Active Ingredient: Each gram of AZELEX® contains azelaic acid......... 0.2 gm (20% w/w).

Inactive Ingredients: cetearyl octanoate; glycerin; glyceryl stearate and cetearyl alcohol and cetyl palmitate and cocoglycerides; PEG-5 glyceryl stearate; propylene glycol; and purified water. Benzoic acid is present as a preservative.

Pharmacokinetics: Following a single application of AZELEX® Cream to human skin in vitro, azelaic acid penetrates into the stratum corneum (approximately 3 to 5% of the applied dose) and other viable skin layers (up to 10% of the dose is found in the epidermis and dermis). Negligible cutaneous metabolism occurs after topical application. Approximately 4% of the topically applied azelaic acid is systemically absorbed. Azelaic acid is mainly excreted unchanged in the urine but undergoes some β-oxidation to shorter chain dicarboxylic acids. The observed half-lives in healthy subjects are approximately 45 minutes after oral dosing and 12 hours after topical dosing, indicating percutaneous absorption rate-limited kinetics.

Azelaic acid is a dietary constituent (whole grain cereals and animal products), and can be formed endogenously from longer-chain dicarboxylic acids, metabolism of oleic acid, and ψ-oxidation of monocarboxylic acids. Endogenous plasma concentration (20 to 80 ng/mL) and daily urinary excretion (4 to 28 mg) of azelaic acid are highly dependent on dietary intake. After topical treatment with AZELEX® Cream in humans, plasma concentration and urinary excretion of azelaic acid are not significantly different from baseline levels.

General:

If sensitivity or severe irritation develop with the use of AZELEX® Cream, treatment should be discontinued and appropriate therapy instituted.

Information for patients:

Patients should be told:

1. To use AZELEX® Cream for the full prescribed treatment period.
2. To avoid the use of occlusive dressings or wrappings.
3. To keep AZELEX® Cream away from the mouth, eyes and other mucous membranes. If it does come in contact with the eyes, they should wash their eyes with large amounts of water and consult a physician if eye irritation persists.
4. If they have dark complexions, to report abnormal changes in skin color to their physician.
5. Due in part to the low pH of azelaic acid, temporary skin irritation (pruritus, burning, or stinging) may occur when AZELEX® Cream is applied to broken or inflamed skin, usually at the start of treatment. However, this irritation commonly subsides if treatment is continued. If it continues, AZELEX® Cream should be applied only once-a-day, or the treatment should be stopped until these effects have subsided. If troublesome irritation persists, use should be discontinued, and patients should consult their physician.

Carcinogenesis, mutagenesis, impairment of fertility:

Azelaic acid is a human dietary component of a simple molecular structure that does not suggest carcinogenic potential, and it does not belong to a class of drugs for which there is a concern about carcinogenicity. Therefore, animal studies to evaluate carcinogenic potential with AZELEX® Cream were not deemed necessary. In a battery of tests (Ames assay, HGPRT test in Chinese hamster ovary cells, human lymphocyte test, dominant lethal assay in mice), azelaic acid was found to be nonmutagenic. Animal studies have shown no adverse effects on fertility.

Pregnancy:

Nursing Mothers:

Equilibrium dialysis was used to assess human milk partitioning in vitro. At an azelaic acid concentration of 25 μg/mL, the milk/plasma distribution coefficient was 0.7 and the milk/buffer distribution was 1.0, indicating that passage of drug into maternal milk may occur. Since less than 4% of a topically applied dose is systemically absorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant change from baseline azelaic acid levels in the milk. However, caution should be exercised when AZELEX® Cream is administered to a nursing mother.

Pediatric Use:

Safety and effectiveness in pediatric patients under 12 years of age have not been established.

Geriatric Use:

Clinical studies of AZELEX® Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.