Tazorac
Tazorac Information
Product Code 54868-4456 Company Name Physicians Total Care, Inc. Dosage From GEL Strength 1 mg Active Ingredient TAZAROTENE
Tazorac (Tazarotene) Description
TAZORAC Gel is a translucent, aqueous gel and contains the compound tazarotene, a member of the acetylenic class of retinoids. It is for topical dermatologic use only. The active ingredient is represented by the following structural formula:
Ethyl 6-[2-(4,4-dimethylthiochroman-6-yl) ethynyl] nicotinate
Tazorac (Tazarotene) Clinical Pharmacology
Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid deesterification in animals and man. AGN 190299 (“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 is unknown.
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 (>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, acne or psoriatic skin.
The human studies described below were conducted with tazarotene gel applied topically at approximately 2 mg/cm and left on the skin for 10 to 12 hours. Both the peak plasma concentration (Cmax) and area under the plasma concentration time curve (AUC) refer to the active metabolite only.
Two single, topical dose studies were conducted using C-tazarotene gel. Systemic absorption, as determined from radioactivity in the excreta, was less than 1% of the applied dose (without occlusion) in six psoriatic patients 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 Cmax 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 Cmax for tazarotenic acid was 0.72 ± 0.58 ng/mL (mean ± SD) occurring 9 hours after the last dose, and the AUC 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 psoriatic patients, 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 Cmax for tazarotenic acid was 12.0 ± 7.6 ng/mL occurring 6 hours after the final dose, and the AUC 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 Cmax of 18.9 ± 10.6 ng/mL and AUC of 172 ± 88 ng·hr/mL.
An 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.
Tazorac (Tazarotene) Clinical Studies
In two large vehicle-controlled clinical studies, tazarotene 0.05% and 0.1% gels applied once daily for 12 weeks were significantly more effective than vehicle in reducing the severity of the clinical signs of stable plaque psoriasis covering up to 20% of body surface area. In one of the studies, patients were followed up for an additional 12 weeks following cessation of therapy with TAZORAC Gel. Mean baseline scores and changes from baseline (reductions) after treatment in these two studies are shown in the following Table:
Global improvement over baseline at the end of 12 weeks of treatment in these two studies is shown in the following Table:
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 section).
In two large vehicle-controlled studies, tazarotene 0.1% gel applied once daily was significantly more effective than vehicle in the treatment of facial acne vulgaris of mild to moderate severity. Percent reductions in lesion counts after treatment for 12 weeks in these two studies are shown in the following Table:
Global improvement over baseline at the end of 12 weeks of treatment in these two studies is shown in the following Table:
Tazorac (Tazarotene) Indications And Usage
TAZORAC (tazarotene) Gel 0.05% and 0.1% are indicated for the topical treatment of patients with stable plaque psoriasis of up to 20% body surface area involvement.
TAZORAC (tazarotene) Gel 0.1% is also indicated for the topical treatment of patients with facial acne vulgaris of mild to moderate severity.
The efficacy of TAZORAC Gel in the treatment of acne previously treated with other retinoids or resistant to oral antibiotics has not been established.
Tazorac (Tazarotene) Contraindications
Retinoids may cause fetal harm when administered to a pregnant woman.
In rats, tazarotene 0.05% gel, administered during gestation days 6 through 17 at 0.25 mg/kg/day (1.5 mg/m/day) resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed with 0.25 mg/kg/day (2.75 mg/m total body surface area/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 daily-exposure (AUC) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 0.62 and 6.7 times, respectively, the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.78 and 8.4 times, respectively, the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15% (targeted) body surface area.
As with other retinoids, when tazarotene was given to experimental animals, developmental delays were seen in rats, and teratogenic effects and post-implantation loss were observed in rats and rabbits at AUC values that were 0.55 and 13.2 times, respectively, the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.68 and 16.4 times, respectively, the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15% (targeted) body surface area.
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 numbers 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 was reported to be related to treatment. This dose produced an AUC that was 1.7 times the AUC observed in psoriatic patients treated with 2 mg/cm tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area) and 2.1 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15% (targeted) body surface area.
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 ACNE OF THE FACE ALONE DUE TO LESS SURFACE AREA FOR APPLICATION, TAZAROTENE IS A TERATOGENIC SUBSTANCE, AND IT IS NOT KNOWN WHAT LEVEL OF EXPOSURE IS REQUIRED FOR TERATOGENICITY IN HUMANS (SEE ).
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.
TAZORAC Gel 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 TAZORAC Gel 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 TAZORAC Gel therapy, which should begin during a normal menstrual period (see also ).
TAZORAC Gel is contraindicated in individuals who have shown hypersensitivity to any of its components.
Tazorac (Tazarotene) Warnings
Pregnancy Category X
CONTRAINDICATIONS
Tazorac (Tazarotene) Precautions
TAZORAC Gel should be applied only to the affected areas. For external use only. Avoid contact with eyes, eyelids, and mouth. If contact with eyes occurs, rinse thoroughly with water. The safety of use of TAZORAC Gel over more than 20% of body surface area has not been established in psoriasis or acne.
Retinoids should not be used on eczematous skin, as they may cause severe irritation.
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 (minimum SPF of 15) 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 and ensure that the precautions outlined in the Information for Patients subsection are observed.
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.
Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established. Alternatively, patients with psoriasis who are being treated with the 0.1% concentration can be switched to the lower concentration.
Weather extremes, such as wind or cold, may be more irritating to patients using TAZORAC Gel.
See attached .
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 TAZORAC Gel is begun.
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 (AUC) in the rat equivalent to 0.32 times the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.38 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15% (targeted) body surface area.
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 (AUC) at the highest dose was 2.0 times the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 2.5 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15 % (targeted) body surface area.
Tazarotene was found to be non-mutagenic in the Ames assay using Salmonella and 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 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 (AUC) in the rat would be equivalent to 0.31 times the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.38 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15 % (targeted) body surface area.
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, which produced an AUC that was 0.95 times the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 1.2 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15 % (targeted) body surface area.
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 2.0 mg/kg/day (see ). This dose produced an AUC which was 1.7 times that observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 2.1 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15% (targeted) body surface area.
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 (AUC) in the rat would be equivalent to 0.31 times the AUC observed in psoriatic patients treated with 2 mg/cm of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.38 times the maximum AUC in acne patients treated with 2 mg/cm of tazarotene gel 0.1% over 15% (targeted) body surface area.
After single topical doses of C-tazarotene 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.
The safety and efficacy of tazarotene have not been established in pediatric patients under the age of 12 years.
Of the total number of subjects in clinical studies of tazarotene gels, 0.05% and 0.1% 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 reliable clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals can not be ruled out. Tazarotene gel for the treatment of acne has not been clinically evaluated in persons over the age of 65.
Tazorac (Tazarotene) Adverse Reactions
In human dermal safety studies, tazarotene 0.05% and 0.1% gels did not induce allergic contact sensitization, phototoxicity or photoallergy.
The most frequent adverse events reported with TAZORAC Gel 0.05% and 0.1% were limited to the skin. Those occurring in 10 to 30% of patients, in descending order, included pruritus, burning/stinging, erythema, worsening of psoriasis, irritation, and skin pain. Events occurring in 1 to 10% of patients 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 patients over the 4th to 12th months 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%.
The most frequent adverse events reported with TAZORAC Gel 0.1% in the treatment of acne occurring in 10 to 30% of patients, in descending order, included desquamation, burning/stinging, dry skin, erythema and pruritus. Events occurring in 1 to 10% of patients included irritation, skin pain, fissuring, localized edema and skin discoloration.
Tazorac (Tazarotene) Overdosage
Excessive topical use of TAZORAC Gel may lead to marked redness, peeling, or discomfort (see ).
TAZORAC Gels 0.05% and 0.1% are 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.
Tazorac (Tazarotene) Dosage And Administration
Application may cause excessive irritation in the skin of certain sensitive individuals. In cases where it has been necessary to temporarily discontinue therapy, or the dosing has been reduced to a lower concentration (in patients with psoriasis) or to an interval the patient can tolerate, therapy can be resumed, or the drug concentration or frequency of application can be increased as the patient becomes able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once daily dosing frequencies.
Tazorac (Tazarotene) How Supplied
TAZORAC (tazarotene) Gel is available in concentration of 0.1%. 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 gm and 100 gm sizes.
® Marks owned by Allergan, Inc.U.S. Patent Numbers 5,089,509; 5,914,334 and 6,258,830 Irvine, California 92612, USA©2004 Allergan, Inc.
Printed in USA8606X, 8607XAJanuary 200471722US10P
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Tazorac (Tazarotene)
Tazorac (Tazarotene) Principal Display Panel
