5.1 Embryofetal Toxicity

Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic absorption, ARAZLO may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy .Safety in pregnant patients has not been established. The potential risk to the fetus outweighs the potential benefit to the mother; therefore, discontinue ARAZLO as soon as pregnancy is recognized.

Tazarotene elicits malformations and developmental effects associated with retinoids after topical and oral administration to pregnant rats and rabbits during organogenesis. However, limited case reports of pregnancy in females enrolled in clinical trials for ARAZLO have not reported a clear association with tazarotene and major birth defects or miscarriage risk [see Contraindications (4), Use in Specific Populations (8.1)] .

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. Tazarotene is a teratogenic substance in animals, and it is not known what level of exposure is required for teratogenicity in humans.

Advise pregnant patients of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to ARAZLO therapy. Initiate ARAZLO therapy during a menstrual period. Advise patients of childbearing potential to use effective contraception during treatment with ARAZLO [see Dosage and Administration (2), Use in Specific Populations (8.3)] .

5.2 Skin Irritation

Patients using ARAZLO may experience application site pain, dryness, exfoliation, erythema, and pruritus. Depending upon severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of the application of ARAZLO, or discontinue use. Therapy can be resumed, or the frequency of application can be increased, as the patient becomes able to tolerate treatment.

Avoid use of concomitant medications and cosmetics that have a strong drying effect. It is recommended to postpone treatment with ARAZLO until the drying effects of these products subside.

Avoid application of ARAZLO to eczematous or sunburned skin.

5.3 Photosensitivity and Risk for Sunburn

Because of heightened burning susceptibility, minimize unprotected exposure to ultraviolet light including sunlight and sunlamps during the use of ARAZLO. Warn patients who normally experience high levels of sun exposure and those with inherent sensitivity to sun to exercise caution. Use sunscreen products and protective clothing over treated areas when sun exposure cannot be avoided. Patients with sunburn should be advised not to use ARAZLO until fully recovered.

ARAZLO should be administered with caution if the patient is taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity.

Weather extremes, such as wind or cold, may be more irritating to patients using ARAZLO.

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 2 multicenter, randomized, double-blind, vehicle-controlled clinical trials, subjects age 9 years and older applied ARAZLO or vehicle once daily for 12 weeks. The majority of subjects were White (74%) and female (66%). Approximately 22% were Hispanic/Latino and 42% were younger than 18 years of age, fourteen of 779 subjects (1.8%) treated with ARAZLO were between 9 years to less than 12 years of age. Adverse reactions reported by ≥1% of subjects treated with ARAZLO and more frequently than subjects treated with vehicle are summarized in Table 1. Most adverse reactions were mild to moderate in severity. Severe adverse reactions represented 1.3% of the subjects treated. Overall, 2.4% (19/779) of subjects discontinued ARAZLO because of local skin reactions.

Table 1:Adverse Reactions Reported by ≥1% of the ARAZLO Group and More Frequently than the Vehicle Group

Skin irritation was evaluated by active assessment of erythema, scaling, itching, burning and stinging, with grades for none, mild, moderate, or severe. The maximum severity generally peaked at Week 2 of therapy and decreased thereafter. The percentage of subjects with these signs and symptoms at any post-baseline visit are summarized in Table 2.

Table 2: Incidence of Local Cutaneous Irritation at any Post-Baseline Visit

8.1 Pregnancy

Risk Summary

ARAZLO is contraindicated in pregnancy.

There are no available data on ARAZLO use in pregnant patients to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, ARAZLO may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The potential risk to the fetus outweighs the potential benefit to the mother; therefore, ARAZLO should be discontinued as soon as pregnancy is recognized.

In animal reproduction studies with pregnant rats, reduced fetal body weights and reduced skeletal ossification were observed after topical administration of a tazarotene gel formulation during the period of organogenesis at a dose equivalent to the maximum recommended human dose (MRHD) (based on AUC comparison). In animal reproduction studies with pregnant rabbits, single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were observed after topical administration of a tazarotene gel formulation at 15 times the MRHD (based on AUC comparison) (see Data).

In animal reproduction studies with pregnant rats and rabbits, malformations, fetal toxicity, developmental delays, and/or behavioral delays were observed after oral administration of tazarotene during the period of organogenesis at doses 1 and 30 times, respectively, the MRHD (based on AUC comparison). In pregnant rats, decreased litter size, decreased numbers of live fetuses, decreased fetal body weights, and increased malformations were observed after oral administration of tazarotene prior to mating through early gestation at doses 6 times the MRHD (based on AUC comparison) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. 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 an embryofetal development study in rats, a tazarotene gel formulation, 0.5% (0.25 mg/kg/day tazarotene) was topically administered to pregnant rats during gestation days 6 through 17. Reduced fetal body weights and reduced skeletal ossification occurred at this dose (equivalent to the MRHD based on AUC comparison). In an embryofetal development study in rabbits, a tazarotene gel formulation, 0.5% (0.25 mg/kg/day tazarotene) was topically administered to pregnant rabbits during gestation days 6 through 18. Single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were noted at this dose (15 times the MRHD based on AUC comparison).

When tazarotene was given orally to animals, developmental delays were seen in rats; malformations and post- implantation loss were observed in rats and rabbits at doses producing 1 and 30 times, respectively, the MRHD (based on AUC comparison).

In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, classic developmental effects of retinoids including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights were observed at this dose (6 times the MRHD based on AUC comparison). A low incidence of retinoid-related malformations was observed at this dose.

In a pre- and postnatal development toxicity study, topical administration of a tazarotene gel formulation (0.125 mg/kg/day) to pregnant female rats from gestation day 16 through lactation day 20 reduced pup survival, but did not affect the reproductive capacity of the offspring. Based on data from another study, the systemic drug exposure in the rat at this dose would be equivalent to the MRHD (based on AUC comparison).

8.2 Lactation

Risk Summary

There are no data on the presence of tazarotene or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. After single topical doses of a 14C-tazarotene gel formulation to the skin of lactating rats, radioactivity was detected in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARAZLO and any potential adverse effects on the breastfed child from ARAZLO.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use ARAZLO for the shortest duration possible while breastfeeding. Advise breastfeeding patients not to apply ARAZLO directly to the nipple and areola to prevent direct infant exposure.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for patients of childbearing potential within 2 weeks prior to initiating ARAZLO therapy which should begin during a menstrual period.

Contraception

Advise patients of childbearing potential to use effective contraception during treatment with ARAZLO.

8.4 Pediatric Use

Safety and effectiveness of ARAZLO for the topical treatment of acne vulgaris have been established in pediatric patients age 9 years and older based on evidence from two multicenter, randomized, double-blind, parallel-group, vehicle-controlled, 12-week clinical trials and an open-label pharmacokinetic study. A total of 300 pediatric subjects aged 9 to less than 17 years received ARAZLO in the clinical studies [see Clinical Pharmacology (12.3)and Clinical Studies (14)] .

The safety and effectiveness of ARAZLO in pediatric patients below the age of 9 years have not been established.

8.5 Geriatric Use

Clinical trials of ARAZLO did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

Tazarotene is a retinoid prodrug which is converted to its active form, tazarotenic acid, 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 acne vulgaris is unknown.

12.3 Pharmacokinetics

Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Tazarotenic acid is highly bound to plasma proteins (greater than 99%).

Systemic exposure following topical application of ARAZLO was evaluated in 28 subjects in an open-label, randomized, pharmacokinetic study. Subjects aged 9 years and older with moderate to severe acne applied approximately 4 grams of ARAZLO to the entire face (excluding eyes and lips), neck, upper chest, upper back and shoulders once daily for 14 Days.

The majority of collected samples had concentrations below the limit of quantification (LOQ) for tazarotene (0.005 ng/mL). The mean C maxand mean AUC (0-t)values for tazarotene from quantifiable samples were 0.007 ng/mL and 0.164 ng•hr/mL on Day 14 to 15, respectively. The mean C maxand AUC (0-t)of tazarotene in subjects aged 9 to less than 12 years was approximately 3.7 and 3.6 fold higher, respectively, compared to that observed in subjects 12 years and older.

Tazarotenic acid concentrations were measurable in the majority of samples following single and repeated topical administration of ARAZLO (LOQ = 0.005 ng/mL). The mean C maxand AUC (0-t)values for tazarotenic acid from quantifiable samples were 0.365 ng/mL and 5.72 ng•hr/mL on Days 14 to 15, respectively. The mean C maxand AUC (0-t)of tazarotenic acid in subjects aged 9 to less than 12 years was approximately 2.4 and 2.3 fold higher, respectively, compared to that observed in subjects 12 years and older.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 the MRHD (based on AUC comparison).

A long-term study with topical application 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. Tazarotenic acid systemic exposures at the highest dose was 7 times the MRHD (based on AUC comparison).

Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in human lymphocytes. Tazarotene was non-mutagenic in CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in an in vivo mouse micronucleus test.

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 a tazarotene gel formulation up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat at the highest dose was equivalent to the MRHD (based on AUC comparison).

No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of tazarotene up to 1 mg/kg/day which produced a systemic exposure 4 times the MRHD (based on AUC comparison).

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 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 which produced a systemic exposure 6 times the MRHD (based on AUC comparison).