
- Thiboutot D, Arsonnaud S, Soto P. Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris. J Drugs Dermatol. 2008 Jun;7(6 Suppl):s3-s10.
- Tanghetti E, Dhawan S, Green L, et al. Randomized comparison of the safety and efficacy of tazarotene 0.1% cream and adapalene 0.3% gel in the treatment of patients with at least moderate facial acne vulgaris. J Drugs Dermatol. 2010 May;9(5):549-58.
- Kircik LH. Tretinoin microsphere gel pump 0.04% versus tazarotene 0.05% cream in the treatment of mild-to-moderate facial acne vulgaris. J Drugs Dermatol. 2009 Jul;8(7):650-4.
- Del Rosso JQ, Tanghetti E. A status report on topical tazarotene in the management of acne vulgaris. J Drugs Dermatol. 2013 Mar;12(3 suppl 2):s53-s58.
- Tanghetti EA, Kircik LH, Green LJ. A phase 2, multicenter, double-blind, randomized, vehicle-controlled clinical study to compare the safety and efficacy of a novel tazarotene 0.045% lotion and tazarotene 0.1% cream in the treatment of moderate-to-severe acne vulgaris. J Drugs Dermatol. 2019 June;18(6):542-8.
- Tanghetti EA, Werschler WP, Lain T, et al. Tazarotene 0.045% lotion for oncedaily treatment of moderate-to-severe acne vulgaris: results from two phase 3 trials. J Drugs Dermatol. 2020 Jan;19(1):70-7.
- Kircik LH, Green L, Guenin E, et al. Dermal sensitization, safety, tolerability, and patient preference of tazarotene 0.045% lotion from five clinical trials. J Dermatolog Treat. 2021 Aug 30:1-9.
- Han G, Wu JJ, Del Rosso JQ. Use of topical tazarotene for the treatment of acne vulgaris in pregnancy: a literature review. J Clin Aesthet Dermatol. 2020 Sep;13(9):E59-E65.
- Hogan DJ, Saenz AB. Phototoxic and photoallergic potential of tazarotene foam 0.1% in 2 phase 1 patch studies. Cutis. 2012 Nov;90(5):266-71.
- Arazlo (tazarotene) lotion, 0.045% [Product monograph]. July 7, 2021. Bausch Health, Canada Inc.
- Culp L, Tuchayi SM, Alinia H, et al. Tolerability of topical retinoids: are there clinically meaningful differences among topical retinoids? J Cut Med Surg. 2015 Nov/Dec;19(6):530-8.