Tazarotene

Tazarotene is an Retinoic Acid Derivative belonging to pharmacology class of Anti-Acne Agent.

Tazarotene is a Retinoic Acid Derivative used in the treatment of Palliation of fine wrinkles, facial ottled hyper-/hypopigmentation, benign facial lentigines, Psoriasis.

Tazarotene Plasma protein binding is highly bound as tazarotenic acid and get Metabolised via esterase hydrolysis to tazarotenic acid and via oxidation to inactive sulfoxides, sulfones, and other polar metabolites and get excreted Via urine and faeces. Elimination half-life: Approx 18 hr.

The common side effects associated with Tazarotene include Increased sensitivity to sunlight, skin peeling, redness, swelling, or dryness.

Tazarotene is available in the form of Cream, foam, gel, lotion.

The molecule is available in India, USA, Japan, Germany.

Synthetic, acetylenic retinoid which modulates differentiation and proliferation of epithelial tissue and exerts some degree of anti-inflammatory and immunological activity.

The onset of action for Tazarotene was within 1 week.

The Duration of action for Tazarotene effects have been observed for up to 3 months after a 3-month course of topical treatment.

Tazarotene is available in Cream, foam, gel, lotion

Topical: All products: Avoid contact with eyes and other mucous membranes. Some products may stain certain fabrics; avoid contact with clothing or furniture. May bleach hair. If bothersome dryness or peeling occurs, reduce dose frequency or drug concentration. If excessive stinging or burning occurs after any single application, remove with mild soap and water; resume use the next day.

Cleansers: Wet skin areas to be treated prior to administration. Gently massage into skin for 10 to 20 seconds, working into a full lather. Rinse thoroughly and pat dry.

Cloths: Wet face with water. Wet cloth with a little water and work into a full lather. Cleanse face with cloth for 10 to 20 seconds. Rinse thoroughly and pat dry.

Cream: Prime pump until the first drop of cream is released prior to first use. Apply to each area of the face (cheek, chin, forehead, nose); avoid eyes, lips, and mouth. Avoid contact with cuts, abrasions, and eczematous or sunburned skin. Wash hands after use.

Foam: Prime can prior to initial. Shake vigorously and tap bottom of can onto palm or solid surface 3 times prior to each use. Dispense foam into palm of hand or applicator pad and cover entire affected area and rub in until completely absorbed. Some products can remain on skin and others should be rinsed off after a brief period of time (refer to manufacturers labeling). Rinse applicator with water and allow to dry after use; wash hands with soap and water after use.

Other dose forms: After cleansing skin, smooth small amount over affected area. Shake lotion well prior to use.

Tazarotene is a Retinoic Acid Derivative used in the treatment of Palliation of fine wrinkles, facial ottled hyper-/hypopigmentation, benign facial lentigines, Psoriasis.

Tazarotene releases free-radical oxygen which oxidizes bacterial proteins in the sebaceous follicles decreasing the number of anaerobic bacteria and decreasing irritating-type free fatty acids.

Tazarotene is approved for use in the following clinical indications

Retinoic Acid Derivative: Topical treatment of Retinoic Acid Derivative in patients ≥9 years of age (Tazarotene) or ≥12 years of age.

Palliation of fine facial wrinkles, facial mottled hyper-/hypopigmentation, benign facial lentigines: Adjunctive agent for use in the mitigation (palliation) of facial fine wrinkling, facial mottled hyper- and hypopigmentation, and benign facial lentigines in patients ≥17 years of age who use comprehensive skin care and sunlight avoidance programs.

Limitations of use: Does not eliminate or prevent wrinkles, repair sun-damaged skin, reverse photoaging, or restore more youthful or younger skin. Has not demonstrated a mitigating effect on significant signs of chronic sunlight exposure, such as coarse or deep wrinkling, tactile roughness, telangiectasia, skin laxity, keratinocytic atypia, melanocytic atypia, or dermal elastosis. Safety and effectiveness for the prevention or treatment of actinic keratoses, skin neoplasms, or lentigo maligna has not been established. Safe and effective daily use >52 weeks is not known.

Psoriasis:

05% and 0.1% cream: Topical treatment of plaque psoriasis in patients ≥18 years of age.

0.05% and 0.1% gel: Topical treatment of stable plaque psoriasis of up to 20% body surface area involvement in patients ≥12 years of age.

Retinoic Acid Derivative:

Note: For moderate to severe acne, may be used as part of an appropriate combination regimen Consider starting with the lowest possible concentration to minimize skin irritation and increase potency as tolerated. In patients experiencing excessive pruritus, burning, skin redness, or peeling, discontinue until integrity of the skin is restored, or reduce dosing to an interval the patient can tolerate.

Topical:

Apply a thin layer to affected area once daily.

Apply a small amount to affected area once daily in the evening.

Tazarotene cream/gel 0.05% or 0.1%: Apply a thin layer (2 mg/cm²) to affected area once daily in the evening.

Palliation of fine facial wrinkles, facial mottled hyper-/hypopigmentation, benign facial lentigines: Topical: Avage: Apply a pea-sized amount to entire face once daily at bedtime. In patients experiencing excessive pruritus, burning, skin redness, or peeling, discontinue until integrity of the skin is restored, or reduce dosing to an interval the patient can tolerate.

Psoriasis: Topical: Tazarotene cream/gel: Initial: 0.05%: Apply once daily in the evening to psoriatic lesions using enough (2 mg/cm²) to cover only the lesion with a thin film. May increase strength to 0.1% if tolerated and necessary. In patients experiencing excessive pruritus, burning, skin redness, or peeling, discontinue until integrity of the skin is restored, or reduce dosing to an interval the patient can tolerate.

Cream, foam, gel, lotion

0.1%, 0.05%, 0.045%

• Dose Adjustment in Pediatric Patient:

Retinoic Acid Derivative:

Cream or gel: Children ≥12 years and Adolescents: Topical: Tazarotene (0.1%): Apply as a thin film (2 mg/cm²) to affected area(s) once daily in the evening.

Foam: Children ≥12 years and Adolescents: Topical: Fabior (0.1%): Apply a small amount to affected area(s) once daily in the evening.

Lotion: Children ≥9 years and Adolescents: Topical: Tazarotene (0.045%): Apply a thin layer to affected area(s) once daily.

Psoriasis:

Cream: Adolescents ≥18 years: Topical: Tazarotene (0.05%): Initial: Apply a thin film (2 mg/cm²) to affected area once daily in the evening; may increase strength to 0.1% if tolerated and necessary.

Gel: Children ≥12 years and Adolescents: Topical: Tazarotene (0.05%): Initial: Apply a thin film (2 mg/cm²) to affected area once daily in the evening; may increase strength to 0.1% if tolerated and necessary; apply to no more than 20% of the body surface area.

Tazarotene may be contraindicated in the following conditions:

Hypersensitivity to tazarotene or any component of the formulation; pregnancy.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Photosensitivity: May cause photosensitivity; exposure to ultraviolet rays (including sunlight/sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized. Risk may be increased by concurrent therapy with known photosensitizers (thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides); use with caution. Use with caution in patients with a personal or family history of skin cancer. Daily sunscreen use and other protective measures recommended. Patients with sunburn should discontinue use until sunburn has healed.

• Skin irritation: Local tolerability reactions (including blistering or skin desquamation) or local hypersensitivity reactions (including urticaria) may occur. Application-site pain, excessive burning, drying, pruritus, peeling, and skin redness may occur, especially during the early weeks of treatment. Treatment can increase skin sensitivity to weather extremes of wind or cold. Concomitant topical medications (eg, medicated or abrasive soaps, cleansers, cosmetics with a strong drying effect) should be avoided due to increased skin irritation. Depending on the severity of the reaction, instruct patients to use a moisturizer, reduce the frequency of use, or discontinue use.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse; some data suggests that benzoate displaces bilirubin from protein binding sites; avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Foam: Propellant is flammable; avoid fire and smoking during and immediately after use.

• Gel: Safety and efficacy of gel applied over >20% of BSA have not been established.

There is no sufficient scientific evidence traceable regarding use and safety of Tazarotene in concurrent use with alcohol.

It is not known if Tazarotene is present in breast milk.

Systemic absorption depends on formulation and size of surface area. In general, the use of topical agents is preferred over systemic agents for the treatment of facial acne and psoriasis in females who are breastfeeding. Avoid applying large amounts over prolonged periods of time to decrease the potential for systemic absorption. When treatment with tazarotene is needed in breastfeeding females, application area should be <20% of body surface area . Topical psoriasis agents needed in the chest area should be applied after breastfeeding and removed prior to the next session.

Pregnancy Category X

There are no adequate and well-controlled studies with Tazarotene Cream in pregnant women. Tazarotene Cream is contraindicated in women who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when Tazarotene Cream 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 Cream therapy, which should begin during a menstrual period. Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In subjects 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 it is not known what level of exposure is required for teratogenicity in humans.

In rats, a tazarotene gel, 0.05% formulation, 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 to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 1.2 and 13 times, respectively, that in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 4 and 44 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area.

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 1.1 and 26 times, respectively, the systemic exposure seen in a psoriatic patient treated topically with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study and 3.5 and 85 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area.

In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, a number of 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 at that dose was observed. The dose produced a systemic exposure 3.4 times that observed in a psoriatic patient treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area.

The adverse reactions related to Tazarotene can be categorized as

Common Adverse effects: Desquamation, Pruritus, Skin redness, Stinging/burning sensation, Worsening of psoriasis

Less Common Adverse effects: Swelling at/near application sites, Skin discoloration (hyper/hypopigmentation), Skin exfoliation and inflammation, Hypersensitivity (e.g. urticaria), Photosensitivity.

Rare Adverse effects: Erythema, Irritation, Dermatitis, Rash.

The clinically relevant drug interactions of Tazarotene is briefly summarized here

Increased photosensitivity w/ drugs known to be photosensitizers (e.g. fluoroquinolones, tetracyclines, thiazide diuretics, sulfonamides, phenothiazines). Increased risk of irritation w/ use of topical medications and cosmetics w/ irritant or strong drying effects.

The common side of Tazarotene include the following

Increased sensitivity to sunlight, Skin peeling, Redness, Swelling, or Dryness.

Pregnancy Category X

There are no adequate and well-controlled studies with Tazarotene Cream in pregnant women. Tazarotene Cream is contraindicated in women who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when Tazarotene Cream 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 Cream therapy, which should begin during a menstrual period. Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In subjects 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 it is not known what level of exposure is required for teratogenicity in humans.

In rats, a tazarotene gel, 0.05% formulation, 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 to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 1.2 and 13 times, respectively, that in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 4 and 44 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area.

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 1.1 and 26 times, respectively, the systemic exposure seen in a psoriatic patient treated topically with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study and 3.5 and 85 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area.

In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, a number of 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 at that dose was observed. The dose produced a systemic exposure 3.4 times that observed in a psoriatic patient treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area.

Labor and Delivery

There is no FDA guidance on use of Tazarotene during labor and delivery.

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. The safe use of Tazarotene Cream during lactation has not been established. A decision should be made whether to discontinue breast-feeding or to discontinue Tazarotene Cream therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Pediatric Use

The safety and efficacy of tazarotene have not been established in patients with psoriasis under the age of 18 years, or in patients with acne under the age of 12 years.

Geriatric Use

Tazarotene Cream for the treatment of acne has not been clinically tested in persons 65 years of age or older.

Of the total number of subjects in clinical trials of Tazarotene Cream for plaque psoriasis, 120 were over the age of 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Currently there is no other clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Gender

There is no FDA guidance on the use of Tazarotene with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tazarotene with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Tazarotene in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Tazarotene in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tazarotene in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tazarotene in patients who are immunocompromised.

Acute Overdose

Signs and Symptoms

Excessive topical use of Tazarotene Cream, 0.05% and 0.1% may lead to marked redness, peeling, or discomfort.

Tazarotene Cream, 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.

Management

If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary.

Chronic Overdose

There is limited information regarding Chronic Overdose of Tazarotene in the drug label.

Pharmacodynamics:

Tazarotene, a synthetic acetylenic retinoid, is a prodrug which is converted to tazarotenic acid then binds to 3 retinoic acid receptors but has relative selectivity for RARβ and RARγ. It regulates gene expression, thus modulating cell proliferation, differentiation, and hyperplasia. 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.

Pharmacokinetics:

Plasma protein binding: highly bound as tazarotenic acid (>99%).

Metabolism: Metabolised via esterase hydrolysis to tazarotenic acid and via oxidation to inactive sulfoxides, sulfones, and other polar metabolites.

Excretion: Via urine and faeces.

Elimination half-life: Approx 18 hr.

1. https://www.uptodate.com/contents/Tazarotene -drug-information?search=Tazarotene &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Tazarotene _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Tazarotene ?type=full&mtype=generic#mechanism-of-action