SUPPORTED BY AN EDUCATIONAL GRANT FROM GALDERMA LABORATORIES, INC.

I I

Adapalene 0.1% gel is better tolerated than tretinoin 0.025% gel in acne patients Alan Clucas, MRCP, Mich~le Verschoore, MD, Val6rie Sorba, PharmD, Michel Poncet, MS, Mike Baker, BS, and Janusz Czernielewski, MD Sophia Antipolis, France

Background: Adapalene is a new naphthoic acid derivative developed for the topical treat- ment of ache ~lgaris. Objective: We describe the results of a combined safety analysis of two multicenter trials conducted in the U.S. and Europe in which adapalene 0.1% gel was compared with tretinoin 0.025% gel in the treatment of mild to moderate ache vulgaris. Methods: A total of 591 ache patients were enrolled in these investigator-masked, random- ized, controlled, parallel group studies. In the two studies, each patient was randomly assigned to receive topical adapalene 0.1% gel or tretinoin 0.025% gel once daily at bedtime, for 12 weeks. In addition to assessments of efficacy and facial s~n tolerance, data on obverse events were recorded at each visit or at any other time the patient reported problems. We extracted data concerning adverse reactions (i.e., adverse events judged to be related to the study treat- ment) from both studies and combined the results to obtain a global comparison of safety of the two products. Results: A total of 15 of 296 patients (5.1%) reported 19 adverse reactions in the adapalene- treated groups, compared with 27 of 295 patients (9.1%) reporting 39 adverse reactions in the tretinoin-treated groups (p < 0.05). The number of patients discontinuing the study because of adverse events was approximately twice as low with adapalene (1.3% compared with 2.4%). Most adverse reactions for both products were related to skin irritation. No sys- temic adverse reactions were reported. Conclusion: The results of these two multicenter clinical studies indicate that adapalene gel is better tolerated than tretinoin gel. (J Am Acad Dermatol 1997;36:$116-8.)

Adapalene is a new chemical entity, developed for the topical treatment of acne vulgaris, Pharma- cologic and biochemical studies have demonstrated modulation of cell proliferation, keratinization, and antiinflammatory activity. 1, 2 Previous studies 3 have demonstrated that adapalene formulated in a lotion, gel, or cream had low irritation potential when applied to healthy human skin. This was later confirmed in studies conducted in patients with ache.4, 5

The purpose of the present publication is to describe the overall results of the safety of adapalene 0.1% gel (Differin® gel, Galderma Laboratories) compared with tretinoin 0.025% gel (Retin-A® gel,

From CIRD Galderma, Sophia Antipolis. Reprint requests: Alan Clucas, MRCP, CIRD Galderma, 635 Route des

Lucioles, 06902 Sophia Antipolis Cedex, France.

Copyright © 1997 by the American Academy of Dermatology, Inc.

0190-9622/97/$5.00 + 0 16/0/81183

Ortho Pharmaceutical Corporation/Janssen-Cilag Laboratories) based on analysis of two large multi- center trials conducted in the U.S. and Europe in pa- tients with mild to moderate ache vulgaris.

PATIENTS AND METHODS

Before initiation of the studies, the protocols were ap- proved by independent ethics committees, and written informed consent was obtained from each patient. Pa- tients were not to have used any interfering topical or systemic therapy that could affect the test results before initiation of treatment.

A total of 323 patients (172 males and 151 nonpregnant females) in the U.S. and 268 (143 males and 125 nonpregnant females) in Europe, from 12 to 30 years old, took part in these studies. Patients with mild to moderate acne (Burke and Cunliffe grade: 1 to 5, inclusive) were included. They had at least 20 noninflammatory lesions and I0 inflammatory lesions on the face. Patients were assigned according to their order of entry to the study in each center, following a computer-generated randomiza-

S l 1 6

Journal of the American Academy of Dermatology Volume 36, Number 6, Part 2 Clucas et aL S117

T a b l e I. Overview of safety o f adapalene and tretinoin in acne trials. Combined U.S. (C-89-32) and

European (CR 89064) multicenter studies

Adapalene 0.1% gel I Tretinoin 0.025% gel I

Study trealment (n = 296) I (n = 295)

Cutaneous adverse reactions:* - skin irritation (erythema, dermatitis, rash) - d r y sk in

- skin discomfort, pruritus - acne flare - infection, herpes - sunburn

Subtotal cutaneous adverse reactions Noncutaneous adverse reactions Total adverse reactions Number of patients reporting adverse reactions

6 (2.0%) 12 (4.1%) 4 (1.3%) 13 (4.4%) 6 (2.0%) 10 (3.4%) 3 (1.0%) 2 (0.7%) o (0%) 1 (0.3%) 0 (0%) l (0.3%)

19 39 0 (0%) 0 (0%)

19 39 15 (5.1%)? 27 (9.1%)

*Adverse reactions are defined as adverse events judged to be probably or definitely related to therapy by the investigator, independent of quan- titative evaluation of signs and symptoms required by the protocol. ?p value <0.05, significant difference for comparison of adapalene versus trelinoin by CMH test stratified by study.

tion sequence, to one of two treatment groups (adapalene 0.1% gel or tretinoin 0.025% gel). They were instmcted to apply a light film of the study drug to the affected area once daily at bedtime for 12 weeks. Patients were allowed to follow their normal washing procedure and use mois- turizers if required (use of the latter was limited to a few patients equally distributed between the two treatment groups).

Efficacy measurements (lesion counts and global severity) and routine skin safety evaluations (erythema, scaling, dryness, pruritus, burning, and oiliness) are described in detail elsewhere. 6, ? Information on adverse events was collected by the investigating physician at each visit (after 2, 4, 8, and 12 weeks of therapy) or at any other time the patient reported problems. For each adverse event, information such as onset, duration, severity, action taken, and outcome was reported on a specific case report form. In addition, the physician was requested to judge the causal relation between the event and treatment on a 5-point scale (from definitely not Mated to definitely re- lated),

D A T A A N A L Y S I S

Many non-study-related events were recorded in the two trials (e.g., minor colds and influenza), as expected during a 12-week observation period of a large popula- tion. We, therefore, limited our analysis to events that were judged to be probably or definitely related to the study treatment. The combined incidence of each type of event was calculated for the entire patient population, and the incidence of any event in the two treatment groups was compared by the Cochran-Mantel-Haenszel (CMH) test

T a b l e I I . Patients discontinuing treatment due to adverse events (dermatologic reasons)

Number of cases

Adapalene 0.1% gel (n = 296)

Tretinoin 0.025% gel

(n = 295)

Ache flare 2 1 Skin irritation 2 4 Dry skin 0 2 Total 4 (1.3%) 7 (2.4%)

stratified by study. Any p value below 0.05 was consid- ered a significant effect.

R E S U L T S

The incidence and description of adverse reac- tions to adapalene and tretinoin are shown in Table I. Most were related to skin irritation, discomfort, or dryness, all of which occurred less frequently with adapalene than tretinoin. No systemic adverse reac- tions were reported for either drug.

There were fewer patients reporting adverse reac- tions to adapalene (5.1%) than tretinoin (9.1%); this difference was statistically significant (p < 0.05). The number of adverse reactions for adapalene (n = 19) was also approximately one half that for tretinoin (n = 39).

Only slightly more than 1% of patients had to discontinue therapy with adapalene because of an adverse event, compared to slightly more than 2%

Journal of the American Academy of Dermatology Sl18 Clucas et aL June 1997

for tretinoin. Skin irritation was the most common reason (Table lI).

D I S C U S S I O N

The nature of the adverse reactions reported in the tretinoin-treated patients in these studies is similar to that in previous studies, i.e., mostly related to skin irritation. 8,9 The incidence may appear relatively low because of the way data were collected. Most cutaneous reactions were rated simply using specific evaluation scales 6, 7 and only clinically significant events were documented as adverse events.

The adverse reactions to adapalene were of the same type but of significantly lower frequency than for tretinoin. This confirms the lower irritation potential of adapalene demonstrated in previous studies in healthy volunteers 3 or acne patient volun- teers. 4 One explanation for the better tolerance of adapalene gel may be because the former is an aqueous formulation whereas the latter contains al- cohol. On the other hand, a study of the irritant ef- fects of adapalene in an alcoholic vehicle similar to tretinoin gel showed that it had a significantly lower irritation profile. 3

No systemic adverse reactions were reported for adapalene in either of the two studies described. This is not surprising because systemic absorption of the drug after topical application is low, 1°, 11 as con- finned by the absence of quantifiable plasma levels in a subset of patients in one of the trials. 7

Despite the lower incidence of cutaneous reac- tions, the efficacy of adapalene in these two studies was equal to or superior to that of trefirlOin. 6' 7

REFERENCES

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2. Hensby CN, Cavey D, Bouclier M, et al. The in vivo and in vitro antMnflammatory activity of CD271, a new retin- oid-like modulator of cell differentiation. In: Reichert U, Shroot B. Pharmacology and the skin: Pharmacology of relinoids in the skin. Basel: Karger, 1989;vol 3, 160-2.

3. Verschoore M, Poncet M, Czemielewski J, et al. Adapalene 0.1% gel has low skin irritation potential. J Am Acad Der- matol 1997;36:104-9.

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7. Cunliffe WJ. European multicentre study of adapalene versus tretinoin gel. Br J Dermatol 1996;$47:135.

8. Christiansen JV, Gadborg E, Ludvigsen K, et al. Topical tretinoin, vitamin A acid (Airol®) in acne vulgaris. Der- matologica 1974;148:82-9.

9. Mandy SA, Thome EG. A comparison of the efficacy and safety of tretinoin cream 0.025% and 0.05%. Advances in therapy 1990;7:94-9.

10. Caron D, Caron JC, Clucas A, et al. Absorption of adapalene after application of adapalene 0.1% gel in humans remains low even under conditions of maximised exposure. Clinical Dermatology 2000, 1996, Vancouver, May 28-31.

11. Caron D, Clucas A, Dunsire JP, et al. Radiolabelled ada- palene is poorly absorbed after topical application of ada- palene 0.1% gel. Clinical Dermatology 2000, 1996, Van- couver, May 28-31.