Prescription Drugs

CLINICAL PHARMACOLOGY 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 is unknown. Pharmacodynamics The pharmacodynamics of TAZORAC® Cream are unknown. Pharmacokinetics Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal, acne or psoriatic skin. In a multiple dose trial with a once daily dose for 14 consecutive days in 9 psoriatic subjects (male=5; female=4), measured doses of TAZORAC® Cream, 0.1% were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%). The Cmax of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC0-24h was 31.2 ± 35.2 ng•hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm² . During clinical trials with TAZORAC® Cream, 0.05% or 0.1% treatment for plaque psoriasis, three out of 139 subjects with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 subjects (LLOQ = 0.05 ng/mL). Three subjects using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown. TAZORAC® Cream 0.1% was applied once daily to either the face (N=8) or to 15% of body surface area (N=10) of female subjects with moderate to severe acne vulgaris. The mean Cmax and AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean Cmax and AUC0-24h values of tazarotenic acid from subjects in the 15% body surface area dosing group were more than 10 times higher than those from subjects in the face-only dosing group. The single highest Cmax throughout the trial period was 1.91 ng/mL on day 15 in the exaggerated dosing group. In the face-only group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 0.10 ± 0.06 ng/mL and 1.54 ± 1.01 ng·hr/mL, respectively, whereas in the 15% body surface area dosing group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 1.20 ± 0.41 ng/mL and 17.01 ± 6.15 ng·hr/mL, respectively. The steady state pharmacokinetics of tazarotenic acid had been reached by day 8 in the face-only and by day 15 in the 15% body surface area dosing groups. In a Phase 3 clinical trial, TAZORAC® Cream, 0.1% was applied once daily for 12 weeks to each of 48 subjects (22 females and 26 males) with facial acne vulgaris. The mean ± SD values of plasma tazarotenic acid at weeks 4 and 8 were 0.078 ± 0.073 ng/mL (N=47) and 0.052 ± 0.037 ng/mL (N=42), respectively. The highest observed individual plasma tazarotenic acid concentration was 0.41 ng/mL at week 4 from a female subject. The magnitude of plasma tazarotenic acid concentrations appears to be independent of gender, age, and body weight. Clinical Studies In two 12-week vehicle-controlled clinical trials, TAZORAC® Cream, 0.05% and 0.1% was significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. TAZORAC® Cream, 0.1% and 0.05% demonstrated superiority over vehicle cream as early as 1 week and 2 weeks, respectively, after starting treatment. In these trials, the primary efficacy endpoint was “clinical success,” defined as the proportion of subjects with none, minimal, or mild overall lesional assessment at Week 12, and shown in Table 1. “Clinical success” was also significantly greater with TAZORAC® Cream, 0.05% and 0.1% versus vehicle at most follow-up visits. Table 1: Subject Numbers and Percentages for Overall Lesional Assessment Scores and “Clinical Success” at Baseline (BL), End of Treatment (Week 12) and 12 Weeks After Stopping Therapy (Week 24)# in Two Controlled Clinical Trials for Psoriasis Score TAZORAC® Cream, 0.05% TAZORAC® Cream, 0.1% Vehicle Cream Trial 1 N=218 Trial 2 N=210 Trial 1 N=221 Trial 2 N=211 Trial 1 N=229 Trial 2 N=214 BL Wk 12 Wk 24 BL Wk 12 BL Wk 12 Wk 24 BL Wk 12 BL Wk 12 Wk 24 BL Wk 12 None (0) 0 1 (0.5%) 1 (0.5%) 0 2 (1%) 0 0 0 0 6 (3%) 0 0 1 (0.4%) 0 1 (0.5%) Minimal (1) 0 11 (5%) 12 (6%) 0 7 (3%) 0 12 (5%) 14 (6%) 0 11 (5%) 0 7 (3%) 6 (3%) 0 1 (0.5%) Mild (2) 0 79 (36%) 60 (28%) 0 76 (36%) 0 75 (34%) 53 (24%) 0 90 (43%) 0 49 (21%) 43 (19%) 0 54 (25%) Moderate (3) 141 (65%) 86 (39%) 90 (41%) 100 (48%) 74 (35%) 122 (55%) 97 (44%) 107 (48%) 96 (45%) 62 (29%) 139 (61%) 119 (52%) 114 (50%) 97 (45%) 99 (46%) Severe (4) 69 (32%) 39 (18%) 51 (23%) 80 (38%) 36 (17%) 91 (41%) 36 (16%) 46 (21%) 86 (41%) 29 (14%) 81 (35%) 51 (22%) 61 (27%) 93 (44%) 47 (22%) Very Severe (5) 8 (4%) 2 (0.9%) 4 (2%) 30 (14%) 15 (7%) 8 (4%) 1 (0.5%) 1 (0.5%) 29 (14%) 13 (6%) 9 (4%) 3 (1%) 4 (2%) 24 (11%) 12 (6%) “Clinical Success” 0 91 (42%*) 73 (33%*) 0 85 (40%*) 0 87 (39%*) 67 (30%*) 0 107 (51%*) 0 56 (24%) 50 (22%) 0 56 (26%) 0 no plaque elevation above normal skin level; may have residual non-erythematous discoloration; no psoriatic scale 1 essentially flat with possible trace elevation; may have up to moderate erythema (red coloration); no psoriatic scale 2 slight but definite elevation of plaque above normal skin level; may have up to moderate erythema (red coloration); fine scales with some lesions partially covered 3 moderate elevation with rounded or sloped edges to plaque; moderate erythema (red coloration); somewhat coarser scales with most lesions partially covered 4 marked elevation with hard, sharp edges to plaque; severe erythema (very red coloration); thick scales with virtually all lesions covered and a rough surface 5 very marked elevation with very hard, sharp edges to plaque; very severe erythema (extreme red coloration); very coarse, thick scales with all lesions covered and a very rough surface Clinical Success defined as an overall lesional assessment score of none, minimal, or mild. # Trial 1 had post-treatment period observations for 12 weeks after stopping therapy, which were not part of Trial 2. * Denotes statistically significant difference for “Clinical Success” compared with vehicle. At the end of 12 weeks of treatment, TAZORAC® Cream, 0.05% and 0.1% was consistently superior to vehicle in reducing the plaque thickness of psoriasis. Improvements in erythema and scaling were generally significantly greater with TAZORAC® Cream, 0.05% and 0.1% than with vehicle. TAZORAC® Cream, 0.1% was also generally more effective than TAZORAC® Cream, 0.05% in reducing the severity of the individual signs of disease. However, TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than TAZORAC® Cream, 0.05%. Table 2: Mean Decreases in Plaque Elevation, Scaling and Erythema in Two Controlled Clinical Trials for Psoriasis Lesion TAZORAC® Cream, 0.05% TAZORAC® Cream, 0.1% Vehicle Cream Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated Trial 1 N=218 Trail 2 N=210 Trail 1 N=218 Trail 2 N=210 Trail 1 N=218 Trail 2 N=210 Trail 1 N=221 Trail 2 N=211 Trail 1 N=221 Trail 2 N=211 Trail 1 N=221 Trail 2 N=211 Trail 1 N=229 Trail 2 N=214 Trail 1 N=229 Trail 2 N=214 Trail 1 N=229 Trail 2 N=214 Plaque elevation B# C12 C24 2.29 -0.83* -0.75* 2.50 -0.98* 2.40 -0.91* -0.73* 2.52 -1.04* 2.28 -0.75* -0.60* 2.51 -0.90* 2.34 -1.08* -0.87* 2.52 -1.25* 2.35 -0.96* -0.73* 2.49 -1.21* -0.63* 2.32 -0.83* 2.51 -1.08* -0.57 2.28 -0.59 2.51 -0.69 2.35 -0.57 -0.49 2.51 -0.68 2.29 -0.48 -0.42 2.51 -0.61 Scaling B# C12 C24 2.26 -0.75 -0.68 2.45 -0.90 2.47 -0.78* -0.62* 2.60 -0.98* 2.32 -0.67* -0.51* 2.47 -0.80 2.37 -0.84* -0.79* 2.45 -1.06* 2.40 -0.76* -0.61* 2.57 -1.13* 2.36 -0.73* -0.59* 2.53 -1.03* 2.34 -0.66 -0.56 2.46 -0.79 2.45 -0.62 -0.45 2.61 -0.76 2.31 -0.46 -0.34 2.53 -0.70 Erythema B# C12 C24 2.26 -0.49 -0.52 2.51 -0.65* 2.17 -0.44 -0.44 2.40 -0.66* 2.23 -0.40 -0.41 2.48 -0.62 2.25 -0.49 -0.55 2.53 -0.82* 2.17 -0.57* -0.52* 2.42 -0.82* 2.21 -0.42* -0.39* 2.51 -0.78* 2.24 -0.42 -0.43 2.47 -0.46 2.17 -0.38 -0.34 2.34 -0.44 2.24 -0.37 -0.33 2.47 -0.47 Plaque elevation, scaling and erythema scored on a 0-4 scale with 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe. B#=Mean Baseline Severity; C-12=Mean Change from Baseline at end of 12 weeks of therapy; C-24=Mean Change from Baseline at week 24 (12 weeks after the end of therapy). *Denotes statistically significant difference compared with vehicle. Acne In two large vehicle-controlled trials, subjects age 12 years and over with facial acne vulgaris of a severity suitable for monotherapy with a topical agent were enrolled. After face cleansing in the evening, TAZORAC® Cream, 0.1% was applied once daily to the entire face as a thin layer. TAZORAC® Cream, 0.1% was significantly more effective than vehicle in the treatment of facial acne vulgaris. Efficacy results after 12 weeks of treatment are shown in Table 3: Table 3: Efficacy Results after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne TAZORAC® Cream, 0.1% Vehicle Cream Trial 1 N=218 Trial 2 N=206 Trial 1 N=218 Trial 2 N=205 Median Percent Reduction in Noninflammatory lesions 46%* 41%* 27% 21% Inflammatory lesions 41%* 44%* 27% 25% Total lesions 44%* 42%* 24% 21% Percent of Subjects with No Acne or Minimal Acne 18%* 20%* 11% 6% Percent of Subjects with No Acne, Minimal Acne, or Mild Acne 55%* 53%* 36% 36% *Denotes statistically significant difference compared with vehicle.

TAZORAC® (tazarotene) Cream DESCRIPTION TAZORAC® (tazarotene) Cream, 0.05% and 0.1% is for topical use and contains the active ingredient, tazarotene. Each gram of TAZORAC® Cream, 0.05% and 0.1% contains 0.5 and 1 mg of tazarotene, respectively in a white cream base. Tazarotene is a member of the acetylenic class of retinoids. Chemically, tazarotene is ethyl 6-[(4,4dimethylthiochroman-6-yl)ethynyl]nicotinate. The compound has an empirical formula of C21H21NO2S and molecular weight of 351.46.  The structural formula is shown below: TAZORAC® Cream contains the following inactive ingredients: benzyl alcohol 1%; carbomer 1342; carbomer homopolymer type B; edetate disodium; medium chain triglycerides; mineral oil; purified water; sodium hydroxide; sodium thiosulfate; and sorbitan monooleate.

INDICATIONS Plaque Psoriasis TAZORAC® (tazarotene) Cream, 0.05% and 0.1% are indicated for the topical treatment of patients with plaque psoriasis. Acne Vulgaris TAZORAC® (tazarotene) Cream, 0.1% is also indicated for the topical treatment of patients with acne vulgaris. DOSAGE AND ADMINISTRATION Psoriasis It is recommended that treatment starts with TAZORAC® Cream, 0.05%, with strength increased to 0.1% if tolerated and medically indicated. Apply a thin film (2 mg/cm²) of TAZORAC® Cream once per day, in the evening, to cover only the psoriatic lesions. If a bath or shower is taken prior to application, the skin should be dry before applying the cream. If emollients are used, they should be applied at least an hour before application of TAZORAC® Cream. Because unaffected skin may be more susceptible to irritation, application of TAZORAC® Cream to these areas should be carefully avoided. Acne Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm²) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. HOW SUPPLIED Dosage Forms And Strengths Cream, 0.05% and 0.1%. Each gram of TAZORAC® Cream, 0.05% and 0.1% contains 0.5 mg and 1 mg of tazarotene, respectively in a white cream base. Storage And Handling TAZORAC® Cream is a white cream available in concentrations of 0.05% and 0.1%. It is supplied in a collapsible aluminum tube with a tamper-evident aluminum membrane over the opening and a white polypropylene screw cap, in 30 g and 60 g sizes. TAZORAC® Cream, 0.05% TAZORAC® Cream, 0.1% 30 g NDC 0023-9155-30 NDC 0023-9156-30 60 g NDC 0023-9155-60 NDC 0023-9156-60 Storage Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from -5°C to 30°C (23°F to 86°F). Manufactured by: Allergan, Inc., Irvine, CA 92612, U.S.A. Revised: December/2013

PATIENT INFORMATION TAZORAC® (TAZ-or-ac) (tazarotene) Cream Important information: TAZORAC® Cream is for use on skin only. Do not use TAZORAC® Cream in your eyes, mouth, or vagina. What is the most important information I should know about TAZORAC® Cream? TAZORAC® Cream may cause birth defects if used during pregnancy. Females must not be pregnant when they start using TAZORAC® Cream or become pregnant during treatment with TAZORAC® Cream. For females who are able to get pregnant: Your doctor should order a pregnancy test for you within 2 weeks before you begin treatment with TAZORAC® Cream to be sure that you are not pregnant. Your doctor will decide when to do the test. You should begin treatment with TAZORAC® Cream during a normal menstrual period. Use an effective form of birth control during treatment with TAZORAC® Cream. Talk with your doctor about birth control options that may be used to prevent pregnancy during treatment with TAZORAC® Cream. Stop using TAZORAC® Cream and tell your doctor right away if you become pregnant while using TAZORAC® Cream. What is TAZORAC® Cream? TAZORAC® Cream 0.05% and 0.1% is a prescription medicine used on the skin (topical) to treat people with plaque psoriasis. TAZORAC® Cream 0.1% is also used on the skin to treat people with acne vulgaris. It is not known if TAZORAC® Cream is safe and effective for treating psoriasis in children under 18 years of age, or for treating acne vulgaris in children under 12 years of age. Who should not use TAZORAC® Cream? Do not use TAZORAC® Cream if you: are pregnant, or you are able to become pregnant and are not using effective birth control. See the section called “What is the most important information I should know about TAZORAC® Cream?” at the beginning of this leaflet. are allergic to any of the ingredients in TAZORAC® Cream. See the end of this leaflet for a complete list of ingredients in TAZORAC® Cream. What should I tell my doctor before using TAZORAC® Cream? Before you use TAZORAC® Cream, tell your doctor if you: have eczema or any other skin problems have any other medical conditions are breastfeeding or plan to breastfeed. It is not known if TAZORAC® Cream passes into your breast milk. You and your doctor should decide if you will use TAZORAC® Cream or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain medicines, vitamins, or supplements may make your skin more sensitive to sunlight. Also, tell your doctor about any cosmetics you use, including moisturizers, creams, lotions, or products that can dry out your skin. How should I use TAZORAC® Cream? Use TAZORAC® Cream exactly as your doctor tells you to use it. If you have psoriasis: If you shower or bathe before applying TAZORAC® Cream, your skin should be dry before applying the cream. You may use a cream or lotion to soften or moisten your skin at least 1 hour before you apply TAZORAC® Cream. Apply a thin layer of TAZORAC® Cream to cover only the psoriasis lesions, 1 time each day, in the evening. If you have acne: Gently wash and dry your face before applying TAZORAC® Cream. Apply a thin layer of TAZORAC® Cream to cover all of the affected skin areas, 1 time each day, in the evening. TAZORAC® Cream should not be applied to unaffected skin. TAZORAC® Cream may cause irritation to unaffected skin. TAZORAC® Cream should not be used on skin with eczema because it may cause severe irritation. Do not get TAZORAC® Cream in your eyes, on your eyelids, or in your mouth. If TAZORAC® Cream gets in or near your eyes, rinse them well with water. Wash your hands after applying TAZORAC® Cream. If you swallow TAZORAC® Cream, call your doctor or go to the nearest hospital emergency room right away. What should I avoid while using TAZORAC® Cream? Avoid sunlight, including sunlamps, as much as possible. TAZORAC® Cream can make your skin more sensitive to the sun, and the light from sunlamps and tanning beds. You could get a severe sunburn. Use sunscreen with at least SPF 15, and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your doctor if you get a sunburn during treatment with TAZORAC® Cream. If you get a sunburn, do not use TAZORAC® Cream until your sunburn is healed. What are the possible side effects of TAZORAC® Cream? TAZORAC® Cream may cause serious side effects, including: Skin irritation. TAZORAC® Cream may cause itching, burning, redness, and peeling of your skin. Also, wind or cold weather may be more irritating to your skin while you are using TAZORAC® Cream. Tell your doctor if you develop any of these symptoms of skin irritation with TAZORAC® Cream. Your doctor may tell you to stop using TAZORAC® Cream until your skin heals, change your dose of TAZORAC® Cream, or your doctor may tell you to use it less often, if you get too much skin irritation. The most common side effects of TAZORAC® Cream in people with plaque psoriasis include: itching redness burning The most common side effects of TAZORAC® Cream in people with acne include: peeling dry skin redness burning Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TAZORAC® Cream. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088. How should I store TAZORAC® Cream? Store TAZORAC® Cream at room temperature between 68°F to 77°F (20°C to 25°C). Keep TAZORAC® Cream and all medicines out of the reach of children. General information about the safe and effective use of TAZORAC® Cream. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TAZORAC® Cream for a condition for which it was not prescribed. Do not give TAZORAC® Cream to other people, even if they have the same symptoms you have. It may harm them. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about TAZORAC® Cream that is written for health professionals. For more information call 1-800-433-8871 or go to www.tazorac.com. What are the ingredients in TAZORAC® Cream? Active ingredient: tazarotene Inactive ingredients: benzyl alcohol 1%, Carbomer 1342, carbomer homopolymer type B, edetate disodium, medium chain triglycerides, mineral oil, purified water, sodium hydroxide, sodium thiosulfate, and sorbitan monooleate

OVERDOSE Excessive topical use of TAZORAC® Cream, 0.05% and 0.1% may lead to marked redness, peeling, or discomfort [see WARNINGS AND PRECAUTIONS]. TAZORAC® Cream, 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. CONTRAINDICATIONS Pregnancy TAZORAC® Cream may cause fetal harm when administered to a pregnant woman. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits [see Use In Specific Populations]. TAZORAC® Cream is contraindicated in women who are pregnant or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Hypersensitivity TAZORAC® Cream is contraindicated in individuals who have shown hypersensitivity to any of its components.

SIDE EFFECTS 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. In human dermal safety trials, TAZORAC® Cream, 0.05% and 0.1% did not induce allergic contact sensitization, phototoxicity, or photoallergy. Psoriasis The most frequent adverse reactions reported with TAZORAC® Cream, 0.05% and 0.1% occurring in 10 to 23% of subjects, in descending order, included pruritus, erythema, and burning. Reactions occurring in greater than 1 to less than 10% of subjects, in descending order, included irritation, desquamation, stinging, contact dermatitis, dermatitis, eczema, worsening of psoriasis, skin pain, rash, hypertriglyceridemia, dry skin, skin inflammation, and peripheral edema. TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than the 0.05% cream. The rates of irritation adverse reactions reported during psoriasis trials with TAZORAC® Cream, 0.1% were 0.1 0.4% higher than those reported for TAZORAC® Cream, 0.05%. Acne The most frequent adverse reactions reported during clinical trials with TAZORAC® Cream 0.1% in the treatment of acne, occurring in 10-30% of subjects, in descending order included desquamation, dry skin, erythema, and burning sensation. Reactions occurring in 1 to 5% of subjects included pruritus, irritation, face pain, and stinging. DRUG INTERACTIONS No formal drug-drug interaction studies were conducted with TAZORAC® Cream. 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 μg ethinyl estradiol, concomitant use of tazarotene administered as 1.1 mg orally (mean ± SD Cmax and AUC0-24 of tazarotenic acid were 28.9 ± 9.4 ng/mL and 120.6 ± 28.5 ng*h/mL) 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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Embryofetal Toxicity Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In patients treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans [see CLINICAL PHARMACOLOGY]. There were thirteen reported pregnancies in subjects who participated in the clinical trials for topical tazarotene. Nine of the subjects were found to have been treated with topical tazarotene, and the other four had been treated with vehicle. One of the subjects who was treated with tazarotene cream elected to terminate the pregnancy for non-medical reasons unrelated to treatment. The other eight pregnant women who were inadvertently exposed to topical tazarotene during clinical trials subsequently delivered apparently healthy babies. As the exact timing and extent of exposure in relation to the gestation times are not certain, the significance of these findings is unknown. Females of Child-bearing Potential Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy. TAZORAC® Cream therapy should begin during a menstrual period [see Use in Specific Populations]. Local Irritation Application of TAZORAC® Cream may cause excessive irritation in the skin of certain sensitive individuals. Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established. Alternatively, patients with psoriasis who are being treated with the 0.1% concentration can be switched to the lower concentration. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Therapy can be resumed, or the drug concentration or frequency of application can be increased as the patient becomes able to tolerate treatment. Concomitant topical medications and cosmetics that have a strong drying effect should be avoided. It is also advisable to “rest” a patient's skin until the effects of such preparations subside before use of TAZORAC® Cream is begun. TAZORAC® Cream, should not be used on eczematous skin, as it may cause severe irritation. Weather extremes, such as wind or cold, may be more irritating to patients using TAZORAC® Cream. Photosensitivity And Risk For Sunburn Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of TAZORAC® Cream. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using TAZORAC® Cream. Patients with sunburn should be advised not to use TAZORAC® Cream until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using TAZORAC® Cream. TAZORAC® Cream should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). Advise the patient of the following: Fetal risk associated with TAZORAC® Cream for females of childbearing potential. Advise patients to use an effective method of contraception during treatment to avoid pregnancy. Advise the patient to stop medication if she becomes pregnant and call her doctor [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and Use In Specific Populations]. For the patient with psoriasis, apply TAZORAC® Cream only to psoriasis skin lesions, avoiding uninvolved skin. If undue irritation (redness, peeling, or discomfort) occurs, reduce frequency of application or temporarily interrupt treatment. Treatment may be resumed once irritation subsides [see DOSAGE AND ADMINSTRATION]. Moisturizers may be used as frequently as desired. Patients with psoriasis may use a cream or lotion to soften or moisten skin at least 1 hour before applying TAZORAC® Cream. Avoid exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps. Use sunscreen and protective clothing if exposure to sunlight is unavoidable when using TAZORAC® Cream. Avoid contact with the eyes. If TAZORAC® Cream gets in or near their eyes, rinse thoroughly with water. Not for ophthalmic, oral, or intravaginal use. Wash their hands after applying TAZORAC® Cream. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in the rat equivalent to 0.6 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/kg/cm²over a 35% body surface area in a controlled pharmacokinetic study. This estimated systemic exposure in rats was 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% cream at 2 mg/cm² over a 15% body surface area. A long-term topical application study of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Systemic exposures at the highest dose was 3.9 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm² over a 35% body surface area in a controlled pharmacokinetic study, and 13 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks. Mutagenesis Tazarotene was found to be non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test. Impairment of Fertility No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm² over a 35% body surface area in a controlled pharmacokinetic study, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. That dose produced a systemic exposure that was 1.9 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm² over a 35% body surface area, and 6.3 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses up to 2 mg/kg/day of tazarotene. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose [see Use in Specific Populations]. That dose produced a systemic exposure that was 3.4 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm² over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm² over a 35% body surface area, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. Use In Specific Populations Pregnancy Pregnancy Category X [see CONTRAINDICATIONS]. There are no adequate and well-controlled studies with TAZORAC® Cream in pregnant women. TAZORAC® Cream is contraindicated in women who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy, which should begin during a menstrual period. Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In subjects treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans [see CLINICAL PHARMACOLOGY]. In rats, a tazarotene gel, 0.05% formulation, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. Systemic exposure to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 1.2 and 13 times, respectively, that in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm² over a 35% body surface area in a controlled pharmacokinetic study, and 4 and 44 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. When tazarotene was given orally to experimental animals, developmental delays were seen in rats; and teratogenic effects and post-implantation loss were observed in rats and rabbits at doses producing 1.1 and 26 times, respectively, the systemic exposure seen in a psoriatic patient treated topically with tazarotene cream, 0.1% at 2 mg/cm² over a 35% body surface area in a controlled pharmacokinetic study and 3.5 and 85 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, a number of classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations at that dose was observed. The dose produced a systemic exposure 3.4 times that observed in a psoriatic patient treated with tazarotene cream, 0.1% at 2 mg/cm² over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area. Nursing Mothers After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. The safe use of TAZORAC® Cream during lactation has not been established. A decision should be made whether to discontinue breast-feeding or to discontinue TAZORAC® Cream therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Pediatric Use The safety and efficacy of tazarotene have not been established in patients with psoriasis under the age of 18 years, or in patients with acne under the age of 12 years. Geriatric Use TAZORAC® Cream for the treatment of acne has not been clinically tested in persons 65 years of age or older. Of the total number of subjects in clinical trials of TAZORAC® Cream for plaque psoriasis, 120 were over the age of 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Currently there is no other clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.