AZELAIC ACID: 1,202 Adverse Event Reports & Safety Profile

FINACEA (azelaic acid) Foam contains 15% (w/w) azelaic acid, a naturally-occurring saturated dicarboxylic acid and is suspended in an oil-in-water emulsion vehicle. It is for topical use. Chemically, azelaic acid is 1,7-heptanedicarboxylic acid. The structural formula of azelaic acid is: Azelaic acid has a molecular formula of C 9 H 16 O 4 and a molecular weight of 188.22. The aluminum containers are filled with hydrophilic emulsion, crimped with a continuous spray valve, and pressurized with propellants consisting of propane, butane, and isobutane. Each gram of FINACEA Foam, 15% contains 0.15 g of azelaic acid.

Finacea

Foam also contains benzoic acid (as a preservative), cetostearyl alcohol, dimethyl isosorbide, medium-chain triglycerides, methylcellulose, mono- and di-glycerides, polyoxyl 40 stearate, polysorbate 80, propylene glycol, purified water, sodium hydroxide (to adjust pH), and xanthan gum as inactive ingredients.

Chemical

Structure

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 )

AND ADMINISTRATION Shake well before use. Cleanse affected area(s) using only very mild soaps or soapless cleansing lotion and pat dry with a soft towel before application of FINACEA Foam. Apply FINACEA Foam twice daily (morning and evening) to the entire facial area (cheeks, chin, forehead, and nose). For a single application, dispense the smallest amount of foam necessary to adequately cover the affected area(s) with a thin layer. Use FINACEA Foam continuously over 12 weeks. Wash hands immediately following application of FINACEA Foam. Cosmetics may be applied after the application of FINACEA Foam 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 (morning and evening) to the entire facial area (cheeks, chin, forehead, and nose). ( 2 ) Use only very mild soaps or soapless cleansing lotion and pat dry with a soft towel before applying FINACEA Foam. ( 2 ) Wash hands immediately following application. ( 2 ) Cosmetics may be applied after the application of FINACEA Foam 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 )

CONTRAINDICATIONS AZELEX ® cream is contraindicated in individuals who have shown hypersensitivity to any of its components.

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.

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%.

PRECAUTIONS 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: To use AZELEX ® cream for the full prescribed treatment period. To avoid the use of occlusive dressings or wrappings. 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. If they have dark complexions, to report abnormal changes in skin color to their physician. 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 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 Teratogenic Effects

Embryotoxic effects were observed in Segment I and Segment II oral studies with rats receiving 2500 mg/kg/day of azelaic acid. Similar effects were observed in Segment II studies in rabbits given 150 to 500 mg/kg/day and in monkeys given 500 mg/kg/day. The doses at which these effects were noted were all within toxic dose ranges for the dams. No teratogenic effects were observed. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Equilibrium dialysis was used to assess human milk partitioning in vitro . At an azelaic acid concentration of 25 mcg/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.

QUATERNIUM-73 --------0.003% CENTELLA ASIATICA LEAF EXTRACT --------0.99% SALICYLIC ACID --------0.07% AZELAIC ACID --------0.002%

WATER PROPYLENE GLYCOL CAPRYLIC/CAPRIC TRIGLYCERIDE ETHYLHEXYL PALMITATE CETEARYL ALCOHOL CETEARYL GLUCOSIDE POLYACRYLAMIDE C13-14 ISOPARAFFIN LAURETH-7 DIMETHICONE GLYCERYL STEARATE PEG-100 STEARATE SODIUM HYDROXIDE SODIUM CARBONATE POLYACRYLATE CROSSPOLYMER-6 PHENOXYETHANOL ETHYLHEXYLGLYCERIN BUTYLENE GLYCOL CENTELLA ASIATICA EXTRACT SCUTELLARIA BAICALENSIS ROOT EXTRACT POLYGONUM CUSPIDATUM ROOT EXTRACT CAMELLIA SINENSIS LEAF EXTRACT KANZOU EKISU CHAMOMILLA RECUTITA (MATRICARIA) FLOWER EXTRACT ROSMARINUS OFFICINALIS (ROSEMARY) LEAF EXTRACT PENTYLENE GLYCOL HYDROXYPHENYL PROPAMIDOBENZOIC ACID METHYLPARABEN ALLANTOIN BISABOLOL PROPYLPARABEN DIPOTASSIUM GLYCYRRHIZATE GLYCYRRHIZA URALENSIS (LICORICE) ROOT EXTRACT MENTHA PIPERITA (PEPPERMINT) OIL DISODIUM EDTA HYDROXYPROPYL CYCLODEXTRIN SALICYLIC ACID ARGININE