Source: FDA, National Drug Code (US) Revision Year: 2018
TAZORAC Gel is contraindicated in:
Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic absorption, TAZORAC 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.
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 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 should be warned of the potential risk and use adequate birth-control measures when TAZORAC 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 TAZORAC Gel therapy. TAZORAC Gel therapy should begin during a normal menstrual period [see Use in Specific Populations (8.1)].
Application of TAZORAC 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 TAZORAC Gel is initiated.
TAZORAC 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 TAZORAC Gel.
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 Gel. Patients must be warned to use sunscreens and protective clothing when using TAZORAC Gel. Patients with sunburn should be advised not to use TAZORAC 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 TAZORAC Gel.
TAZORAC 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.
The following serious adverse reactions are discussed in more detail in other sections of the labeling:
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.
A total of 439 subjects 14 to 87 years of age were treated with TAZORAC Gel, 0.05% and 0.1% in two controlled clinical trials. The most frequent adverse events reported with TAZORAC 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 TAZORAC Gel 0.05% was 2 to 5% lower than that seen with TAZORAC Gel 0.1%.
A total of 596 subjects 12 to 44 years of age were treated with TAZORAC Gel, 0.05% and 0.1% in two controlled clinical trials. The most frequent adverse events reported during clinical trials with TAZORAC Gel, 0.1% in the treatment of acne occurring in 10 to 30% of subjects, in descending order, included desquamation, burning/stinging, dry skin, erythema and pruritus. Reactions occurring in 1 to 10% of subjects included irritation, skin pain, fissuring, localized edema and skin discoloration.
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.
No formal drug-drug interaction studies were conducted with TAZORAC 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 Cmax and AUC0-24 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.
Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, TAZORAC 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 TAZORAC Gel during pregnancy; therefore, TAZORAC 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 TAZORAC 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.
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/cm² 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%.
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 TAZORAC 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 TAZORAC Gel and any potential adverse effects on the breastfed child from TAZORAC Gel or from the underlying maternal condition.
Pregnancy testing is recommended for females of reproductive potential within 2 weeks prior to initiating TAZORAC Gel therapy which should begin during a menstrual period.
Based on animal studies, TAZORAC 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 TAZORAC Gel.
The safety and efficacy of TAZORAC Gel have not been established in pediatric patients with psoriasis or acne under the age of 12 years.
Of the total number of subjects in clinical trials of TAZORAC 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 TAZORAC 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. Tazarotene gel for the treatment of acne has not been clinically evaluated in persons over the age of 65.
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