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

Abstract

Background: Metronidazole 0.75% gel and azelaic acid 15% gel are commonly used to treat rosacea. Irritation is a common side effect.

Objective: To assess the cumulative irritation potential of metronidazole 0.75% gel and azelaic acid 15% gel.

Methods: Metronidazole 0.75% gel, azelaic acid 15% gel, and a white petrolatum negative control were applied under occlusive conditions to the upper back of a total of 33 healthy subjects. There were twelve 24-hour applications (4 times a week) and three 72-hour applications on weekends during a 3-week period. Skin reactions (erythema score [ or -] other local reaction) were assessed within 15 to 30 minutes of removal of the products.

Results: The mean cumulative irritancy index of metronidazole 0.75% gel was significantly lower than that of azelaic acid 15% gel and not significantly higher than the negative control product. There was increasing cumulative irritancy with azelaic acid; no cumulative irritancy was seen for either metronidazole or white petrolatum.

Conclusion: Metronidazole 0.75% gel is less irritating in sustained use than azelaic acid 15% gel.

Introduction

Topical medications, such as metronidazole and azelaic acid, are effective treatments for rosacea (1) and can enhance the efficacy of oral antibiotics. (2,3) One limitation to topical treatment of rosacea is irritation--including dry skin, redness, stinging, and burning. (4,5) Because these irritation reactions can exacerbate the inflammatory component of rosacea, minimizing the irritation potential of topical treatment may be beneficial.

Few studies have been done to compare the irritancy of rosacea medications. Overall, metronidazole has shown a low incidence of adverse events and unwanted side effects. (6) In a comparative trial, symptoms of burning, stinging, and pruritus were less frequent in patients treated with topical metronidazole (7% of subjects) than in those who were treated with topical azelaic acid (26% of subjects). (7)

A cumulative irritation test is a widely-accepted way of determining the irritation potential of certain substances. (8-10) These irritant reactions are the result of direct damage to epidermal cells of the skin and have no immunologic component. After initial and repeated contact with the substance, the skin gradually becomes erythematous and may demonstrate drying, cracking, crusting, and erosion. Vesicles and edema may also develop after repeated exposure to the irritant. (8) In this study, we conducted a single center, active- and negative-controlled, randomized, investigator-blinded, intra-individual study to compare the irritation potential of metronidazole 0.75% gel and azelaic acid 15% gel using a 21-day cumulative irritation patch test.

Methods

Subjects

A total of 33 healthy subjects, 31 females and 2 males between the ages of 20 and 75, were enrolled. Of the 33 subjects enrolled into the study, 31 (94%) completed the study. Two subjects (6%) discontinued. One of the discontinued subjects withdrew due to an adverse event and the other requested withdrawal because of a family emergency. Inclusion criteria required that subjects have a skin photo-type between I and IV on the Fitzpatrick scale (11) so as not to interfere with the reading of skin reactions. Females of childbearing potential were required a negative urine pregnancy test and practice of an effective method of contraception during the study. All subjects had to be willing to comply with the requirements of the frequent visit schedule and concomitant therapy prohibitions and signed a written informed consent.

Subjects who met any of the following criteria were excluded from the study: were pregnant, nursing or planning to become pregnant during the course of the study; had any surgical or medical condition (ie, history of atopic dermatitis or psoriasis) which, in the judgment of the investigator, might have put the subject at risk or interfered with interpretation of the study results; had any known allergies to any of the ingredients of the products or to adhesive tape; had scars, moles, hairs, sunburn, abnormal pigmentation of the skin, or other blemishes in the test area which would have interfered with grading; had participated in another investigational drug or device research study within 3 months or inclusion; and had not respected the washout periods for topical (metronidazole or azelaic acid, 4 weeks; other topicals, 1 week) and/or systemic treatments (corticosteroids or non-steroidal anti-inflammatory drugs, 2 weeks; oral metronidazole, 3 months).

Each subject received instructions as to specific requirements to follow while participating in the study. During the study, the subjects were to avoid exposure to the sun (no sunbathing or other excessive exposure or UV irradiation), use of any cosmetics on the study sites, and baths and showers of the upper back. Participation in any other clinical trial was prohibited during the course of the study.

Design

FDA-approved formulations of metronidazole 0.75% gel (MetroGel[R], Galderma Laboratories, L.P., Fort Worth, TX) and azelaic acid 15% gel (Finacea[TM] Gel, Berlex Laboratories, Montville, NJ) were used at the approved doses. A 0.2 g amount of each of the 2 products and white petrolatum was applied under occlusion to 3 pre-defined, randomized sites (2 cm X 2 cm) that were selected on the upper back of each subject, avoiding any moles, hairs, or non-flat areas. The occlusive dressings were replaced approximately every 24 hours on Monday through Thursday of each week for the 3 weeks of the study. The Friday applications were left in place over the weekend (approximately 72 hours). The Friday evening applications were left in place over the weekend (approximately 72 hours). Each patch site on each subject's back was assessed for erythema and other local cutaneous irritation prior to the initial patch application, and again at every study visit approximately 15 to 30 minutes after patch removal, prior to the following patch application.