FDA Label for Tazarotene

1.1 Plaque Psoriasis

Tazarotene gel, 0.05% is indicated for the topical treatment of patients with plaque psoriasis of up to 20% body surface area involvement.

1.3 Limitations Of Use

The safety of tazarotene gel use on more than 20% body surface area has not been established in psoriasis  [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.1)].

2 Dosage And Administration

Tazarotene gel is for topical use only. Tazarotene gel is not for ophthalmic, oral, or intravaginal use. Avoid accidental transfer of tazarotene gel 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.

2.1 Psoriasis

It is recommended that treatment starts with tazarotene gel, 0.05%, with strength increased to 0.1% if tolerated and medically indicated. Apply a thin film (2 mg/cm ²) of tazarotene gel once per day, in the evening, to cover only the psoriatic lesions on no more than 20% of body surface area. If a bath or shower is taken prior to application, the skin should be dry before applying the gel. If emollients are used, they should be applied at least an hour before application of tazarotene gel. Because unaffected skin may be more susceptible to irritation, application of tazarotene to these areas should be carefully avoided. Tazarotene gel was investigated for up to 12 months during clinical trials for psoriasis.

3 Dosage Forms And Strengths

Gel, 0.05%, in 30 g and 100 g tubes. Each gram of tazarotene gel, 0.05% contains 0.5 mg of tazarotene in a clear to yellow translucent, aqueous gel.

4 Contraindications

Tazarotene gel 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)].

5.1 Embryofetal Toxicity

Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic absorption, tazarotene gel may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Tazarotene elicits malformations and developmental effects associated with retinoids after topical and oral administration to pregnant rats and rabbits during organogenesis.

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 and causes fetal malformations in animals, 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 had 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 the 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 tazarotene gel 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 tazarotene gel therapy. Tazarotene gel therapy should begin during a normal menstrual period [see Use in Specific Populations ( 8.1)].

5.2 Local Irritation And Hypersensitivity Reactions

Application of tazarotene gel may cause excessive irritation in the skin of certain sensitive individuals. Local reactions (including blistering and skin desquamation, pruritus, burning, erythema) and hypersensitivity adverse reactions (including urticaria) have been observed with topical tazarotene.

If these adverse reactions occur, consider discontinuing the medication or reducing the dosing frequency, as appropriate, until the integrity of the skin is restored. 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 treatment with tazarotene gel is initiated.

Tazarotene gel, 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 tazarotene gel.

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 tazarotene gel. Patients must be warned to use sunscreens and protective clothing when using tazarotene gel. Patients with sunburn should be advised not to use tazarotene gel 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 tazarotene gel.

Tazarotene gel 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 Adverse Reactions

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

• Embryofetal toxicity [see Warnings and Precautions ( 5.1)]
• Photosensitivity and Risk of Sunburn [see Warnings and Precautions ( 5.3)]

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.

Psoriasis

A total of 439 subjects 14 to 87 years of age were treated with tazarotene gel, 0.05% and 0.1% in two controlled clinical trials. The most frequent adverse events reported with tazarotene gel, 0.05% and 0.1% occurring in 10 to 30% of subjects, in descending order, included pruritus, burning/stinging, erythema, worsening of psoriasis, irritation, and skin pain. Reactions occurring in 1 to 10% of subjects included rash, desquamation, irritant contact dermatitis, skin inflammation, fissuring, bleeding, and dry skin. Increases in “psoriasis worsening” and “sun-induced erythema” were noted in some subjects over the 4th to 12th months of treatment as compared to the first three months of a 1 year study. In general, the incidence of adverse events with tazarotene gel 0.05% was 2 to 5% lower than that seen with tazarotene gel 0.1%.

6.2 Postmarketing Experience

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

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.

7 Drug Interactions

No formal drug-drug interaction studies were conducted with tazarotene gel.

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 mcg ethinyl estradiol, concomitant use of tazarotene administered as 1.1 mg orally (mean ± SD C _max and AUC _0-24 of tazarotenic acid were 28.9 ± 9.4 ng/mL and 120.6 ± 28.5 ng•hr/mL, respectively) 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.

8.1 Pregnancy

Risk Summary

Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, tazarotene gel 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 gel during pregnancy; therefore, tazarotene gel 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 gel 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 0.5 times the maximum systemic exposure in subjects treated with the maximum recommended human dose (MRHD) of tazarotene gel, 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 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%, there were single incidences 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 0.5 and 13 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 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 2 times higher than the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 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 2-4% and 15-20%, respectively.

Data

Animal Data

In rats, a tazarotene gel, 0.05% formulation dosed topically during gestation days 6 through 17 at 0.25 mg/kg/day, which represented 0.5 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1% (i.e., 2 mg/cm ² over a 20% 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 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%, during gestation days 6 through 18 were noted with single incidences 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 producing 0.5 and 13 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%.

In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, which represented 2 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 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 0.3 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene gel, 0.1%.

8.2 Lactation

Risk Summary

There is no information regarding the presence of tazarotene in human milk, the effects on the breastfed infant, or the effects on milk production. After single topical doses of ¹⁴C-tazarotene gel to the skin of lactating rats, radioactivity was detected in rat milk. The lack of clinical data during lactation precludes a clear determination of the risk of tazarotene gel to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tazarotene gel and any potential adverse effects on the breastfed child from tazarotene gel or from the underlying maternal condition.

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 gel therapy which should begin during a menstrual period.

Contraception

Females

Based on animal studies, tazarotene gel 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 gel.

8.4 Pediatric Use

The safety and efficacy of tazarotene gel have not been established in pediatric patients with psoriasis under the age of 12 years.

8.5 Geriatric Use

Of the total number of subjects in clinical trials of tazarotene gel for plaque psoriasis, 163 were over the age of 65. Subjects over 65 years of age experienced more adverse events and lower treatment success rates after 12 weeks of use of tazarotene gel compared with those 65 years of age and younger. 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.

10 Overdosage

Excessive topical use of tazarotene gel, 0.05% may lead to marked redness, peeling, or discomfort [see Warnings and Precautions ( 5.2)].

Tazarotene gel, 0.05% is 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.

11 Description

Tazarotene gel, 0.05% is for topical use and contains the active ingredient, tazarotene. Each gram of tazarotene gel, 0.05% contains 0.5 mg of tazarotene in a clear to yellow translucent, aqueous gel.

Tazarotene is a member of the acetylenic class of retinoids. Chemically, tazarotene is ethyl 6-[(4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate. The compound has an empirical formula of C ₂₁H ₂₁NO ₂S and molecular weight of 351.46. The structural formula is shown below:

Chemical Structure - structural formula

Tazarotene gel contains the following inactive ingredients: benzyl alcohol 1%; ascorbic acid; butylated hydroxyanisole; butylated hydroxytoluene; carbomer homopolymer type B; edetate disodium; hexylene glycol; poloxamer 407; polyethylene glycol 400; polysorbate 40; purified water; and tromethamine.

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 RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings for the treatment of plaque psoriasis is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of tazarotene gel in the treatment of plaque psoriasis are 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 or psoriatic skin.

The human in vivo studies described below were conducted with tazarotene gel applied topically at approximately 2 mg/cm ² and left on the skin for 10 to 12 hours. Both the peak plasma concentration (C _max) and area under the plasma concentration time curve (AUC) refer to the active metabolite only.

Two single, topical dose studies were conducted using ¹⁴C-tazarotene gel. Systemic absorption, as determined from radioactivity in the excreta, was less than 1% of the applied dose (without occlusion) in six subjects with psoriasis and approximately 5% of the applied dose (under occlusion) in six healthy subjects. One non-radiolabeled single-dose study comparing the 0.05% gel to the 0.1% gel in healthy subjects indicated that the C _max and AUC were 40% higher for the 0.1% gel.

After 7 days of topical dosing with measured doses of tazarotene 0.1% gel on 20% of the total body surface without occlusion in 24 healthy subjects, the C _max for tazarotenic acid was 0.72 ± 0.58 ng/mL (mean ± SD) occurring 9 hours after the last dose, and the AUC _0-24hr for tazarotenic acid was 10.1 ± 7.2 ng·hr/mL. Systemic absorption was 0.91 ± 0.67% of the applied dose.

In a 14-day study in five subjects with psoriasis, measured doses of tazarotene 0.1% gel were applied daily by nursing staff to involved skin without occlusion (8 to 18% of total body surface area; mean ± SD: 13 ± 5%). The C _max for tazarotenic acid was 12.0 ± 7.6 ng/mL occurring 6 hours after the final dose, and the AUC _0-24hr for tazarotenic acid was 105 ± 55 ng·hr/mL. Systemic absorption was 14.8 ± 7.6% of the applied dose. Extrapolation of these results to represent dosing on 20% of total body surface yielded estimates for tazarotenic acid with C _max of 18.9 ± 10.6 ng/mL and AUC _0-24hr of 172 ± 88 ng·hr/mL.

An in vitro percutaneous absorption study, using radiolabeled drug and freshly excised human skin or human cadaver skin, indicated that approximately 4 to 5% of the applied dose was in the stratum corneum (tazarotene: tazarotenic acid = 5:1) and 2 to 4% was in the viable epidermis-dermis layer (tazarotene: tazarotenic acid = 2:1) 24 hours after topical application of the gel.

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 0.3 times that seen in subjects treated with the MRHD of tazarotene gel, 0.1%.

A long-term study with topical administration 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 to vehicle control animals. Systemic exposure at the highest dose was 2 times that seen in subjects treated with the MRHD of tazarotene gel, 0.1%.

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.

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 at the highest dose was 0.3 times that observed in subjects treated with the MRHD of tazarotene gel, 0.1%.

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, which produced systemic exposure that was approximately equivalent to that observed in subjects treated with the MRHD of tazarotene gel, 0.1%.

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 systemic exposure 2 times that observed in subjects treated with the MRHD of tazarotene gel, 0.1% [see Use in Specific Populations ( 8.1)] .

14 Clinical Studies

Psoriasis:In two large vehicle-controlled clinical trials, tazarotene gel, 0.05% and 0.1% applied once daily for 12 weeks was significantly more effective than vehicle in reducing the severity of the clinical signs of plaque psoriasis covering up to 20% of body surface area. In one of the studies, subjects were followed up for an additional 12 weeks following cessation of therapy with tazarotene gel. Mean baseline scores and changes from baseline (reductions) after treatment in these two trials are shown in Table 1.

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).Global improvement over baseline at the end of 12 weeks of treatment in these two trials is shown in Table 2.

The 0.1% gel was more effective than the 0.05% gel, but the 0.05% gel was associated with less local irritation than the 0.1% gel [see Adverse Reactions ( 6.1)] .

16 How Supplied/Storage And Handling

Tazarotene gel is a clear to yellow translucent, aqueous gel, available in concentration of 0.05%. It is available in a collapsible aluminum tube with a tamper-evident aluminum membrane over the opening and a white propylene screw cap, in 30 g and 100 g sizes.

Tazarotene gel 0.05%               30 g    NDC 0713-0805-31

Tazarotene gel 0.05%               100 g  NDC 0713-0805-99

Storage: Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F).

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Embryofetal Toxicity

Inform females of reproductive potential of the potential risk to a fetus. Advise these patients to use effective contraception during treatment with tazarotene gel. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.1, 8.3)] .

Photosensitivity and Risk of Sunburn

Advise patients to avoid excessive sun exposure and to use of sunscreens and protective measures (hat, visor). Advise patients to avoid using tazarotene gel if also taking other medicines may increase sensitivity to sunlight.

Important Administration Instructions

Advise the patient of the following:

• For the patient with psoriasis, apply tazarotene gel 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 ( 2.1)] .
• 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 tazarotene gel.
• Avoid contact with the eyes. If tazarotene gel gets in or near eyes, rinse thoroughly with water. Seek medical attention if eye irritation continues.
• Tazarotene gel is for topical use only. Do not apply to eyes, mouth, or other mucous membrane. Not for ophthalmic, oral, or intravaginal use.
• Wash hands thoroughly after applying tazarotene gel.

Distributed by:

Cosette Pharmaceuticals, Inc.

South Plainfield, NJ 07080

8-0805CPLNC1

Revised: 10/2021   VC7598

Pharmacist: Please cut or tear at dotted line and provide this patient package insert to your customer.