Brands, Medical Use, Clinical Data
Drug Category
- Dermatologic Agents
- Keratolytic Agents
- Prodrugs
- Teratogens
Dosage Forms
- Cream or gel (0.05% or 0.1%)
Brands / Synonyms
Avage; Tazarotene [USAN:INN]; Tazorac; Zorac
Indications
Used to treat psoriasis, acne and sun damaged skin (photodamage).
Pharmacology
Tazarotene is a prodrug and a member of the acetylenic class of retinoids. Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. When treating acne tazarotene may be taken in conjunction with an oral antibiotic. Tazarotene has been shown in peer-reviewed double blinded studies to reduce: mottling and hyperpigmentation, sallowness, fine wrinkling and coarse wrinkling in sun damaged skin. Histological studies have shown that long term (greater than 1 year) use of Tazarotene is associated with a significant reduction in atypical melanocytes and keratocytes - cells considered to be precursors of skin cancer. Some studies have shown long term use of Tazarotene to be associated with increased collagen production and better organization of skin collagen bundles.
Mechanism of Action
Although the exact mechanism of tazarotene action is not known, studies have shown that the active form of the drug (tazarotenic acid) binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARb, and RARg, but shows relative selectivity for RARb, and RARg and may modify gene expression.
Absorption
Minimal systemic absorption of tazarotene occurs due to its rapid metabolism in the skin to the active metabolite, tazarotenic acid, which can be systemically absorbed and further metabolized. Gender had no influence on the systemic bioavailability of tazarotenic acid.
Toxicity
Excessive topical use may lead to marked redness, peeling, or discomfort. Oral ingestion of the drug may affect liver function causing hypertriglyceridemia. Other symptoms may include conjunctival irritation, hair loss, headache, edema, fatigue, dermatitis, nausea, and visual disturbances. Oral administration of this material to rats and rabbits at doses of 0.20 mg/kg/day (rabbits) and 0.25 mg/kg/day (rats) resulted in developmental toxicity. A no effect level of 0.05 mg/kg/day was established. Similar teratogenic effects have been reported for other retinoid compounds.
Biotrnasformation / Drug Metabolism
Undergoes esterase hydrolysis in skin to form its active metabolite, tazarotenic acid. Tazarotenic acid is further metabolized in skin and, after systemic absorption, hepatically metabolized to sulfoxides, sulfones, and other polar products for elimination.
Contraindications
Retinoids may cause fetal harm when administered to a pregnant woman.
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 (AUC0-24h) to tazarotenic acid at topical doses of 0.25 mg/kg/day
tazarotene in a gel formulation in rats and rabbits represented 2.4 and 26 times, respectively, the maximum
AUC0-24h in patients treated with 2 mg/cm2 of tazarotene cream 0.1% over 15% body surface area
for fine wrinkling and mottled hyperpigmentation. As with other retinoids, when tazarotene was given 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 producing 2.1 and 52 times, respectively, the maximum AUC0-24h in
patients treated with 2 mg/cm2 of tazarotene cream 0.1% over 15% body surface area for fine wrinkling and mottled
hyperpigmentation. In a study of the effect of oral tazarotene on fertility and early embryonic development in rats,
decreased number of implantation sites, decreased litter size, decreased number of live fetuses, and decreased fetal
body weights, all classic developmental effects of retinoids, were observed when female rats were administered 2
mg/kg/day from 15 days before mating through gestation day 7. A low incidence of retinoid-related malformations at
that dose were reported to be related to treatment. That dose produced an AUC0-24h that was 6.7 times the
maximum AUC0-24h in patients treated with 2 mg/cm2 of tazarotene cream 0.1% over 15% body surface area for signs of
fine wrinkling and mottled hyperpigmentation.
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. As a retinoid, tazarotene is a teratogenic substance, and it is not known what level
of exposure is required for teratogenicity in humans. However, there may be less systemic exposure in the treatment
of the face alone, due to less surface area for application.
There were thirteen reported pregnancies in patients who participated in clinical trials for topical
tazarotene. Nine of the patients were found to have been treated with topical tazarotene, and the other four had been
treated with vehicle. One of the patients 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 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.
AVAGE™ Cream is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient apprised
of the potential hazard to the fetus. Women of child-bearing potential should be warned of the potential risk and use
adequate birth-control measures when AVAGE™ Cream is used. The possibility that a woman of childbearing
potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy
test having a sensitivity down to at least 50 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within
2 weeks prior to AVAGE™ Cream therapy, which should begin during a normal menstrual period.
AVAGE™ Cream is contraindicated in individuals who have shown hypersensitivity to any of its
components.
Drug Interactions
Concomitant dermatologic 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 use of
AVAGE™ Cream is begun.
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 1.4
times the maximum AUC0-24h in patients treated with 2 mg/cm2 of tazarotene cream 0.1% over 15% body
surface area for fine wrinkling and mottled hyperpigmentation.
In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the
number of tumors increased in hairless mice following chronic topical dosing with intercurrent exposure to
ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40
weeks. 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 1.0 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; untreated control animals were not completely evaluated. Systemic exposure (AUC0-12h) at the
highest dose was 7.8 times the maximum AUC0-24h in patients treated with 2 mg/cm2 of tazarotene cream 0.1%
over 15% body surface area for fine wrinkling and mottled hyperpigmentation.
Tazarotene was found to be non-mutagenic in the Ames assays using Salmonella and E. coli and
did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was also 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 would be equivalent to 1.2 times the maximum AUC0-24h in patients treated with 2
mg/cm2 of tazarotene cream 0.1% over 15% body surface area for fine wrinkling and mottled hyperpigmentation.
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 1.0 mg/kg/day tazarotene. That dose produced an AUC0-24h that was 3.7
times the maximum AUC0-24h in patients treated with 2 mg/cm2 of tazarotene cream 0.1% over 15%
body surface area for fine wrinkling and mottled hyperpigmentation.
No effect on parameters of mating performance or fertility was observed in female rats treated for 15
days prior to mating and continuing through day 7 of gestation with oral doses of tazarotene up to 2.0 mg/kg/day.
However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at
that dose. That dose produced an AUC0-24h that was 6.7 times the maximum AUC0-24h in patients
treated with 2 mg/cm2 of tazarotene cream 0.1% over 15% body surface area for signs of fine wrinkling and mottled
hyperpigmentation.
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 systemic drug exposure in the
rat would be equivalent to 1.2 times the maximum AUC0-24h in patients treated with 2 mg/cm2 of tazarotene
cream 0.1% over 15% body surface area for fine wrinkling and mottled hyperpigmentation.
Pregnancy: Teratogenic Effects: Pregnancy Category X:
See CONTRAINDICATIONS section. Women of child-bearing potential should use adequate
birth-control measures when AVAGE™ Cream is used. The possibility that a woman of childbearing potential is
pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test having a
sensitivity down to at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to AVAGE™ Cream therapy,
which should begin during a normal menstrual period. There are no adequate and well-controlled studies in pregnant
women. As a retinoid, tazarotene is a teratogenic substance, and it is not known what level of exposure is required
for teratogenicity in humans. However, there may be less systemic exposure in the treatment of the face alone, due to
less surface area for application (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Nursing mothers
After single topical doses of 14C-tazarotene gel 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. Caution should be exercised when tazarotene is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of tazarotene cream have not been established in patients under the age of 17
years with facial fine wrinkling, facial mottled hypo-and hyperpigmentation, and benign facial lentigines.
Geriatric Use
In the studies of facial fine wrinkling, facial mottled hypo- and hyperpigmentation, and benign
facial lentigines , 44 male patients and 180 female patients out of the total population of 1131 patients were older
than 65 years of age. No overall differences in safety or effectiveness were observed between these patients and
younger patients, and other clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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