Limitations of Use

Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

5.1 Hypersensitivity

Hypersensitivity reactions, including cases of angioedema, eye swelling, facial swelling, dyspnea, urticaria, and adverse skin reactions, have been reported during post marketing surveillance.

Avoid the use of azelaic acid gel in patients with known hypersensitivity to any component of the gel. If hypersensitivity develops during treatment, discontinue azelaic acid gel and institute appropriate therapy.

5.2 Skin Reactions

Skin irritation (i.e. pruritus, burning or stinging) may occur during use of azelaic acid gel, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists, discontinue treatment and institute appropriate therapy.

There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

5.3 Eye and Mucous Membranes Irritation

Azelaic acid gel has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If azelaic acid gel comes in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists [see Adverse Reactions (6.2)].

5.4 Exacerbation of Asthma

Worsening of asthma has been reported in patients using azelaic acid formulations including azelaic acid gel. Consult a physician if asthma is exacerbated with use of azelaic acid gel.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In two vehicle-controlled and one active-controlled U.S. clinical trials, treatment safety was monitored in 788 subjects who used twice-daily azelaic acid gel for 12 weeks (N=333) or 15 weeks (N=124), or the gel vehicle (N=331) for 12 weeks. In all three trials, the most common treatment-related adverse events were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). In the active-controlled trial, overall adverse reactions (including burning, stinging/tingling, dryness/tightness/scaling, itching, and erythema/irritation/redness) were 19.4% (24/124) for azelaic acid gel compared to 7.1% (9/127) for the active comparator gel at 15 weeks.

In patients using azelaic acid formulations, the following adverse events have been reported: worsening of asthma, vitiligo, depigmentation, small depigmented spots, hypertrichosis, reddening (signs of keratosis pilaris) and exacerbation of recurrent herpes labialis.

6.2 Postmarketing Experience

The following adverse reactions have been identified post approval of azelaic acid gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure:

Eyes: iridocyclitis upon accidental exposure of the eyes to azelaic acid gel.

Hypersensitivity: angioedema, eye swelling, facial swelling, urticaria.

Respiratory: worsening of asthma, dyspnea, wheezing.

Skin reactions: application site rash.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of azelaic acid gel have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of azelaic acid gel did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

12.1 Mechanism of Action

The mechanism(s) by which azelaic acid interferes with the pathogenic events in rosacea are unknown.

12.2 Pharmacodynamics

The pharmacodynamics of azelaic acid in association with the treatment of rosacea are unknown.

12.3 Pharmacokinetics

The percutaneous absorption of azelaic acid after topical application of azelaic acid gel could not be reliably determined. Mean plasma azelaic acid concentrations in rosacea subjects treated with azelaic acid gel twice daily for at least 8 weeks are in the range of 42 ng/mL to 63.1 ng/mL. These values are within the maximum concentration range of 24.0 ng/mL to 90.5 ng/mL observed in rosacea subjects treated with vehicle only. This indicates that azelaic acid gel does not increase plasma azelaic acid concentration beyond the range derived from nutrition and endogenous metabolism.

In vitro and human data suggest negligible cutaneous metabolism of 3H-azelaic acid after topical application of 20% azelaic acid cream. Azelaic acid is mainly excreted unchanged in the urine, but undergoes some ß-oxidation to shorter chain dicarboxylic acids.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year dermal mouse carcinogenicity study, azelaic acid pre-foam emulsion was administered twice daily to CD-1 mice at topical doses of 5%, 15%, and 30% (500, 1500, and 3000 mg/kg/day azelaic acid). No drug-related tumors were noted at concentrations up to 30% azelaic acid (396 times the MRHD based on AUC comparison).

Azelaic acid was not mutagenic or clastogenic in a battery of in vitro [Ames assay, HGPRT in V79 cells (Chinese hamster lung cells), and chromosomal aberration assay in human lymphocytes] and in vivo (dominant lethal assay in mice and mouse micronucleus assay) genotoxicity tests.

Oral administration of azelaic acid at dose levels up to 2500 mg/kg/day (162 times the MRHD based on BSA comparison) did not affect fertility or reproductive performance in male or female rats.

How Supplied

Azelaic acid gel, 15% is a white to yellowish white opaque gel supplied in a 50 g tube (NDC 51672-1389-3).

Storage and Handling

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Administration Instructions

• For topical use only.
• Before applying azelaic acid gel, cleanse affected area(s) with a very mild soap or a soapless cleansing lotion and pat dry with a soft towel.
• Wash hands immediately following application of azelaic acid gel.
• Cosmetics may be applied after the application of azelaic acid gel has dried.
• Avoid the use of occlusive dressings or wrappings.
• Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents [see Dosage and Administration (2)].

Hypersensitivity

• If allergic reactions occur, discontinue use and consult their healthcare provider [see Warnings and Precautions (5.1)].

Skin Irritation

• Skin irritation (e.g., pruritus, burning, or stinging) may occur during use of azelaic acid gel, usually during the first few weeks of treatment. If irritation is excessive or persists, or allergic reactions occur, discontinue use and consult your physician [see Warnings and Precautions (5.2)].

Hypopigmentation

• Advise patients to report abnormal changes in skin color to their healthcare provider [see Warnings and Precautions (5.2)].

Eye and Mucous Membranes Irritation

• Avoid contact with the eyes, mouth and other mucous membranes. If azelaic acid gel comes in contact with the eyes, wash the eyes with large amounts of water and consult their healthcare provider if eye irritation persists [see Warnings and Precautions (5.3)].

Exacerbation of Asthma

• Advise patients to report any worsening of asthma to their healthcare provider [see Warnings and Precautions (5.4)].