tazarotene

1 INDICATIONS AND USAGE • Tazarotene gel, 0.05% and 0.1% is a retinoid indicated for the topical treatment of plaque psoriasis of up to 20% body surface area involvement. ( 1.1 ) • Tazarotene gel, 0.1% is indicated for the topical treatment of mild to moderate facial acne vulgaris. ( 1.2 ) Limitations of Use • The safety of tazarotene gel use on more than 20% body surface area has not been established. ( 1.3 ) 1.1 Plaque Psoriasis Tazarotene gel, 0.05% and 0.1% are indicated for the topical treatment of patients with plaque psoriasis of up to 20% body surface area involvement. 1.2 Acne Vulgaris Tazarotene gel, 0.1% is also indicated for the topical treatment of patients with facial acne vulgaris of mild to moderate severity. The efficacy of tazarotene gel in the treatment of acne previously treated with other retinoids or resistant to oral antibiotics has not been established. 1.3 Limitations of Use The safety of tazarotene gel use on more than 20% body surface area has not been established in psoriasis or acne [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] .

2 DOSAGE AND ADMINISTRATION Tazarotene gel is for topical use only. Tazarotene gel is not for ophthalmic, oral, or intravaginal use. Avoid accidental transfer of tazarotene gel into eyes, mouth, or other mucous membranes. If contact with mucous membranes occurs, rinse thoroughly with water [see Warnings and Precautions (5.2)] . Wash hands thoroughly after application. • Apply a thin layer of tazarotene gel only to the affected area once daily in the evening. ( 2.1 , 2.2 ) • Not for ophthalmic, oral, or intravaginal use. ( 2.2 ) • If contact with eyes occurs, rinse thoroughly with water. ( 2.2 ) 2.1 Psoriasis It is recommended that treatment starts with tazarotene gel, 0.05%, with strength increased to 0.1% if tolerated and medically indicated. Apply a thin film (2 mg/cm 2 ) of tazarotene gel once per day, in the evening, to cover only the psoriatic lesions on no more than 20% of body surface area. If a bath or shower is taken prior to application, the skin should be dry before applying the gel. If emollients are used, they should be applied at least an hour before application of tazarotene gel. Because unaffected skin may be more susceptible to irritation, application of tazarotene to these areas should be carefully avoided. Tazarotene gel was investigated for up to 12 months during clinical trials for psoriasis. 2.2 Acne Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm 2 ) of tazarotene gel 0.1% once per day, in the evening, to the skin where acne lesions appear. Use enough to cover the entire affected area. Tazarotene gel was investigated for up to 12 weeks during clinical trials for acne. Use effective sunscreens and wear protective clothing while using tazarotene gel [see Warnings and Precautions (5.3)] .

3 DOSAGE FORMS AND STRENGTHS Gel, 0.05% and 0.1%, in 30 g and 100 g tubes. Each gram of Tazarotene Gel, 0.05% and 0.1% contains 0.5 mg and 1 mg of tazarotene, respectively in a translucent, aqueous gel. Gel, 0.05% and 0.1% ( 3 )

4 CONTRAINDICATIONS Tazarotene gel is contraindicated in: • Pregnancy. Retinoids may cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)] . • Individuals who have known hypersensitivity to any of its components [see Warnings and Precautions (5.2)] . • Pregnancy ( 4 , 8.1 ) • Hypersensitivity ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Embryofetal toxicity [see Warnings and Precautions ( 5.1 )] Photosensitivity and Risk of Sunburn [see Warnings and Precautions ( 5.3 )] Plaque Psoriasis: Most common adverse reactions occurring in 10 to 30% of patients are pruritus, burning/stinging, erythema, worsening of psoriasis, irritation, and skin pain. ( 6.1 ) Acne Vulgaris: Most common adverse reactions occurring in 10 to 30% of patients are desquamation, burning/stinging, dry skin, erythema and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 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 clinical practice. Psoriasis A total of 439 subjects 14 to 87 years of age were treated with tazarotene gel, 0.05% and 0.1% in two controlled clinical trials. The most frequent adverse events reported with tazarotene gel, 0.05% and 0.1% occurring in 10 to 30% of subjects, in descending order, included pruritus, burning/stinging, erythema, worsening of psoriasis, irritation, and skin pain. Reactions occurring in 1 to 10% of subjects included rash, desquamation, irritant contact dermatitis, skin inflammation, fissuring, bleeding, and dry skin. Increases in “psoriasis worsening” and “sun-induced erythema” were noted in some subjects over the 4th to 12th months of treatment as compared to the first three months of a 1 year study. In general, the incidence of adverse events with tazarotene gel 0.05% was 2 to 5% lower than that seen with tazarotene gel 0.1%. Acne A total of 596 subjects 12 to 44 years of age were treated with tazarotene gel, 0.05% and 0.1% in two controlled clinical trials. The most frequent adverse events reported during clinical trials with tazarotene gel, 0.1% in the treatment of acne occurring in 10 to 30% of subjects, in descending order, included desquamation, burning/stinging, dry skin, erythema and pruritus. Reactions occurring in 1 to 10% of subjects included irritation, skin pain, fissuring, localized edema and skin discoloration. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during postapproval use of tazarotene. Skin and subcutaneous tissue disorders: blister, dermatitis, urticaria, skin exfoliation, skin discoloration (including skin hyperpigmentation or skin hypopigmentation), swelling at or near application sites, and pain.

7 DRUG INTERACTIONS No formal drug-drug interaction studies were conducted with tazarotene gel. In a trial of 27 healthy female subjects between the ages of 20–55 years receiving a combination oral contraceptive tablet containing 1 mg norethindrone and 35 mcg ethinyl estradiol, concomitant use of tazarotene administered as 1.1 mg orally (mean ± SD C max and AUC 0-24 of tazarotenic acid were 28.9 ± 9.4 ng/mL and 120.6 ± 28.5 ng•hr/mL, respectively) did not affect the pharmacokinetics of norethindrone and ethinyl estradiol over a complete cycle. The impact of tazarotene on the pharmacokinetics of progestin only oral contraceptives (i.e., minipills) has not been evaluated.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, tazarotene gel may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Safety in pregnant females has not been established. The potential risk to the fetus outweighs the potential benefit to the mother from tazarotene gel during pregnancy; therefore, tazarotene gel should be discontinued as soon as pregnancy is recognized [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] . Limited case reports of pregnancy in females enrolled in clinical trials for tazarotene gel have not established a clear association with tazarotene and major birth defects or miscarriage risk. Because the exact timing and extent of exposure in relation to the gestational age are not certain, the significance of these findings is unknown. In animal reproduction studies with pregnant rats, tazarotene dosed topically during organogenesis at 0.5 times the maximum systemic exposure in subjects treated with the maximum recommended human dose (MRHD) of tazarotene gel, 0.1% resulted in reduced fetal body weights and reduced skeletal ossification. In animal reproduction studies with pregnant rabbits dosed topically with tazarotene gel at 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%, there were single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. In animal reproduction studies with pregnant rats and rabbits, tazarotene dosed orally during organogenesis at 0.5 and 13 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1% resulted in malformations, fetal toxicity, developmental delays, and/or behavioral delays. In pregnant rats, tazarotene dosed orally prior to mating through early gestation resulted in decreased litter size, decreased numbers of live fetuses, decreased fetal body weights, and increased malformations at doses approximately 2 times higher than the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1% [see Data] . The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In rats, a tazarotene gel, 0.05% formulation dosed topically during gestation days 6 through 17 at 0.25 mg/kg/day, which represented 0.5 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1% (i.e., 2 mg/cm 2 over a 20% body surface area), resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel, which represented 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%, during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. When tazarotene was given orally to animals, developmental delays were seen in rats, and malformations and post-implantation loss were observed in rats and rabbits at doses producing 0.5 and 13 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%. In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, which represented 2 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%, classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased …

12.1 Mechanism of Action Tazarotene is a retinoid prodrug which is converted to its active form, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings for the treatment of plaque psoriasis and facial acne vulgaris is unknown.

11 DESCRIPTION Tazarotene gel, 0.05% and 0.1% is for topical use and contains the active ingredient, tazarotene. Each gram of tazarotene gel, 0.05% and 0.1% contains 0.5 and 1 mg of tazarotene, respectively in a translucent, aqueous gel. Tazarotene is a member of the acetylenic class of retinoids. Chemically, tazarotene is ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate. The compound has an empirical formula of C 21 H 21 NO 2 S and molecular weight of 351.46. The structural formula is shown below: Tazarotene gel, 0.05% and 0.1% contains the following inactive ingredients: benzyl alcohol 1%; ascorbic acid; butylated hydroxyanisole; butylated hydroxytoluene; carbomer homopolymer type B; edetate disodium; hexylene glycol; poloxamer 407; polyethylene glycol 400; polysorbate 40; purified water; and tromethamine. structure

10 OVERDOSAGE Excessive topical use of tazarotene gel, 0.05% and 0.1% may lead to marked redness, peeling, or discomfort [see Warnings and Precautions ( 5.2 )] . Tazarotene gel, 0.05% and 0.1% are not for oral use. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or other retinoids. If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary.

16 HOW SUPPLIED/STORAGE AND HANDLING Tazarotene gel is a translucent, aqueous gel, available in concentrations of 0.05% and 0.1%. It is available in a collapsible aluminum tube with a tamper-evident aluminum membrane over the opening and a white propylene screw cap, in 30 g and 100 g sizes. Tazarotene gel, 0.05% 30 g NDC 73473-309-30 Tazarotene gel, 0.05% 100 g NDC 73473-309-10 Tazarotene gel, 0.1% 30 g NDC 73473-310-30 Tazarotene gel, 0.1% 100 g NDC 73473-310-10 Storage: Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F).