TAZORAC
Allergan
Tazarotene Antipsoriasis
Antiacne
Action and Clinical
Tazarotene is a retinoid prodrug which is converted to its active form, M1 (“tazarotenic acid”, or AGN 190299), by rapid de-esterification in most biological systems. “Tazarotenic acid” binds to and regulates gene expression through all three members of the RAR family of retinoid nuclear receptors, RAR a, RAR b, and RAR g, but shows selectivity for RAR b and RAR g.:
Psoriasis: The exact mechanisms of tazarotene action in psoriasis are not completely defined. Among its specific pharmacological activities, demonstrated in cellular and in in vivo studies, topical tazarotene blocks induction of epidermal ornithine decarboxylase (ODC) activity, which is associated with cell proliferation and hyperplasia, suppresses expression of MRP8, an inflammatory marker present in psoriatic epidermis at high levels, and inhibits cornified envelope formation and build-up, which is an element of psoriatic scale. Improvement in psoriatic patients appears to occur in association with restoration of normal cutaneous morphology and reduction of the inflammatory markers ICAM-1 and HLA-DR. There is also a diminution of markers of epidermal hyperplasia and abnormal differentiation such as keratinocyte transglutaminase, involucrin and keratin 16.
In 2 large vehicle-controlled clinical studies, tazarotene 0.1 and 0.05% gels applied once daily were significantly more effective than vehicle in reducing the severity of the clinical signs of plaque psoriasis. Tazarotene gels demonstrated effectiveness as early as 1 week after starting treatment, with initial treatment success (good or excellent response or complete clearing) reached significantly earlier than with vehicle. 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. In one of these studies, patients were also evaluated for 12 weeks following cessation of therapy, and it was found that subjects treated with the 0.1 and 0.05% tazarotene gels continued to show a therapeutic effect during the 12-week post-treatment period.
Acne: Tazarotene is thought to act against several of the factors that contribute to acne vulgaris. Animal and in vitro studies show that tazarotene inhibits corneocyte accumulation in rhino mouse skin (in vivo) and cross-linked envelope formation in cultured human keratinocytes (in vitro). The primary mechanisms of action in humans are believed to be the normalizing of keratinization and a decrease in the coherence of follicular keratinocytes. Both mechanisms contribute to a comedolytic effect against existing comedones and prevention of the development of new microcomedones. Tazarotene also exhibits activity against inflammatory acne.
In 2 large vehicle-controlled studies, tazarotene 0.1 and 0.05% gels applied once daily were significantly more effective than their vehicle in the treatment of acne vulgaris. 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.
Pharmacokinetics: Controlled clinical pharmacokinetic studies with 0.1%
Following application, the drug undergoes esterase hydrolysis to its primary active metabolite, tazarotenic acid (the only metabolite of tazarotene known to have retinoid activity), and oxidative metabolism to inactive sulfoxide and sulfone derivatives. Following topical dosing with
Indications And Clinical Uses :
For topical application in the treatment of plaque psoriasis and acne vulgaris.
Contra-Indications: Individuals who have shown hypersensitivity to retinoic compounds, or to any of the product excipients (see Supplied). Topical retinoids should not be used in the presence of seborrheic dermatitis.
Warnings:
Warnings in Clinical States:
Topical retinoids should not be used on eczematous skin.
Keep away from the eyes, nose, mouth, and other mucous membranes. In the event of contact with the eye, flush with cold water.
In some patients, temporary skin irritation may occur, especially during the early weeks of treatment. If excessive pruritus, burning, skin redness or peeling occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be adjusted to a level or interval the patient can tolerate.
Pregnancy: Topical tazarotene should be used by females of childbearing age only after contraceptive counselling. It is recommended that topical tazarotene should not be used by pregnant females.
Tazarotene 0.05% gel, administered topically during gestation days 6 through 17 in rats and days 6 through 18 in rabbits, has been shown to be nonteratogenic and nonfetotoxic at maximum tolerated doses of 0.25 mg/kg/day. However, at these doses, slightly reduced fetal body weights and reduced skeletal ossification occurred in rats. These changes may be considered variants of normal development and were usually corrected after weaning. As with other retinoids, teratogenic effects were seen when tazarotene was given orally to rats and rabbits at doses of 0.25 and 0.2 mg/kg/day, respectively. Very low drug exposure to the fetus was observed after oral administration of
Precautions:
General: For external use only. Excessive use should be avoided.
Excessive exposure to sun or ultraviolet light should be minimized or avoided. Sunscreen and protective clothing should be used when exposed to sunlight.
The safety of use over more than 20% of body surface area has not been established.
The treatment area should not be covered with dressings or bandages.
In patients with psoriasis, application to normal skin should be avoided.
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 tazarotene gels begins.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies of tazarotene following topical application in mice and oral administration to rats showed no indications of increased carcinogenic risks related to treatment. Marked skin irritation, possibly contributing to enhancement of photocarcinogenesis, was observed in hairless mice following chronic topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0.001, 0.005, and 0.01% for up to 40 weeks. Relevance of these studies to use in humans has not been established, but patients should minimize exposure to sun or ultraviolet light.
Tazarotene was found to be nonmutagenic and nonclastogenic in a standard battery of in vitro and in vivo tests.
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.
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.
Lactation: After single topical doses of
Children: The safety and efficacy of tazarotene have not been established in pediatric patients under the age of 12 years.
Adverse Reactions:
:Psoriasis: The most frequent adverse reactions (³ 5%) reported during clinical trials with tazarotene gel included pruritus, burning, erythema, skin irritation, skin pain, and worsening of psoriasis. Reported less frequently (1 to <5%) were desquamation, rash, contact irritant dermatitis, skin inflammation, stinging, and dry skin. Rarely reported reactions (<1%) included fissuring of the skin, bleeding, skin discharge, increased skin fragility, and localized edema. The incidence and severity of adverse reactions appeared to be dose related.
Acne: The most frequent adverse reactions (³5%) reported during clinical trials with tazarotene gels in the treatment of acne included burning, desquamation, dry skin, erythema, and pruritus. Reported less frequently (1 to <5%) were skin irritation, and stinging. The following reactions were reported rarely (<1%) by study subjects: skin pain, skin tightness, fissuring of the skin, cheilitis, skin discoloration, worsening of acne, contact irritant dermatitis, and localized edema. The incidence and severity of adverse reactions appeared to be dose related.
In human topical safety studies, tazarotene 0.1% and 0.05% gels did not induce contact sensitization, phototoxicity or photoallergy.
Symptoms And Treatment Of Overdose :
OverdoseExcessive topical use of tazarotene may lead to marked redness, peeling, or discomfort (see Warnings). Inadvertent oral ingestion of tazarotene may lead to the same adverse effects as those associated with excessive oral intake of vitamin A including teratogenesis in women of childbearing age. If accidental oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary, including pregnancy testing in women of childbearing age.
Dosage And Administration:
General: Application may cause a transitory feeling of burning or stinging. If irritation becomes problematic, the dosage may be altered by choosing the lower drug concentration or temporarily reducing the frequency of application.
Excessive exposure to sun or ultraviolet light should be minimized or avoided. Sunscreen and protective clothing should be used when exposed to sunlight.
Psoriasis: Apply once a day, in the evening, to psoriatic lesions, using enough to cover only the lesion with a thin film. 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 and allowed to absorb into the skin before application. Because unaffected skin may be more susceptible to irritation, application to these areas should be carefully avoided.
Acne: Cleanse the skin gently. After the skin is dry, apply a thin film once a day, in the evening, to the skin where acne lesions appear. Use enough to cover the entire affected area.
Availability And Storage:
Each g of colorless to light yellow, translucent homogeneous gel contains: tazarotene 0.05% or 0.1% (w/w). Nonmedicinal ingredients: ascorbic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, carbomer 934P, edetate disodium, hexylene glycol, poloxamer 407, polyethylene glycol, polysorbate 40, purified water and tromethamine. Collapsible aluminum tubes of 10, 30 and 100 g. Sample sizes of 3.5 g for physicians. Store at room temperature (15 to 25°C).
TAZORACÂ Allergan Tazarotene Antipsoriasis–Antiacne
Posted by RxMed