ma: consult a physician if asthma is exacerbated with azelaic acid gel 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 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.

) cosmetics may be applied after the application of azelaic acid gel 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 )

ritation (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. table 1: adverse events occurring in ≥1% of subjects in the rosacea trials by treatment group and maximum intensity* azelaic acid gel, 15% vehicle n=457 n=331 (100%) (100%) mild moderate severe mild moderate severe n=99 n =61 n =27 n =46 n =30 n =5 (22%) (13%) (6%) (14%) (9%) (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 ˃ 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 and its vehicle caused irritant reactions at the application site in human dermal safety studies. azelaic acid gel 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. 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.

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. 8.2 lactation risk summary azelaic acid is naturally present in human milk. when used as prescribed, azelaic acid is unlikely to be absorbed through the skin in clinically relevant amounts to cause a change in azelaic acid concentration in milk or milk production; therefore, breastfeeding is not expected to result in exposure of the infant to azelaic acid gel. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for azelaic acid gel and any potential adverse effects on the breastfed child from azelaic acid gel or from the underlying maternal condition. 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.

. azelaic acid is mainly excreted unchanged in the urine, but undergoes some ß-oxidation to shorter chain dicarboxylic acids.

re instructed to avoid spicy foods, thermally hot food/drink and alcoholic beverages during the study. subjects were also instructed to use only very mild soaps or soapless cleansing lotion for facial cleansing. the primary efficacy endpoints included both 1) change from baseline in inflammatory lesion counts as well as 2) success defined as a score of “clear” or “minimal” with at least a 2-step reduction from baseline on the investigator’s global assessment (iga), defined as follows below: clear: no papules and/or pustules; no or residual erythema; no or mild to moderate telangiectasia minimal: rare papules and/or pustules; residual to mild erythema; mild to moderate telangiectasia mild: few papules and/or pustules; mild erythema; mild to moderate telangiectasia mild to moderate: distinct number of papules and/or pustules; mild to moderate erythema; mild to moderate telangiectasia moderate: pronounced number of papules and/or pustules; moderate erythema; mild to moderate telangiectasia moderate to severe: many papules and/or pustules, occasionally with large inflamed lesions; moderate erythema; moderate degree of telangiectasia severe: numerous papules and/or pustules, occasionally with confluent areas of inflamed lesions; moderate or severe erythema; moderate or severe telangiectasia primary efficacy assessment was based on the “intent-to-treat” (itt) population with the “last observation carried forward” (locf). both trials demonstrated a statistically significant difference in favor of azelaic acid gel over its vehicle in both reducing the number of inflammatory papules and pustules associated with rosacea (table 2) as well as demonstrating success on the iga in the itt-locf population at the end of treatment. table 2: inflammatory papules and pustules (itt population)* study one study one study two study two azelaic acid gel, 15% vehicle azelaic acid gel, 15% vehicle n=164 n=165 n=167 n=166 mean lesion count baseline 17.5 17.6 17.9 18.5 end of treatment * 6.8 10.5 9.0 12.1 mean percent reduction end of 57.9% 39.9% 50.0% 38.2% treatment * * itt population with last observation carried forward (locf) although some reduction of erythema which was present in subjects with papules and pustules of rosacea occurred in clinical trials, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. azelaic acid gel was superior to the vehicle with regard to success based on the iga of rosacea on a 7-point static score at the end of treatment (itt population; table 3). table 3: investigator’s global assessment at the end of treatment* study one study one study two study two azelaic acid gel, 15% vehicle azelaic acid gel, 15% vehicle n=164 n=165 n=167 n=166 clear, minimal or mild at end of treatment 61% 40% 61% 48% (% of subjects) * itt population with last observation carried forward (locf)

sult 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)] . teva pharmaceuticals usa, inc. north wales, pa 19454 rev. b 5/2022