1.1 Plaque Psoriasis

TAZORAC® (tazarotene) Cream, 0.05% and 0.1% are indicated for the topical treatment of patients with plaque psoriasis.

1.2 Acne Vulgaris

TAZORAC (tazarotene) Cream, 0.1% is also indicated for the topical treatment of patients with acne vulgaris.

2.1 Important Administration Instructions

TAZORAC Cream is for topical use only. TAZORAC Cream is not for ophthalmic, oral, or intravaginal use. If contact with mucous membranes occurs, rinse thoroughly with water [see Warnings and Precaution (5.2)].

Wash hands thoroughly after application.

2.2 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.

2.3 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.

Use effective sunscreens and wear protective clothing while using TAZORAC Cream [see Warnings and Precaution (5.3)].

5.1 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 (12.3)].

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 (8.1)].

5.2 Local Irritation and Hypersensitivity Reactions

Local tolerability reactions (including blistering and skin desquamation) and hypersensitivity adverse reactions (including urticaria) have been observed with topical tazarotene. 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.

5.3 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 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.

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.

In human dermal safety trials, TAZORAC Cream, 0.05% and 0.1% did not induce allergic contact sensitization, phototoxicity, or photoallergy.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tazarotene. 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.

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of TAZORAC Cream 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.

8.5 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 subjects, but greater sensitivity of some older individuals cannot be ruled out.

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 RARɣ, but shows relative selectivity for RARβ, and RARɣ and may modify gene expression. The clinical significance of these findings is unknown.

12.3 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.

13.1 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/cm2 over 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 (8.1)]. 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.

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).