Avage Side Effects, and Drug Interactions - Tazarotene

Avage Side Effects, and Drug Interactions - Tazarotene

SIDE EFFECTS

In human dermal safety studies, tazarotene 0.05% and 0.1% creams did not induce allergic contact sensitization, phototoxicity or photoallergy. The most frequent treatment-related adverse reactions (5%) reported during the clinical trials with AVAGE™ (TAZAROTENE) Cream 0.1% in the treatment of facial fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines were limited to the skin. Those occurring in >10%, in descending order, included: desquamation, erythema, burning sensation, and dry skin. Events occurring in ³1% to £10% of patients, in descending order included: skin irritation, pruritus, irritant contact dermatitis, stinging, acne, rash or cheilitis. Common adverse events observed in the clinical trials are presented in the following table:

A few patients reported adverse events at Week 0; however, for patients who were treated with AVAGE™ the highest number of new reports for each adverse event was at Week 2. When combining data from the two pivotal studies, 5.3% of patients in the tazarotene cream group and 0.9% of patients in the vehicle group discontinued due to adverse events.

Overall, 20/567 (3.5%) patients in the AVAGE™ (TAZAROTENE) Cream 0.1% group and 16/564 (2.8%) patients in the vehicle group reported adverse events (including edema, irritation, and inflammation) directly related to the eye or eyelid. The majority of these conditions were mild.

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.

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 AUC_0-24h 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 (AUC_0-12h) at the highest dose was 7.8 times the maximum AUC_0-24h 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 AUC_0-24h 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 AUC_0-24h that was 3.7 times the maximum AUC_0-24h 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 (see CONTRAINDICATIONS). That dose produced an AUC_0-24h that was 6.7 times the maximum AUC_0-24h 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 AUC_0-24h in patients treated with 2 mg/cm2 of tazarotene cream 0.1% over 15% body surface area for fine wrinkling and mottled hyperpigmentation.

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).

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.

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.

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.