Tazarotene

Abstract

A multicenter, double-blind, randomized, parallel-group trial compared tazarotene 0.1% cream with adapalene 0.1% cream, once daily for 12 weeks, in 173 patients with facial acne vulgaris. Tazarotene was associated with a significantly greater incidence of patients achieving 50% or greater global improvement (77% vs. 55%, P [less than or equal to] .01), and a significantly greater reduction in comedo count (median of 68% vs. 36%, P [less than or equal to] .001, compared with adapalene. A significant between-group difference in baseline inflammatory lesion count precluded a comparison of efficacy against inflammatory acne. The most common adverse events were dryness, peeling/flaking, itching, redness/erythema, burning, and facial irritation with comparable incidences of each between groups. Mean peeling and burning levels were milder with adapalene, though were trace or less in both groups throughout. There were no significant between-group differences in the incidence of patients discontinuing due to lack of efficacy or adverse events. Tazarotene cream offers significantly greater efficacy and comparable tolerability to adapalene cream.

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Introduction

Topical retinoids are the mainstay of treatment for acne vulgaris as they not only offer efficacy against existing acne lesions, but also help prevent the development of new lesions. The therapeutic and preventive actions of topical retinoids result from their ability to help normalize the abnormal desquamation of follicular epithelium in the infrainfundibular portion of the pilosebaceous unit--thereby promoting drainage of microcomedos and comedos. By inhibiting the development of acne at the subclinical microcomedo stage, topical retinoids inhibit the subsequent development of both inflammatory and non-inflammatory acne lesions. Topical retinoids also have some indirect antibacterial activity by virtue of the fact that their actions render the follicular microclimate (biofilm) less hospitable to P. acnes.

Three topical retinoids have been approved by the US Food and Drug Administration for the treatment of acne vulgaris: tretinoin, tazarotene, and adapalene. Initial studies in the 1960s and early 1970s involved tretinoin 0.05% solution and, although efficacy was readily apparent, tolerability was a problem due to significant irritation, erythema, and peeling. Over the years, less irritating formulations of tretinoin have been developed including creams, gels, and, most recently, a microsponge gel. Tazarotene and adapalene were introduced in the 1990s--initially in gel formulations and subsequently in cream formulations (and, for adapalene, in a solution formulation).

In various well-controlled trials directly comparing the gel formulations of these topical retinoids, tazarotene 0.1% gel has shown superior efficacy to tretinoin 0.025% gel, tretinoin 0.1% microsponge gel, and adapalene 0.1% gel, (1-3) with the latter 3 gels generally reported to have comparable efficacy to one another. (4-8) Adapalene gel has a tolerability advantage over the other retinoid gels--although it is important to note that the sensitivity of an individual's skin is at least as important a determinant of tolerability as the individual retinoid applied. (9)

Many patients prefer cream formulations to gel formulations and creams are especially suitable for those with dry or sensitive skin and those living in cold, dry climates. Although several clinical trials have directly compared gel formulations, studies comparing creams are lacking. A multi-center, double-blind, randomized, parallel-group study has recently been performed to compare tazarotene 0.1% cream with adapalene 0.1% cream. To our knowledge, this is the first report comparing cream formulations of different retinoids.

Methods

Patients

Patients were eligible to enroll in this multicenter, double-blind, randomized, parallel-group trial if they had stable facial acne vulgaris--defined as approximately 10 to 60 papules and/or pustules, 10 to 100 open and/or closed comedos, and no more than 5 nodulocystic lesions (of [less than or equal to] 5 mm in diameter) on the face. Patients were also required to be at least 12 years of age and to have conformed to the following washout periods: 14 days for topical acne medications; 30 days for systemic antibiotics and investigational drugs; 12 weeks for estrogens or birth control pills if these had been used for less than 12 weeks (however, patients having used these for more than 12 weeks before entering the study were still eligible for enrollment); and 12 months for oral retinoids.

Exclusion criteria included any patient who had acne vulgaris known to be resistant to oral antibiotics, an uncontrolled systemic disease, was pregnant or breastfeeding, was female and not using a reliable method of contraception, or had any skin disorder that might interfere with the diagnosis or evaluation of acne vulgaris.

The study was approved by the relevant institutional review boards and was performed according to Good Clinical Practice guidelines. All patients gave written informed consent.

Treatment Regimen

Patients were randomly assigned to treatment with either tazarotene 0.1% cream or adapalene 0.1% cream, once daily in the evening for 12 weeks. Patients were requested to apply a pea-sized amount of the study medication to their face 15 minutes after washing it with a gentle non-soap cleanser and patting it dry with a soft towel. In the event of skin dryness, moisturizer use was allowed as necessary. Patients were supplied with a mild cleanser (Cetaphil[R] Facial Cleanser) and non-comedogenic moisturizer with sunscreen (Neutrogena Moisture[R] SPF 15) and were required not to use any other anti-acne treatment during the study.

Outcome Measures

Patients were evaluated by the investigator every 4 weeks. Primary efficacy outcome measures were the incidence of 50% or greater global improvement (treatment success) and the reduction in lesion count (open plus closed comedos and papules plus pustules) from baseline. Secondary outcome measures included the incidence of 75% or greater global improvement and the level of overall disease severity, peeling, erythema, dryness, burning, and perception of oiliness (Table 1). In addition to these investigator assessments, patients also rated the severity of their acne.

[FIGURE 2 OMITTED]

Statistical Analyses

It was calculated that a sample size of 87 patients in each treatment group (70 patients that could be evaluated in each group) was required to detect a clinically significant difference between the treatment groups--defined as a between-group difference of 20% in the incidence of treatment success or a between-group difference of 15 in the reduction in comedo count from baseline. This assumed a power of 80%, a dropout rate of 20%, two-sided statistical tests, and a P value of .05 or less for statistical significance.

Between-group differences in the following measures were analyzed using a Mantel-Haenszel chi-square test: categorical baseline variables, the incidence of 50% or greater or 75% or greater global improvement, and the distribution of scores for overall disease severity, patient-rated overall acne severity, peeling, erythema, dryness, burning, and perception of oiliness. Other between-group differences were analyzed using a t-test for continuous baseline variables, chi-square/Fisher's exact test for the incidence of premature discontinuations and adverse events, and the Wilcoxon rank-sum test for reductions in lesion count.

Results

Patients

A total of 173 patients were enrolled (86 tazarotene, 87 adapalene), of whom 148 (86%) completed the study and 25 discontinued (13 tazarotene, 12 adapalene). The majority of patients were Caucasian (71%) and their mean age was 20 years. Most had an oily component to their skin; 40% had normal to oily skin, 22% had mixed oily/dry skin, and 16% had oily skin (Table 2). There were no significant between-group differences in baseline demographics except that the mean papule plus pustule count was significantly lower in the tazarotene group than the adapalene group (16 vs. 18; P [less than or equal to] .05). There were no significant between-group differences in the incidence of patients discontinuing due to lack of efficacy, adverse events, or other reasons. The study was started in October 2001 and completed in September 2002.

Efficacy

Tazarotene was associated with a significantly greater incidence of patients achieving 50% or greater global improvement (ie, treatment success) compared with adapalene (77% vs. 55% at week 12, P [less than or equal to] .01; Figure 1). Similarly, tazarotene was associated with a significantly greater incidence of patients achieving 75% or greater global improvement (55% vs. 34% at week 12, P [less than or equal to] .01; Figure 1).

Tazarotene was also associated with a significantly greater reduction in comedo count than adapalene (median of 68% vs. 36% at week 12, P [less than or equal to] .001; Figure 2). As previously mentioned, the mean papule plus pustule count was significantly different between the two groups at baseline (16 vs. 18), thus precluding a meaningful comparison of the effect of treatment on inflammatory lesions. (The inflammatory lesion count was reduced by a median of 62% with tazarotene and 50% with adapalene at week 12 [NS].) Investigator ratings of overall disease severity and patient ratings of overall acne severity (Figure 3) both showed significantly less severe acne overall in the tazarotene group than the adapalene group at week 12. At the end of the study, 32% of the tazarotene group and 16% of the adapalene group considered they had no more than trace levels of acne, and 76% of the tazarotene group and 61% of the adapalene group considered they had no more than mild levels of acne.

Tolerability

The mean scores for peeling, erythema, dryness, and burning were trace or less throughout the study in both treatment groups. The mean score for perception of oiliness declined from mild levels at baseline to trace levels from week 4 onward in both groups. There were no significant between-group differences in the distribution of scores for erythema, dryness, or the perception of oiliness. For peeling and burning, the distribution of scores transiently showed statistically significantly higher levels with tazarotene than adapalene at weeks 4 and/or 8. However, there were no significant between-group differences again by week 12.

The most common treatment-related adverse effects were dryness (incidence of 7% with tazarotene vs. 8% with adapalene), peeling/flaking (6% vs. 2%), itching (3% vs. 5%), redness/erythema (6% vs. 2%), burning (1% vs. 5%), and facial irritation (2% vs. 2%). These were predominantly of mild or moderate severity and there were no significant between-group differences in the incidence of any of these adverse events.

Discussion

Results from this study indicate that once-daily tazarotene 0.1% cream is significantly and rapidly more effective than once-daily adapalene 0.1% cream in the treatment of comedonal acne. Both agents are also effective against inflammatory acne lesions. A meaningful comparison of the efficacy of the two agents against inflammatory acne was precluded due to a significant difference in the inflammatory lesion count between groups at baseline. However, in an earlier study with the gel formulations of these topical retinoids, tazarotene 0.1% gel was shown to be significantly and rapidly more effective than adapalene 0.1% gel against both inflammatory and non-inflammatory acne lesions. (3)

Tazarotene and adapalene cream are both well-tolerated with mean levels of peeling, erythema, dryness, and burning only trace or less in this study. Although significant between-group differences in the levels of peeling and burning were evident in the early weeks of treatment, the absolute levels were too low for these differences to be clinically significant. The most common treatment-related adverse events were dryness, peeling/flaking, itching, redness/erythema, burning, and facial irritation and there were no significant between-group differences in the incidences of these. These results confirm those from several well-controlled split-face investigator-masked facial tolerability studies. In these studies, there were no significant differences in the degree of erythema or dryness/peeling associated with once-daily applications of tazarotene 0.1% cream and adapalene 0.1% cream on either normal or sensitive skin. (9) These facial tolerability studies also compared the facial tolerability of tazarotene and adapalene creams with that of tretinoin 0.1% cream. On normal skin, tazarotene 0.1% cream--but not adapalene 0.1% cream--was associated with significantly lower levels of both erythema and dryness/peeling than tretinoin 0.1% cream. (9) On sensitive skin, both creams had significantly lower levels of dryness/peeling than tretinoin 0.1% cream.

Conclusions

The results from this study demonstrate that tazarotene 0.1% cream is significantly and rapidly more effective than adapalene 0.1% cream in the treatment of facial acne vulgaris and has comparable tolerability. The effect of tazarotene cream on the comedonal aspect of acne was particularly striking and suggests that it is a valuable option for both initial and maintenance therapy. These results together with those from a previous trial comparing the gel formulations of these retinoids suggest that, regardless of whether creams or gels are used, 0.1% tazarotene is significantly and rapidly more effective than 0.1% adapalene.

Disclosure: Dr. Shalita has been a consultant and investigator for Allergan, Inc., and an advisory board member and investigator for Galderma Laboratories, LP. Dr Miller has received research support from, and been a speaker and consultant for, Allergan, Inc. Drs. Menter and Abramovits have received research support from, and been speakers and consultants for, Allergan, Inc., and Galderma Laboratories, LP. Dr. Loven has been an investigator and speaker for Allergan, Inc., and an investigator for Galderma Laboratories, LP. Dr. Kakita has no financial disclosures or conflicts of interest.

References

1. Webster GF, Berson D, Stein LF, et al. Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis. 2001; 67(6 Suppl):4-9.

2. Leyden JJ, Tanghetti EA, Miller B, et al. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1 % microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis. 2002; 69(2 Suppl):12-19.

3. 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; 69(2 Suppl):4-11.

4. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized controlled trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001; 68(4 Suppl):10-19.

5. Nyirady J, Grossman RM, Nighland M, et al. A comparative trial of two retinoids commonly used in the treatment of acne vulgaris. J Dermatolog Treat. 2001;12(3):149-57.

6. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol. 1998;139 Suppl 52:48-56.

7. Grosshans E, Marks R, Mascaro JM, et al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life. Br J Dermatol. 1998; 139 Suppl 52:26-33.

8. Alirezai M, Meynadier J, Jablonska S, et al. Comparative study of the efficacy and tolerability of 0.1 and 0.03 p. 100 adapalene gel and 0.025 p. 100 tretinoin gel in the treatment of acne. Ann Dermatol Venereol. 1996;123:165-70. [French]

9. Leyden JJ, Grove G, Zerweck C. Facial tolerability of topical retinoid therapy. J Drugs Dermatol. 2004;3(6):641-651.

A. Shalita MD, (a) B. Miller MD, (b) A. Menter MD, (c) W. Abramovits MD, (c) K. Loven MD, (d) L. Kakita MD (e)

a. Department of Dermatology, State University of New York Downstate Medical Center, Brooklyn, NY

b. Oregon Medical Research Center, Portland, OR

c. Division of Dermatology, Baylor University Medical Center, Dallas, TX

d. Rivergate Dermatology & Skin Care Center, Goodlettsville, TN

e. Department of Dermatology, University of California Los Angeles, Glendale, CA

Address for Correspondence

Alan Shalita, MD

Professor & Chairman

Department of Dermatology

State University of New York Downstate

Medical Center

450 Clarkson Avenue, Box 46

Brooklyn, NY 11203-2098

Phone: 718-270-1229

Fax: 718-270-2794

e-mail: ashalita@downstate.edu

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