ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Overall, treatment related adverse events, including burning, stinging/tingling, dryness/tightness/scaling, itching, and erythema/irritation/redness, were 19.4% (24/124) for FINACEA Gel, 15%, and 7.1% (9/127) for the active comparator gel at 15 weeks.In two vehicle controlled, and one active controlled U.S. clinical studies, treatment safety was monitored in 788 patients who used twice daily FINACEA Gel, 15%, for 12 weeks (N=333) or for 15 weeks (N=124), or the gel vehicle (N=331) for 12 weeks.Table 3. Cutaneous Adverse Events Occurring in >=1% of Subjects in the Rosacea Trials by Treatment Group and Maximum IntensitySubjects may have >1 cutaneous adverse event; thus, the sum of the frequencies of preferred terms may exceed the number of subjects with at least cutaneous adverse event. FINACEA Gel, 15%N=457 (100%)VehicleN=331 (100%)Mildn=99(22%)Moderaten=61(13%)Severen=27(6%)Mildn=46(14%)Moderaten=30(9%)Severen=5(2%)Burning/stinging/tingling71 (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/dryskin/xerosis 21 (5%)10 (2%)5 (1%)31 (9%)14 (4%)1 (<1%)Erythema/irritation6 (1%)7 (2%)2 (<1%)8 (2%)4 (1%)2 (1%)Contactdermatitis (<1%)3 (1%)0 (0%)1 (<1%)0 (0%)0 (0%)Edema (1%)2 (<1%)0 (0%)3 (1%)0 (0%)0 (0%)Acne3 (1%)1 (<1%)0 (0%)1 (<1%)0 (0%)0 (0%)FINACEA Gel, 15%, and its vehicle caused irritant reactions at the application site in human dermal safety studies. FINACEA Gel, 15%, caused significantly more irritation than its vehicle in cumulative irritation study. Some improvement in irritation was demonstrated over the course of the clinical studies, but this improvement might be attributed to subject dropouts. No phototoxicity or photoallergenicity were reported in human dermal safety studies.In patients using azelaic acid formulations, the following additional adverse experiences have been reported rarely: worsening of asthma, vitiligo depigmentation, small depigmented spots, hypertrichosis, reddening (signs of keratosis pilaris), and exacerbation of recurrent herpes labialis.Post-marketing safety-Skin: facial burning and irritation; Eyes: iridocyclitis on accidental exposure with FINACEA Gel, 15%, to the eye (see PRECAUTIONS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility:. Systemic long-term animal studies have not been performed to evaluate the carcinogenic potential of azelaic acid. In 26-week dermal carcinogenicity study using transgenic (Tg.AC) mice, FINACEA Gel, 15%, and the gel vehicle, when applied once or twice daily, did not increase the number of female Tg.AC animals with papillomas at the treatment site. No statistically significant increase in the number of animals with papillomas at the treatment site was observed in male Tg.AC animals after once daily application. After twice daily application, FINACEA Gel, 15%, and the gel vehicle induced statistically significant increase in the number of male animals with papillomas at the treatment site when compared to untreated males. This suggests that the positive effect may be associated with the vehicle application. The clinical relevance of the findings in animals to humans is not clear.Azelaic acid was not mutagenic or clastogenic in 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 maximum recommended human dose based on body surface area) did not affect fertility or reproductive performance in male or female rats.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. FINACEA Gel, 15%, was evaluated for the treatment of mild to moderate papulopustular rosacea in clinical trials comprising total of 664 (333 active to 331 vehicle) patients. Both trials were multicenter, randomized, double-blind, vehicle-controlled 12-week studies with identical protocols. Overall, 92.5% of patients were Caucasian and 73% of patients were women, and the mean age was 49 (range 21 to 86) years. Enrolled patients had mild to moderate rosacea with mean lesion count of 18 (range to 60) inflammatory papules and pustules. Subjects without papules and pustules, with nodules, rhinophyma, or ocular involvement, and history of hypersensitivity to propylene glycol or to any other ingredients of the study drug were excluded. FINACEA Gel, 15%, or its vehicle were to be applied twice daily for 12 weeks; no other topical or systemic medication affecting the course of rosacea and/or evaluability was to be used during the studies. Patients were instructed to avoid spicy foods, thermally hot foods and drinks, and alcoholic beverages during the study, and to use only very mild soaps or soapless cleansing lotion for facial cleansing.The primary efficacy endpoints were both1.change from baseline in inflammatory lesion counts and 2.success defined as score of clear or minimal with at least 2 step reduction from baseline on the Investigators Global Assessment (IGA):CLEAR:No papules and/or pustules; no or residual erythema; no or mild to moderate telangiectasiaMINIMAL:Rare papules and/or pustules; residual to mild erythema; mild to moderate telangiectasiaMILD:Few papules and/or pustules; mild erythema; mild to moderate telangiectasiaMILD TO MODERATE:Distinct number of papules and/or pustules; mild to moderate erythema; mild to moderate telangiectasiaMODERATE:Pronounced number of papules and/or pustules; moderate erythema; mild to moderate telangiectasiaMODERATE TO SEVERE:Many papules and/or pustules, occasionally with large inflamed lesions; moderate erythema; moderate degree of telangiectasiaSEVERE:Numerous papules and/or pustules, occasionally with confluent areas of inflamed lesions; moderate or severe erythema; moderate or severe telangiectasiaPrimary efficacy assessment was based on the intent-to-treat (ITT) population with last observation carried forward (LOCF).Both studies demonstrated statistically significant difference in favor of FINACEA Gel, 15%, over its vehicle in reducing the number of inflammatory papules and pustules associated with rosacea (Table 1) and with success on the IGA in the ITT-LOCF population at the end of treatment.Table 1. Inflammatory Papules and Pustules (ITT population)ITT population with last observation carried forward (LOCF); Study OneFINACEA Gel,15%N 164Study OneVEHICLEN 165Study TwoFINACEA Gel,15%N 167Study TwoVEHICLEN 166Mean LesionCountBaseline17.517.617.918.5End ofTreatment 6.810.59.012.1Mean PercentReductionEnd ofTreatment 57.9%39.9%50.0%38.2%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.FINACEA Gel, 15%, was superior to the vehicle with regard to success based on the investigators global assessment of rosacea on 7-point static score at the end of treatment, (ITT population; Table 2).Table 2. Investigators Global Assessment at the End of TreatmentITT population with last observation carried forward (LOCF); Study OneFINACEA Gel, 15%N 164Study OneVEHICLEN 165Study TwoFINACEA Gel, 15%N 167Study TwoVEHICLEN 166CLEAR, MINIMALor MILD at Endof Treatment(%of Patients)61%40%61%48%. 1.change from baseline in inflammatory lesion counts and 2.success defined as score of clear or minimal with at least 2 step reduction from baseline on the Investigators Global Assessment (IGA):.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients using FINACEA Gel, 15%, should receive the following information and instructions:oFINACEA Gel, 15%, is to be used only as directed by the physician. oFINACEA Gel, 15%, is for external use only. It is not to be used orally, intravaginally, or for the eyes. oCleanse affected area(s) with very mild soap or soapless cleansing lotion and pat dry with soft towel before applying FINACEA Gel, 15%. Avoid alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. oAvoid contact of FINACEA Gel, 15%, with the mouth, eyes and other mucous membranes. If it does come in contact with the eyes, wash the eyes with large amounts of water and consult physician if eye irritation persists. oThe hands should be washed following application of FINACEA Gel, 15%. oCosmetics may be applied after FINACEA Gel, 15%, has dried. oSkin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, 15%, usually during the first few weeks of treatment. If irritation is excessive or persists, use of FINACEA Gel, 15%, should be discontinued, and patients should consult their physician (see ADVERSE REACTIONS). oAvoid any foods and beverages that might provoke erythema, flushing, and blushing (including spicy food, alcoholic beverages, and thermally hot drinks, including hot coffee and tea). oPatients should report abnormal changes in skin color to their physician. oAvoid the use of occlusive dressings or wrappings.. oFINACEA Gel, 15%, is to be used only as directed by the physician. oFINACEA Gel, 15%, is for external use only. It is not to be used orally, intravaginally, or for the eyes. oCleanse affected area(s) with very mild soap or soapless cleansing lotion and pat dry with soft towel before applying FINACEA Gel, 15%. Avoid alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. oAvoid contact of FINACEA Gel, 15%, with the mouth, eyes and other mucous membranes. If it does come in contact with the eyes, wash the eyes with large amounts of water and consult physician if eye irritation persists. oThe hands should be washed following application of FINACEA Gel, 15%. oCosmetics may be applied after FINACEA Gel, 15%, has dried. oSkin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, 15%, usually during the first few weeks of treatment. If irritation is excessive or persists, use of FINACEA Gel, 15%, should be discontinued, and patients should consult their physician (see ADVERSE REACTIONS). oAvoid any foods and beverages that might provoke erythema, flushing, and blushing (including spicy food, alcoholic beverages, and thermally hot drinks, including hot coffee and tea). oPatients should report abnormal changes in skin color to their physician. oAvoid the use of occlusive dressings or wrappings.

PRECAUTIONS SECTION.

PRECAUTIONS. General:. Contact with the eyes should be avoided. If sensitivity or severe irritation develops with the use of FINACEA Gel, 15%, treatment should be discontinued and appropriate therapy instituted.In transgenic mouse study, chronic use of FINACEA Gel led to an increased number of animals with papillomas at the treatment site (see PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility). The clinical relevance of the findings in animal studies to humans is not clear.. Information for Patients. Patients using FINACEA Gel, 15%, should receive the following information and instructions:oFINACEA Gel, 15%, is to be used only as directed by the physician. oFINACEA Gel, 15%, is for external use only. It is not to be used orally, intravaginally, or for the eyes. oCleanse affected area(s) with very mild soap or soapless cleansing lotion and pat dry with soft towel before applying FINACEA Gel, 15%. Avoid alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. oAvoid contact of FINACEA Gel, 15%, with the mouth, eyes and other mucous membranes. If it does come in contact with the eyes, wash the eyes with large amounts of water and consult physician if eye irritation persists. oThe hands should be washed following application of FINACEA Gel, 15%. oCosmetics may be applied after FINACEA Gel, 15%, has dried. oSkin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, 15%, usually during the first few weeks of treatment. If irritation is excessive or persists, use of FINACEA Gel, 15%, should be discontinued, and patients should consult their physician (see ADVERSE REACTIONS). oAvoid any foods and beverages that might provoke erythema, flushing, and blushing (including spicy food, alcoholic beverages, and thermally hot drinks, including hot coffee and tea). oPatients should report abnormal changes in skin color to their physician. oAvoid the use of occlusive dressings or wrappings.. oFINACEA Gel, 15%, is to be used only as directed by the physician. oFINACEA Gel, 15%, is for external use only. It is not to be used orally, intravaginally, or for the eyes. oCleanse affected area(s) with very mild soap or soapless cleansing lotion and pat dry with soft towel before applying FINACEA Gel, 15%. Avoid alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. oAvoid contact of FINACEA Gel, 15%, with the mouth, eyes and other mucous membranes. If it does come in contact with the eyes, wash the eyes with large amounts of water and consult physician if eye irritation persists. oThe hands should be washed following application of FINACEA Gel, 15%. oCosmetics may be applied after FINACEA Gel, 15%, has dried. oSkin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, 15%, usually during the first few weeks of treatment. If irritation is excessive or persists, use of FINACEA Gel, 15%, should be discontinued, and patients should consult their physician (see ADVERSE REACTIONS). oAvoid any foods and beverages that might provoke erythema, flushing, and blushing (including spicy food, alcoholic beverages, and thermally hot drinks, including hot coffee and tea). oPatients should report abnormal changes in skin color to their physician. oAvoid the use of occlusive dressings or wrappings.. Drug Interactions:. There have been no formal studies of the interaction of FINACEA Gel, 15%, with other drugs.. Carcinogenesis, Mutagenesis, Impairment of Fertility:. Systemic long-term animal studies have not been performed to evaluate the carcinogenic potential of azelaic acid. In 26-week dermal carcinogenicity study using transgenic (Tg.AC) mice, FINACEA Gel, 15%, and the gel vehicle, when applied once or twice daily, did not increase the number of female Tg.AC animals with papillomas at the treatment site. No statistically significant increase in the number of animals with papillomas at the treatment site was observed in male Tg.AC animals after once daily application. After twice daily application, FINACEA Gel, 15%, and the gel vehicle induced statistically significant increase in the number of male animals with papillomas at the treatment site when compared to untreated males. This suggests that the positive effect may be associated with the vehicle application. The clinical relevance of the findings in animals to humans is not clear.Azelaic acid was not mutagenic or clastogenic in 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 maximum recommended human dose based on body surface area) did not affect fertility or reproductive performance in male or female rats.. Pregnancy:. Teratogenic Effects. Pregnancy Category B. There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women. The experience with FINACEA Gel, 15%, when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.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 maximum recommended human dose based on body surface area), rabbits given 150 or 500 mg/kg/day (19 or 65 times the maximum recommended human dose based on body surface area) and cynomolgus monkeys given 500 mg/kg/day (65 times the maximum recommended human dose based on body surface area) azelaic acid. No teratogenic effects 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 dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose that generated some maternal toxicity (2500 mg/kg/day; 162 times the maximum recommended human dose based on body surface area). In addition, slight disturbances in the postnatal 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 maximum recommended human dose based on body surface area). No effects on sexual maturation of the fetuses were noted in this study.Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.. Nursing Mothers:. Equilibrium dialysis was used to assess human milk partitioning in vitro. At an azelaic acid concentration of 25 ug/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 topically applied dose of azelaic acid cream, 20%, is systemically absorbed, the uptake of azelaic acid into maternal milk is not expected to cause significant change from baseline azelaic acid levels in the milk. However, caution should be exercised when FINACEA Gel, 15%, is administered to nursing mother.. Pediatric Use:. Safety and effectiveness of FINACEA Gel, 15%, in pediatric patients have not been established.. Geriatric Use:. Clinical studies of FINACEA Gel, 15%, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

PREGNANCY SECTION.

Pregnancy:. Teratogenic Effects. Pregnancy Category B. There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women. The experience with FINACEA Gel, 15%, when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.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 maximum recommended human dose based on body surface area), rabbits given 150 or 500 mg/kg/day (19 or 65 times the maximum recommended human dose based on body surface area) and cynomolgus monkeys given 500 mg/kg/day (65 times the maximum recommended human dose based on body surface area) azelaic acid. No teratogenic effects 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 dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose that generated some maternal toxicity (2500 mg/kg/day; 162 times the maximum recommended human dose based on body surface area). In addition, slight disturbances in the postnatal 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 maximum recommended human dose based on body surface area). No effects on sexual maturation of the fetuses were noted in this study.Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category B. There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women. The experience with FINACEA Gel, 15%, when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.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 maximum recommended human dose based on body surface area), rabbits given 150 or 500 mg/kg/day (19 or 65 times the maximum recommended human dose based on body surface area) and cynomolgus monkeys given 500 mg/kg/day (65 times the maximum recommended human dose based on body surface area) azelaic acid. No teratogenic effects 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 dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose that generated some maternal toxicity (2500 mg/kg/day; 162 times the maximum recommended human dose based on body surface area). In addition, slight disturbances in the postnatal 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 maximum recommended human dose based on body surface area). No effects on sexual maturation of the fetuses were noted in this study.Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.