Cumulative irritation potential of metronidazole gel compared to azelaic acid gel after repeated applications to healthy skin

Journal of Drugs in Dermatology, Nov-Dec, 2005 by Kristin Ziel, Christopher B. Yelverton, Rajesh Balkrishnan, Steven R. Feldman

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Both the product vehicle and mechanism may play roles in the irritancy potential. The metronidazole preparation used in this study is 95% water (personal communication, Cris Osborn, Galderma Laboratories). Though the primary vehicles for metronidazole and azelaic acid were not included among our controls, petrolatum was used because it is generally thought to be non-irritating. Therefore, we are unable to conclude with absolute certainty what component(s) in the azelaic acid gel are more irritating based on this study, and further research may be warranted.

The sample size utilized in this study was small compared to those used in clinical trials evaluating the efficacy and safety of these compounds. However, an n > 30 is generally considered to be a number sufficient to constitute a normal distribution, and our results do not directly conflict with the results of those trials. While the cumulative irritation assay is validated, other potential limitations include variation in the skin irritation response, and intra- and inter-individual variability. (13,14) The severe erythema scores seen in the 5 subjects that dropped out could indicate several things. As no pre-screening patch tests were conducted to ensure that each subject was not allergic to the ingredients of the medications, we cannot definitively say that these scores indicate irritation only and not preexisting sensitization to a component of the azelaic acid gel. Neither can we rule out the induction of sensitization without performing a patch test at an untreated site following the 3-week induction phase. Another limitation is that the irritancy test system is done on the back of healthy volunteers, not the faces of patients with rosacea. However, this is not a major limitation as the validity of the methodology has been well-documented and is suitable for assessing the irritancy of topical agents used on acneiform facial eruptions. (10,15)

Disclosure: This study was funded by Galderma Laboratories, L.P.

References

1. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999;40(6 Pt 1):961-5.

2. Altinyazar H, Koca R, Tekin N, Esturk E. Adapalene vs. metronidazole gel for the treatment of rosacea. Int J Dermatol. 2005;44(3):252.

3. Ratnavel R. Rosacea. eMedicine. June 18, 2003. Available from: www.emedicine.com/derm/topic377.htm. Accessed November 3, 2004.

4. Gupta A, Chaudhry M. Topical metronidazole for rosacea. Skin Therapy Lett. 2002;7(1).

5. Drugs Approved by the FDA, Drug Name: Finacea (azelaic acid) Gel, 15%. June 29, 2004. Available from: www.centerwatch.com/patient/drugs/dru818.html. Accessed November 3, 2004.

6. McClellan KJ, Noble S. Topical metronidazole. A review of its use in rosacea. Am J Clin Dermatol. 2000;1(3):191-9.

7. Elewski BE, Fleischer AB, Jr., Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003;139(11):1444-50.

8. Philips L, Steinberg M, Maibach HI, Akers WA. Comparison of rabbit and human skin response to certain irritants. Toxicol Appl Pharmacol. 1972;21:369.