FABIOR (Page 2 of 5)

7 DRUG INTERACTIONS

No formal drug-drug interaction studies were conducted with FABIOR Foam.

Concomitant dermatologic medications and cosmetics that have a strong drying effect should be avoided. It is recommended to postpone treatment until the effects of these products subside before use of FABIOR Foam is started.

Concomitant use with oxidizing agents, such as benzoyl peroxide, may cause degradation of tazarotene and may reduce the clinical efficacy of tazarotene. If combination therapy is required, they should be applied at different times of the day (e.g., one in the morning and the other in the evening).

The impact of tazarotene on the pharmacokinetics of progestin-only oral contraceptives (i.e., minipills) has not been evaluated.

In a trial of 27 healthy female subjects between the ages of 20 to 55 years receiving a combination oral contraceptive tablet containing 1 mg norethindrone and 35 mcg ethinyl estradiol, concomitant use of tazarotene did not affect the pharmacokinetics of norethindrone and ethinyl estradiol over a complete cycle.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X.

FABIOR Foam is contraindicated in pregnancy [see Contraindications (4)].

There are no adequate and well-controlled studies with FABIOR Foam in pregnant women. FABIOR Foam is contraindicated in females who are or may become pregnant [see Contraindications (4)]. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when FABIOR Foam 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 serum or urine result for pregnancy test having a sensitivity down to at least 25 mIU/mL for hCG should be obtained within 2 weeks prior to therapy with FABIOR Foam, which should begin during a normal menstrual period for females of childbearing potential.

In rats, tazarotene 0.05% gel 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 (AUC) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits were 15 and 166 times, respectively, the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

As with other retinoids, when tazarotene was administered 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 13 and 325 times, respectively, the AUC to tazarotenic acid in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

In female rats orally administered 2 mg/kg/day 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 was also observed. AUC in rats was 42 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

8.3 Nursing Mothers

After single topical doses of 14 C-tazarotene 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 FABIOR Foam during lactation has not been established. A decision should be made whether to discontinue breastfeeding or to discontinue therapy with FABIOR Foam taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

8.4 Pediatric Use

The safety and effectiveness of FABIOR Foam in pediatric patients younger than 12 years have not been established. Clinical studies of FABIOR Foam included 860 patients aged 12 to 17 years with acne vulgaris.

8.5 Geriatric Use

FABIOR Foam for the treatment of acne has not been clinically evaluated in persons over the age of 65.

10 OVERDOSAGE

Excessive topical application of FABIOR Foam may lead to marked redness, peeling, or discomfort. [see Warnings and Precautions (5.2)]. Management of accidental ingestion or excessive application to the skin should be as clinically indicated.

11 DESCRIPTION

FABIOR (tazarotene) Foam, 0.1% contains the compound tazarotene, a member of the acetylenic class of retinoids. It is for topical use only.

Chemically, tazarotene is ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate. The structural formula is represented below:

Chemical Structure
(click image for full-size original)

Molecular Formula: C21 H21 NO2 S Molecular Weight: 351.46

Tazarotene is a pale yellow to yellow substance. FABIOR Foam contains tazarotene, 1 mg/g, in aqueous-based white to off-white foam vehicle consisting of butylated hydroxytoluene, ceteareth-12, citric acid anhydrous, diisopropyl adipate, light mineral oil, potassium citrate monohydrate, potassium sorbate, purified water, and sorbic acid. FABIOR Foam is dispensed from an aluminum can pressurized with a hydrocarbon (propane/n-butane/isobutane) propellant.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tazarotene is a retinoid prodrug that is converted to its active form, the cognate carboxylic acid of tazarotene, by rapid deesterification in animals and man. Tazarotenic acid binds to all 3 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.

The mechanism of tazarotene action in acne vulgaris is not defined. However, the basis of tazarotene’s therapeutic effect in acne may be due to its anti-hyperproliferative, normalizing-of-differentiation and anti-inflammatory effects. Tazarotene inhibited corneocyte accumulation in rhino mouse skin and cross- linked envelope formation in cultured human keratinocytes. The clinical significance of these findings is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of FABIOR Foam are unknown.

12.3 Pharmacokinetics

Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. 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.

Systemic exposure following topical application of FABIOR Foam 0.1% was evaluated in one trial. Patients aged 15 years and older with moderate-to-severe acne applied approximately 3.7 grams of FABIOR Foam 0.1% (N = 13) to approximately 15% body surface area (face, upper chest, upper back, and shoulders) once daily for 22 days. On Day 22, the mean (±SD) tazarotenic acid Cmax was 0.43 (±0.19) ng/mL, the AUC0 -24h was 6.98 (±3.56) ng∙h/mL, and the half-life was 21.7 (±15.7) hours. The median Tmax was 6 hours (range: 4.4 to 12 hours). The AUC0-24h for tazarotenic acid was approximately 50-fold higher compared with the parent compound tazarotene. The mean (±SD) half-life of tazarotene was 8.1 (±3.7) hours.

Accumulation was observed upon repeated once-daily dosing as the tazarotenic acid predose concentrations were measurable in the majority of subjects. Steady state was attained within 22 days of daily application. Once-daily dosing resulted in little to no accumulation of tazarotene as predose concentrations were mostly below the quantitation limit throughout the study.

13 NONCLINICAL TOXICOLOGY

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 risk. 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 rats approximately 2 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

A long-term topical application study of up to 0.1% 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 with vehicle control animals. AUC at the highest dose in mice was 49 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

In evaluation of photocarcinogenicity, median time to onset of tumors was decreased and the number of tumors increased in hairless mice following chronic topical dosing with 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 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 was observed 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 at the 0.125 mg/kg/day dose in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% 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. AUC at the highest dose in rats was 23 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

No effect on parameters 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 of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose [see Pregnancy (8.1)]. AUC at the highest dose in rats was 42 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% 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 AUC in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

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