Azelaic Acid Gel

1 INDICATIONS AND USAGE Azelaic Acid Gel, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea. 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. Azelaic Acid Gel, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea ( 1 ). Limitations of Use Efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. ( 1 )

2 DOSAGE AND ADMINISTRATION Cleanse affected area(s) using only very mild soaps or soapless cleansing lotion and pat dry with a soft towel before application of Azelaic Acid Gel, 15%. Apply and gently massage a thin layer of Azelaic Acid Gel, 15% into the affected areas on the face twice daily (morning and evening). Wash hands immediately following application of Azelaic Acid Gel,15%. Cosmetics may be applied after the application of Azelaic Acid Gel,15% has dried. Reassess the diagnosis if no improvement is observed upon completing 12 weeks of therapy. Avoid the use of occlusive dressings or wrappings. Instruct patients to avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. For topical use. Not for oral, ophthalmic or intravaginal use. Apply a thin layer twice daily to affected area(s). ( 2 ) Use only very mild soaps or soapless cleansing lotion and pat dry with a soft towel before applying Azelaic Acid Gel, 15%. (2 ) Wash hands immediately following application. ( 2 ) Cosmetics may be applied after the application of Azelaic Acid Gel, 15% has dried. ( 2 ) Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. ( 2 ) For topical use. ( 2 ) Not for oral, ophthalmic or intravaginal use. ( 2 )

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity: Hypersensitivity reactions, including cases of angioedema, eye swelling, facial swelling, dyspnea, urticaria, and adverse skin reactions, have been reported. In case of known hypersensitivity to any component of the gel, avoid the use of Azelaic Acid Gel, 15%. If hypersensitivity develops, discontinue treatment and institute appropriate therapy. ( 5.1 ) Skin Reactions: Skin irritation (i.e. pruritus, burning or stinging) may occur, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists, discontinue treatment and institute appropriate therapy. ( 5.2 ) Hypopigmentation: Isolated cases of hypopigmentation occurred after azelaic acid use. Monitor patients with dark complexion for early signs of hypopigmentation ( 5.2 ) Eye and Mucous Membrane Irritation: Azelaic Acid Gel, 15% has been reported to cause irritation of the eyes. Avoid contact with the eyes and mucous membranes. ( 5.3 ) Exacerbation of Asthma: Consult a physician if asthma is exacerbated with Azelaic Acid Gel, 15% use. ( 5.4 ) 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,15% in patients with known hypersensitivity to any component of the gel. If hypersensitivity develops during treatment, discontinue Azelaic Acid Gel,15% and institute appropriate therapy. 5.2 Skin Reactions Skin irritation (i.e. pruritus, burning or stinging) may occur during use of Azelaic Acid Gel,15%, 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, 15% has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Azelaic Acid Gel, 15% 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,15%. Consult a physician if asthma is exacerbated with use of Azelaic Acid Gel,15%.

6 ADVERSE REACTIONS The most common adverse reactions are burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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,15% 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, 15% compared to 7.1%(9/127) for the active comparator gel at 15 weeks. Table 1: Adverse Events Occurring in ≥1% of Subjects in the Rosacea Trials by Treatment Group and Maximum Intensity* Azelaic acid gel, 15% N=457 (100%) Vehicle N=331 (100%) Mild N=99 (22%) Moderate N=61 (13%) Severe N=27 (6%) Mild N=46 (14%) Moderate N=30 (9%) Severe N=5 (2%) Burning/stinging/tingling 71 (16%) 42 (9%) 17 (4%) 8 (2%) 6 (2%) 2 (1%) Pruritus 29 (6%) 18 (4%) 5 (1%) 9 (3%) 6 (2%) 0 (0%) Scaling/dry skin/xerosis 21 (5%) 10 (2%) 5 (1%) 31 (9%) 14 (4%) 1 (<1%) Erythema/irritation 6 (1%) 7 (2%) 2 (<1%) 8 (2%) 4 (1%) 2 (1%) Contact dermatitis 2 (<1%) 3 (1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) Edema 3 (1%) 2 (<1%) 0 (0%) 3 (1%) 0 (0%) 0 (0%) Acne 3 (1%) 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) *Subjects may have & gt; 1 cutaneous adverse event; thus, the sum of the frequencies of preferred terms may exceed the number of subjects with at least 1 cutaneous adverse event. 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. Local Tolerability Studies Azelaic Acid Gel, 15% and its vehicle caused irritant reactions at the application site in human dermal safety studies. Azelaic Acid Gel, 15% caused significantly more irritation than its vehicle in a cumulative irritation study. Some improvement in irritation was demonstrated over the course of the clinical trials, but this improvement might be attributed to subject dropouts. No phototoxicity or photoallergenicity were reported in human dermal safety studies. 6.2 Postmarketing Experience The following adverse reactions have been identified post approval of Azelaic Acid Gel, 15%. 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, 15%. Hypersensitivity : angioedema, eye swelling, facial swelling, urticaria. Respiratory : worsening of asthma, dyspnea, wheezing, Skin reactions : application site rash.

8.1 Pregnancy Risk Summary Azelaic acid is minimally absorbed systemically following topical route of administration, and maternal use is not expected to result in fetal exposure to the drug [ see Clinical Pharmacology (12.3) ]. In animal reproduction studies, embryofetal toxicity was noted when azelaic acid was administered orally during the period of organogenesis at doses 162, 19, and 65 times the maximum recommended human dose (MRHD) in rats, rabbits, and monkeys, respectively. Maternal toxicity was noted at these doses but no malformations were observed in these embryofetal developmental studies (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 times the MRHD based on body surface area (BSA) comparison], rabbits given 150 or 500 mg/kg/day (19 or 65 times the MRHD based on BSA comparison) and cynomolgus monkeys given 500 mg/kg/day (65 times the MRHD based on BSA comparison) azelaic acid. No malformations were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys. An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose of 2500 mg/kg/day (162 times the MRHD based on BSA comparison) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/kg/day; 32 and 162 times the MRHD based on BSA comparison). No effects on sexual maturation of the fetuses were noted in this study.