Avage (Tazarotene) - Warnings and Precautions

WARNINGS

Pregnancy Category X. See CONTRAINDICATIONS section. 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 child-bearing 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 milli International Units per mL for hCG should be obtained within 2 weeks prior to AVAGE^® Cream therapy, which should begin during a normal menstrual period.

PRECAUTIONS

General:

AVAGE^® Cream should be applied only to the affected areas. For external use only. Avoid contact with eyes and mouth. If contact with eyes occurs, rinse thoroughly with water.

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 AVAGE^® Cream. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using AVAGE^® Cream. Patients with sunburn should be advised not to use AVAGE^® Cream 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 AVAGE^® Cream and ensure that the precautions outlined in the Information for Patients subsection are observed.

AVAGE^® Cream 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. Weather extremes, such as wind or cold, may be more irritating to patients using AVAGE^® Cream.

Some facial pigmented lesions are not lentigines, but rather lentigo maligna, a type of melanoma. Facial pigmented lesions of concern should be carefully assessed by a qualified physician (e.g., dermatologist) before application of AVAGE^® (tazarotene) Cream. Lentigo maligna should not be treated with AVAGE^® (tazarotene) Cream.

Information for Patients:

AVAGE^® (tazarotene) Cream 0.1% is to be used as described below when used for treatment of facial fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines, unless otherwise directed by your physician:

1. It is for use on the face.
2. Avoid contact with the eyes and mouth. AVAGE^® (tazarotene) Cream 0.1% may cause severe redness, itching, burning, stinging, and peeling.
3. Before applying AVAGE^® (tazarotene) Cream 0.1% once per day, gently wash your face with a mild soap. Make sure skin is dry before applying AVAGE^® (tazarotene) Cream 0.1%. Apply only a small pea sized amount (about 1/4 inch or 5 millimeter diameter) of AVAGE^® (tazarotene) Cream 0.1% to your face at one time. This should be enough to lightly cover the entire face.
4. For best results, you are advised that if emollients or moisturizers are used, they can be applied either before or after tazarotene cream, ensuring that the first cream or lotion has absorbed into the skin and dried completely.
5. In the morning, apply a moisturizing sunscreen, SPF 15 or greater.
6. AVAGE^® (tazarotene) Cream 0.1% is a serious medication. Do not use AVAGE^® (tazarotene) Cream 0.1% if you are pregnant or attempting to become pregnant. If you become pregnant while using AVAGE^® (tazarotene) Cream 0.1%, please contact your physician immediately.
7. Avoid sunlight and other medicines that may increase your sensitivity to sunlight. For the mitigation of fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines, avoidance of excessive sun exposure and the use of sunscreens with protective measures (hat, visor) are recommended.
8. AVAGE^® (tazarotene) Cream 0.1% does not remove or prevent wrinkles or repair sun-damaged skin.

Please refer to the Patient Package Insert for additional patient information.

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 AUC_0-24hr 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 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_0-12hr) at the highest dose was 7.8 times the maximum AUC_0-24hr 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_0-24hr 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 mg/kg/day tazarotene. That dose produced an AUC_0-24hr that was 3.7 times the maximum AUC_0-24hr 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 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_0-24hr that was 6.7 times the maximum AUC_0-24hr 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_0-24hr 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 child-bearing 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.