Tazarotene

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Tazarotene Prescribing Information

Apply a pea-sized amount of tazarotene cream to lightly cover the entire face once daily at bedtime. (
2 DOSAGE AND ADMINISTRATION
Apply a pea-sized amount of tazarotene cream to lightly cover the entire face once daily at bedtime.
If contact with eyes occurs, rinse thoroughly with water.
Not for ophthalmic, oral, or intravaginal use.
2.1 Assessment Prior to Treatment Initiation
Obtain a pregnancy test within 2 weeks prior to tazarotene cream therapy. Initiate tazarotene cream therapy during a menstrual period
[see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]
.
Carefully assess facial pigmented lesions of concern by a qualified physician (e.g., dermatologist) before application of tazarotene cream
[see Warnings and Precautions (5.4)]
.
2.2 Important Administration Instructions
Avoid accidental transfer of tazarotene cream 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.
Emollients or moisturizers can be applied either before or after applying tazarotene cream. However, ensure that the first cream or lotion has absorbed into the skin and has dried completely before subsequent cream or lotion application. Use facial moisturizers as frequently as desired
[see Warnings and Precautions (5.2)].
Tazarotene cream is for topical use only. Tazarotene cream is not for ophthalmic, oral, or intravaginal use.
Use effective sunscreens and wear protective clothing while using tazarotene cream
[see Warnings and Precautions (5.3)].
2.3 Dosage and Administration Instructions
Remove any makeup before applying tazarotene cream to the face. Dry the skin before applying the cream after face washing, bathing, or showering.
Apply a pea-sized amount once a day at bedtime to lightly cover the entire face, including the eyelids, if desired.
Wash hands thoroughly after application.
)
If contact with eyes occurs, rinse thoroughly with water. (
2 DOSAGE AND ADMINISTRATION
Apply a pea-sized amount of tazarotene cream to lightly cover the entire face once daily at bedtime.
If contact with eyes occurs, rinse thoroughly with water.
Not for ophthalmic, oral, or intravaginal use.
2.1 Assessment Prior to Treatment Initiation
Obtain a pregnancy test within 2 weeks prior to tazarotene cream therapy. Initiate tazarotene cream therapy during a menstrual period
[see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]
.
Carefully assess facial pigmented lesions of concern by a qualified physician (e.g., dermatologist) before application of tazarotene cream
[see Warnings and Precautions (5.4)]
.
2.2 Important Administration Instructions
Avoid accidental transfer of tazarotene cream 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.
Emollients or moisturizers can be applied either before or after applying tazarotene cream. However, ensure that the first cream or lotion has absorbed into the skin and has dried completely before subsequent cream or lotion application. Use facial moisturizers as frequently as desired
[see Warnings and Precautions (5.2)].
Tazarotene cream is for topical use only. Tazarotene cream is not for ophthalmic, oral, or intravaginal use.
Use effective sunscreens and wear protective clothing while using tazarotene cream
[see Warnings and Precautions (5.3)].
2.3 Dosage and Administration Instructions
Remove any makeup before applying tazarotene cream to the face. Dry the skin before applying the cream after face washing, bathing, or showering.
Apply a pea-sized amount once a day at bedtime to lightly cover the entire face, including the eyelids, if desired.
Wash hands thoroughly after application.
)
Not for ophthalmic, oral, or intravaginal use. (
2 DOSAGE AND ADMINISTRATION
Apply a pea-sized amount of tazarotene cream to lightly cover the entire face once daily at bedtime.
If contact with eyes occurs, rinse thoroughly with water.
Not for ophthalmic, oral, or intravaginal use.
2.1 Assessment Prior to Treatment Initiation
Obtain a pregnancy test within 2 weeks prior to tazarotene cream therapy. Initiate tazarotene cream therapy during a menstrual period
[see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]
.
Carefully assess facial pigmented lesions of concern by a qualified physician (e.g., dermatologist) before application of tazarotene cream
[see Warnings and Precautions (5.4)]
.
2.2 Important Administration Instructions
Avoid accidental transfer of tazarotene cream 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.
Emollients or moisturizers can be applied either before or after applying tazarotene cream. However, ensure that the first cream or lotion has absorbed into the skin and has dried completely before subsequent cream or lotion application. Use facial moisturizers as frequently as desired
[see Warnings and Precautions (5.2)].
Tazarotene cream is for topical use only. Tazarotene cream is not for ophthalmic, oral, or intravaginal use.
Use effective sunscreens and wear protective clothing while using tazarotene cream
[see Warnings and Precautions (5.3)].
2.3 Dosage and Administration Instructions
Remove any makeup before applying tazarotene cream to the face. Dry the skin before applying the cream after face washing, bathing, or showering.
Apply a pea-sized amount once a day at bedtime to lightly cover the entire face, including the eyelids, if desired.
Wash hands thoroughly after application.
)

Risk Summary

Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, tazarotene cream 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 cream during pregnancy; therefore, tazarotene cream should be discontinued as soon as pregnancy is recognized

[see

4 CONTRAINDICATIONS

Tazarotene cream 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.
Known Hypersensitivity.

5.1 Embryofetal Toxicity

Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic absorption, tazarotene cream 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 cream use during pregnancy; therefore, discontinue tazarotene cream 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 tazarotene cream 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 these orally treated animals. Although there may be less systemic exposure in the treatment of the face alone due to less surface area for application, tazarotene is a teratogenic substance in animals, and it is not known what level of exposure is required for teratogenicity in humans

[see Clinical Pharmacology (12.3)].

Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to tazarotene cream therapy. Initiate tazarotene cream therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with tazarotene cream

[see Dosage and Administration (2), Use in Specific Populations (8.3)]

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.

Tazarotene cream 0.1% was topically applied once daily over four weeks to either the face (6 females and 2 males) or to 15% of body surface area (8 females and 8 males) in subjects with fine wrinkling and mottled hyperpigmentation. In the "face-only" dosing group, the maximum average C_maxand AUC_0-24hrvalues of tazarotenic acid occurred on Day 15 with mean ± SD values of C_maxand AUC_0-24hrof tazarotenic acid being 0.236 ± 0.255 ng/mL (N=8) and 2.44 ± 1.38 ng∙hr/mL (N=8), respectively. The mean C_maxand AUC_0-24hrvalues of tazarotenic acid from subjects in the 15% body surface area dosing group were approximately 10 times higher than those from subjects in the face-only dosing group. The single highest C_maxthroughout the trial period was 3.43 ng/mL on day 29 from subjects in the 15% body surface area dosing group. Gender had no influence on the systemic bioavailability of tazarotenic acid.

Blood samples were collected from one of the two phase 3 trials to evaluate the systemic exposure following application of tazarotene cream 0.1% once daily for 24 weeks (double-blind period) followed by 28 weeks (open-label) under clinical conditions. The mean plasma tazarotenic acid concentrations, following topical treatment with tazarotene cream 0.1% over 52 weeks, ranged between 0.092 ± 0.073 ng/mL and 0.127 ± 0.142 ng/mL. The single highest observed tazarotenic acid concentration throughout the 52-week trial was 0.705 ng/mL (observed at week 36). Systemic availability of tazarotenic acid was minimal and remained steady following once daily application of tazarotene cream 0.1% to the faces of subjects in the trial for up to 52 weeks.

Limited case reports of pregnancy in females enrolled in clinical trials for tazarotene cream 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 2 times the maximum systemic exposure in subjects treated with the maximum recommended human dose (MRHD) of tazarotene cream, 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 26 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, there was a single incident 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 2 and 52 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 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 7 times higher than the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%

[see

Data

Animal Data

In rats, a tazarotene 0.05% gel formulation dosed topically during gestation days 6 through 17 at 0.25 mg/kg/day, which represented 2 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1% (

i.e.

, 2 mg/cm²over a 15% 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 26 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, during gestation days 6 through 18, had a single incident 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 representing 2 and 52 times, respectively, the maximum systemic exposure seen in subjects treated with the MRHD of tazarotene cream, 0.1%.

In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, which represented 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, 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 observed at that dose.

In a pre- and postnatal development toxicity study, topical administration of tazarotene gel (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 maximum systemic exposure in the rat would be equivalent to the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%.

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 to 4% and 15 to 20%, respectively.

Tazarotene cream is contraindicated in:

Pregnancy. Retinoids may cause fetal harm when administered to a pregnant female

[see

5.1 Embryofetal Toxicity
Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic absorption, tazarotene cream 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 cream use during pregnancy; therefore, discontinue tazarotene cream 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 tazarotene cream 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 these orally treated animals. Although there may be less systemic exposure in the treatment of the face alone due to less surface area for application, tazarotene is a teratogenic substance in animals, and it is not known what level of exposure is required for teratogenicity in humans
[see Clinical Pharmacology (12.3)].
Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to tazarotene cream therapy. Initiate tazarotene cream therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with tazarotene cream
[see Dosage and Administration (2), Use in Specific Populations (8.3)]
.
,

8.1 Pregnancy
Risk Summary
Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, tazarotene cream 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 cream during pregnancy; therefore, tazarotene cream 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 cream 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 2 times the maximum systemic exposure in subjects treated with the maximum recommended human dose (MRHD) of tazarotene cream, 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 26 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, there was a single incident 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 2 and 52 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 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 7 times higher than the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 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 to 4% and 15 to 20%, respectively.
Data
Animal Data
In rats, a tazarotene 0.05% gel formulation dosed topically during gestation days 6 through 17 at 0.25 mg/kg/day, which represented 2 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1% (
i.e.
, 2 mg/cm²over a 15% 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 26 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, during gestation days 6 through 18, had a single incident 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 representing 2 and 52 times, respectively, the maximum systemic exposure seen in subjects treated with the MRHD of tazarotene cream, 0.1%.
In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, which represented 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, 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 observed at that dose.
In a pre- and postnatal development toxicity study, topical administration of tazarotene gel (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 maximum systemic exposure in the rat would be equivalent to the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%.
,

8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential within 2 weeks prior to initiating tazarotene cream therapy which should begin during a menstrual period.
Contraception
Females
Based on animal studies, tazarotene cream may cause fetal harm when administered to a pregnant woman
[see Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with tazarotene cream.
]

.
Individuals who have known hypersensitivity to any of its components.

[see

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 tazarotene 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 adverse reactions occur, discontinue the medication until the integrity of the skin is restored, or reduce the dosing to an interval the patient can tolerate. Closely monitor the frequency of application by carefully observing the therapeutic response and skin tolerance.
Avoid concomitant use of topical medications and cosmetics that have a strong drying effect. It is also advisable to "rest" a patient's skin until the effects of such preparations subside before use of tazarotene cream is begun.
Avoid using tazarotene cream on eczematous skin because such use may cause severe irritation.
Weather extremes, such as wind or cold, may be more irritating to patients using tazarotene cream.
].

Embryo-Fetal Toxicity:
May cause fetal harm when administered to a pregnant woman. Obtain a pregnancy test in females of reproductive potential within 2 weeks prior to initiating treatment. Advise females of reproductive potential to use effective contraception. (

5.1 Embryofetal Toxicity
Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic absorption, tazarotene cream 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 cream use during pregnancy; therefore, discontinue tazarotene cream 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 tazarotene cream 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 these orally treated animals. Although there may be less systemic exposure in the treatment of the face alone due to less surface area for application, tazarotene is a teratogenic substance in animals, and it is not known what level of exposure is required for teratogenicity in humans
[see Clinical Pharmacology (12.3)].
Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to tazarotene cream therapy. Initiate tazarotene cream therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with tazarotene cream
[see Dosage and Administration (2), Use in Specific Populations (8.3)]
.
)
Local Irritation:
Some individuals may experience excessive pruritus, burning, skin redness, or peeling. If these adverse reactions occur, discontinue tazarotene cream until the integrity of the skin has been restored or reduce dosing interval. Avoid using tazarotene cream on eczematous skin, as such use may cause severe irritation. (

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 tazarotene 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 adverse reactions occur, discontinue the medication until the integrity of the skin is restored, or reduce the dosing to an interval the patient can tolerate. Closely monitor the frequency of application by carefully observing the therapeutic response and skin tolerance.
Avoid concomitant use of topical medications and cosmetics that have a strong drying effect. It is also advisable to "rest" a patient's skin until the effects of such preparations subside before use of tazarotene cream is begun.
Avoid using tazarotene cream on eczematous skin because such use may cause severe irritation.
Weather extremes, such as wind or cold, may be more irritating to patients using tazarotene cream.
)
Photosensitivity and Risk of Sunburn:
Avoid exposure to sunlight, sunlamps, and weather extremes. Wear sunscreen daily. Avoid using tazarotene cream if the patient is also taking drugs known to be photosensitizers. (

5.3 Photosensitivity and Risk of Sunburn
Because of heightened burning susceptibility, minimize exposure to ultraviolet rays (including sunlight and sun lamps) during the use of tazarotene cream. Patients must be warned to use sunscreens and protective clothing when using tazarotene cream. Advise patients with sunburn not to use tazarotene cream until the sunburn is fully recovered.
Patients who may have considerable sun exposure because of their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using tazarotene cream.
Avoid using tazarotene cream 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.
)
Lentigo Maligna:
Carefully assess facial pigmented lesions of concern before application of tazarotene cream. (

5.4 Lentigo Maligna
Some facial pigmented lesions are not lentigines, but rather lentigo maligna, a type of melanoma. Before application of tazarotene cream, carefully assess facial pigmented lesions of concern by a qualified physician (e.g., dermatologist) to exclude a diagnosis of lentigo maligna.
)

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