isotretinoin gel

CLINICAL

THERAPEUTICSVVOL.

23 NO. 2,200l

Comparison of the Cumulative Irritation Potential of Adapalene Gel and Cream with That of ErythromycW’Iketinoin Solution and Gel and ErythromyckDsotretinoin Gel Catherine Queille-Roussel, MD,’ Michel Poncet, MS,2 Stephane Mesaros, PharmD,2 Alan Clucas, MD,2 Michael Baker, BS,3 and Andrew-Marc SolofJ; MS3 ICentre de Pharmacologic Unique Applique a la Dermatologie, Nice, 2Galderma R&D, Sophia Antipolis, France, and 3Galderma R&D Inc, Cranbury New Jersey

ABSTRACT Background: Adapalene is a naphthoic acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris. Objective: This study assessed the cumulative irritation potential of adapalene gel (0.1%) and adapalene cream (0.1%) compared with that of erythromycin (4%)/tretinoin (0.025%) solution, erythromycin (4%)/tretinoin (0.025%) gel, erythromycin (2%)/isotretinoin (0.05%) gel, and white petrolatum (negative control). Methods: This was a single-center, randomized, controlled, investigator-blinded, intraindividual comparison study in healthy subjects with normal skin. The cumulative irritation assay (patch test) was used to assess the potential for irritation (including erythema) of the treatments. Each subject received all study treatments, randomly applied under occlusion (patch), to sites on either side of the midline on the mid-thoracic area of the back. All patches were applied to the same sites throughout the study, unless the degree of reaction to the treatment or adhesive necessitated removal. For 3 weeks, each test material was applied daily, Monday through Friday, for -24 hours; the Friday patches were left in place over the weekend for -72 hours. Results: All 36 subjects (26 men, 10 women; age, 18-49 years [mean, 30 years]) completed the study. In the course of the study, all subjects had 21 application discontinued prematurely on 21 site due to intolerance. There were no discontinuations with white petrolaturn. All erythromycin/tretinoin gel patches were discontinued at day 10; 35 of 36 erythromycin/isotretinoin gel patches were discontinued at day 9; and 35 of 36 erythromycin/ tretinoin solution patches were discontinued at day 11 or day 17. The adapalene products, although slightly more irritating (mean cumulative irritation index, 0.25-l) than white petrolatum, were significantly less irritating than the erythromycin/tretinoin and erythromycin/ isotretinoin products (P < 0.01). Accepted for publication December 13, 2000. Printed in the USA. Reproduction

0149-2918/01/$19.00

in whole or part is not permitted

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CLINICAL THERAPEUTIC9

Conclusions: Adapalene gel and cream were well tolerated, with possible benefits for compliance. Their low irritation potential should be considered when prescribing a topical retinoid for the treatment of acne vulgaris. Key words: adapalene, erythromycin, tretinoin, isotretinoin, acne vulgaris. (C/in Thel: 2001;23:205-212)

INTRODUCTION Adapalene* is a naphthoic acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne in both gel and vulgaris. Is2 Adapalene cream formulations has been shown to be significantly better tolerated than several tretinoin (retinoic acid) formulations, including tretinoin in a microsphere ge1.3-6 This study compared the cumulative irritation potential of adapalene gel (0.1%) and cream (0.1%) with that of erythromytin (4%)/tretinoin (0.025%) solution,+ erythromycin (4%)/tretinoin (0.025%) gel,t and erythromycin (2%)/isotretinoin (0.05%) gel.5 The cumulative irritation assay (patch test) used in this study is designed to assess the irritation potential of topically applied materials. It measures irritation resulting from direct damage to epidermal cells and not from an immunologic (allergic) mechanism.7~8 Results of this assay are widely accepted to be excellent indicators of irritation.9

*Trademark: Differin@ (Galderma Laboratories, Inc, Fort Worth, Texas). +Trademark: Akne-mycin Plus@ (Healthpoint, Fort Worth, Texas). *Trademark: Erylik@ (Laboratoires Biorga, Trappes, France). “Trademark: Isotrexina (Stiefel Laboratories Ltd. High Wycombe, United Kingdom).

206

SUBJECTS

AND METHODS

Study Design This was a single-center, randomized, controlled, investigator-blinded, intraindividual comparison study in healthy subjects with normal skin. All subjects gave their written informed consent. All subjects received all study treatments: adapalene gel and cream, erythromycin/ tretinoin solution and gel, erythromycin/ isotretinoin gel, and white petrolatum (negative control). All treatments were commercially available formulations used at the approved concentrations and applied at either 0.2 mL or 0.2 g per patch, depending on the formulation. All treatments were applied under occlusion (patch) to sites on either side of the midline on the mid-thoracic area of the back. For 3 weeks, each test material was applied daily, Monday through Friday, for -24 hours; the Friday patches were left in place over the weekend for -72 hours. All patches were applied to the same sites throughout the course of the study, unless the degree of reaction to the treatment or adhesive necessitated their removal. Assessment of Irritation Irritation (erythema and other local skin reactions) was assessed 30 minutes after removal of the patches. Subjects’ backs were photographed before each assessment. The following scale was used to assess erythema: 0 = no reaction; 0.5 = barely visible erythema; 1 = mild erythema; 2 = moderate erythema; and 3 = severe erythema. Other cutaneous reactions, including adhesive reactions, occurring around test sites were noted.

C. QUEILLE-ROUSSEL

ET AL.

If grade 3 erytbema occurred in relation to any study treatment on any site, application was discontinued at that site and the last score was carried forward. If an irritation reaction related to the adhesive prohibited application of a patch to any site, all sites were discontinued in that subject. However, the subject was not discontinued from the study unless the investigator (a board-certified dermatologist) reviewed the subject’s skin and judged there to be a safety concern. In this case, an adverse event form was completed.

Safety and Tolerability Assessment Cutaneous tolerability was assessed using a cumulative irritation index9 (CII) for each treatment and subject. This was calculated by dividing the sum of the erythema scores by the number of assessments. The following conventions were applied in calculating the CII. The baseline score (day 0) was excluded from the calculation. If the erythema reaction was 3 for any site or if product application was discontinued at a site for other severe intoler-

Table I. Demographic

ance, a score of 3 was imputed for the remaining readings (last observation carried forward). CII values were submitted to analysis of variance, with effects for subject, zone, and product. Individual CII values were averaged across subjects to obtain a mean CII (MCII) for each treatment. MCI1 values were translated into an irritation classification as follows: co.25 = nonirritating; from 0.25 to
RESULTS Thirty-six subjects (26 men, 10 women) aged between 18 and 49 years (mean age, 30 years) entered and completed the study (Table I). No interfering drug therapies were reported to the investigator. Figure 1 shows the back of 1 subject on day 11. Figure 2 shows the number of premature discontinuations of product application

and baseline characteristics

of study subjects (N = 36).

Age,Y Mean Minimum Maximum Sex, no. (%) Male Female White race, no. (%) Skin phototype,* no. (%) II III IV

30

18 49 26 (72.2) 10 (27.8) 36 (100)

5 (13.9) 30 (83.3) 1 (2.8)

*From:FitzpatrickTB. Ultraviolet induced pigmentarychanges: Benefitsand hazards. In: Honigsmann H, Sting1 G, eds. Therapeufic Photomedicine.

Basel, Switzerland:

Karger;

1986:287&2879.

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CLINICAL THERAPEUTICS”

Erythromycini Tretinoin Solution

Erythromycin/ lsotretinoin Gel

Erythromycin/ Tretinoin Gel

Adapalene

White Petrolatum

Gel

Adapalene

Figure 1. Representative

results of the application

of the 6 study treatments

Cream

at day 11.

* Adapalene gel Adapalene cream 0 ErythromyciMtretinoin solution * Erythromycin/tretinoin gel n Erythromycinlisotretinoin gel n White petrolatum l

35 rn .-g 30 5 = 25 .& E g 20 g 15 6 6 10 z 5

0

1

2

3

4

7

8

9

10

11

14

15

16

17 18

21

Day

Figure 2. Number of premature discontinuations course of the study.

208

of application

of each treatment over the

C. QUEILLE-ROUSSEL ET AL.

4

* Adapalene gel 0 Adapalene cream l Erythromycinktinoin solution l ErythromycinMetinoin gel n Erythromycin/isotretinoin gel n White petrolatum

1

0

1

2

3.4.7

a

9

.lO.

11

14.15.

16.17.

ia

21.

Day

Figure 3. Cumulative irritation index (CII) ratings (mean + SD) for each treatment the course of the study. over the course of the study. Treatment discontinuations were not always related to an erythema score of 3; in 39% of discontinuations, the cause was other clinical aspects of severe intolerance, such as epiderma1 peeling with subsequent superficial erosion (without severe erythema). Three of the 6 tested formulations were discontinued in the second week of the study because of epidermal peeling: erythromyciti tretinoin gel (all applications stopped at day lo), erythromycin/isotretinoin gel (applications stopped in 35 of 36 subjects at day 9; the remaining subject completed the study), and erytbromycin/tretinoin solution (applications stopped in 35 of 36 subjects at day 11; the remaining subject stopped at day 17). Thirty-five of 36 subjects completed all applications of adapalene gel (1 subject discontinued at day 4), and 32 of 36

over

subjects completed all applications of adapalene cream (1 subject stopped at day 8 for an eczema-like reaction, and 3 subjects stopped at day 18). After completion of the study, the subject with the eczema-like reaction was challenged with adapalene and had a negative result on the patch test.

Cumulative

Irritation

The CIIs for each treatment over time are illustrated in Figure 3. The MCIIs for the 6 treatments are listed in Table II and presented graphically in Figure 4. Table III shows the results of the statistical comparison of the MCIIs using the Tukey multiplecomparison test. Erythromycin/tretinoin solution, erythromycin/tretinoin gel, and erythromycinlisotretinoin gel were significantly more irritating than white petrolatum,

CLINICAL THERAPEUTICS”

Table II. Mean cumulative irritation index* (MCII) for each study treatment, order of irritation. Product

MCI1 + SD

White petrolatum Adapalene gel Adapalene cream Erythromycinkretinoin Erythromycinkotretinoin Erythromycinltretinoin

0.13 0.37 0.41 2.19 2.29 2.31

solution gel gel

f + + + + +

in ascending

Classification

0.14 0.43 0.47 0.29 0.39 0.11

Nonirritating Slightly irritating Slightly irritating Very irritating Very irritating Very irritating

*The CII was calculated by dividing the sum of the erythema scores for each treatment by the number of assessments. Erythema was rated using the following scale: 0 = no reaction; 0.5 = barely visible erythema;

1=

mild erythema; 2 = moderate erythema; and 3 = severe erythema.

I Erythromycin/tretinoin gel n Erythromycinkotretinoin gel 0 Erythromycinltretinoin solution I Adapalene cream q Adapalene gel q White petrolatum

3

2

g

1

T

T

0

Study Treatment Figure 4. Mean cumulative

irritation

index (MCII) ratings for each study treatment.

adapalene gel, and adapalene cream. Analysis of variance found a statistically significant effect for the products (P < O.OOl),zones (P = O.OOS),and subjects (P < 0.001). A total of 21 adverse events were reported during the study, most of them ear, nose, and throat complaints or headache.

210

None of these adverse events were judged to be related to study treatment.

DISCUSSION The 2 formulations containing tretinoin and the 1 formulation containing isotret-

C. QUEILLE-ROUSSEL

ET AL.

Table III. Results of the Tukey multiple-comparison test for the mean cumulative irritation indexes of the 6 study treatments, performed at the 1% and 5% levels of significance. Ery/Tre

White Petrolatum

Gel

Adapalene Gel

Adapalene Cream

EryAso Gel

Ery/Tre gel

1St00

White petrolatum Adapalene gel

0.000 0.000

1.OOo 0.006

1.000

Adapalene cream

0.000

0.001

0.991

1.000

Ery/Iso gel

1.000

0.000

0.000

0.000

1.000

Erymre solution

0.479

0.000

0.000

0.000

0.668

EqvTre = erythromycinkretinoin;

inoin

were

when applied

very poorly

Eryko

tolerated

under occlusion.

Ery/Tre Solution

1.ooo

= erythromycidsotretinoin.

locally

Only 1 sub-

ject received all applications of the tretinoin-containing solution, whereas no subject received all applications of the tretinoin-containing gel or the isotretinoincontaining gel. Specifically, epidermal peeling occurred during the second week of application, and the unprotected dermis at the site of application became highly irritated, resulting in discontinuation of application of the implicated products. The 2 formulations of adapalene were not associated with irritation, with 35 and 32 subjects completing all applications of the gel and cream, respectively. Moreover, adapalene has been shown not to break down in the presence of lighti and has demonstrated anti-inflammatory activity”; tretinoin was inactive under the same assay conditions. I1

CONCLUSIONS In this study, adapalene gel and adapalene cream were better tolerated, both statistically and clinically, than erythromycin/ tretinoin solution, erythromycin/tretinoin

gel, and erythromycin/isotretinoin gel. Their low irritation potential should be considered when prescribing a topical retinoid for the treatment of acne vulgaris.

REFERENCES 1. Verschoore M, Langner A, Wolska H, et al. Vehicle controlled study of CD 271 lotion in the topical treatment of acne vulgaris. J Invest Dermatol. 1993;100:221-223. 2. Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol. 1991;124:368-371. 3. Verschoore M, Poncet M, Czemielewski J, et al. Adapalene 0.1% gel has low skinirritation potential. J Am Acad Dermatol. 1997;36:S1044109. 4. Caron D, Sorba V, Kerrouche N, Clucas A. Split-face comparison of adapalene 0.1% gel and tretinoin 0.025% gel in acne patients. J Am Acad Dermatol. 1997;36: SllO-s112. 5. Cunliffe WJ, Caputo R, Dreno B et al. Clinical efficacy and safety comparison of

211

CLINICAL THERAPEUTICS’

adapalene gel and tretinoin gel in the treatment of acne vulgaris. Europe and U.S. multicenter trials. J Am Acad Dermatol. 1997;36:S126-S134.

8. Phillips L II, Steinberg M, Maibach HI, Akers WA. A comparison of rabbit and human skin response to certain irritants. Toxicol Appl Phanacol. 1972;21:369-382.

Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: A multicenter trial. J Am Acad Dermatol. 1996;34:482485.

9. Berger RS, Bowman JP. A reappraisal of the 21-day cumulative irritation test in man. J Toxic01 Cutaneous Ocul Toxicol. 1982;1:109-115.

Lanman BM, Elvers EB, Howard CJ. The role of human patch testing in a product development program. Presented at: Joint Conference on Cosmetic Sciences; April 21-23, 1968; Washington, DC.

Address Drive,

212

correspondence

Suite 1, Cranbury,

to: Michael Baker, New Jersey 085 12.

10. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol. 1993;6(Suppl 1):61-69. and 11. Shroot B, Michel S. Pharmacology chemistry of adapalene. J Am Acad Dermatol. 1997;36:S96-S103.

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Inc, 5 Cedar

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