Avage

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® (tazarotene) 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® (tazarotene) Cream therapy, which should begin during a normal menstrual period.

PRECAUTIONS

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

AVAGE® (tazarotene) 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® (tazarotene) 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 ¼ 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.

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_0-24h 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 (AUC0-12h) 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 of 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.

Pregnancy: Teratogenic Effects: Pregnancy Category X

See CONTRAINDICATIONS section. Women of child-bearing potential should use adequate birth-control measures when AVAGE® (tazarotene) 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® (tazarotene) 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.

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 ≥ 1% 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:

TABLE OF ADVERSE EVENTS SEEN IN CLINICAL TRIALS WITH AVAGE® (TAZAROTENE) Cream 0.1% 

Adverse Event	AVAGE ® N=567	Vehicle N=564
Desquamation	40%	3%
Erythema	34%	3%
BurningSensation	26%	<1%
DrySkin	16%	3%
Irritation Skin	10%	1%
Pruritus	10%	1%
Irritant Contact Dermatitis	8%	1%
Stinging	3%	<1%
Acne	3%	3%
Rash	3%	1%
Cheilitis	1%	0%

A few patients reported adverse events at Week 0; however, for patients who were treated with AVAGE® (tazarotene) 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.

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® (tazarotene) Cream is begun.

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 ≥ 1% 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:

TABLE OF ADVERSE EVENTS SEEN IN CLINICAL TRIALS WITH AVAGE® (TAZAROTENE) Cream 0.1% 

Adverse Event	AVAGE ® N=567	Vehicle N=564
Desquamation	40%	3%
Erythema	34%	3%
BurningSensation	26%	<1%
DrySkin	16%	3%
Irritation Skin	10%	1%
Pruritus	10%	1%
Irritant Contact Dermatitis	8%	1%
Stinging	3%	<1%
Acne	3%	3%
Rash	3%	1%
Cheilitis	1%	0%

A few patients reported adverse events at Week 0; however, for patients who were treated with AVAGE® (tazarotene) 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.

Excessive topical use of AVAGE® (tazarotene) Cream 0.1% may lead to marked redness, peeling, or discomfort (see PRECAUTIONS: General). AVAGE® (tazarotene) Cream 0.1% is 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.

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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.

Overdosage & Contraindications

OVERDOSE

Excessive topical use of AVAGE® (tazarotene) Cream 0.1% may lead to marked redness, peeling, or discomfort (see PRECAUTIONS: General). AVAGE® (tazarotene) Cream 0.1% is 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.

CONTRAINDICATIONS

Retinoids may cause fetal harm when administered to a pregnant woman.

In rats, tazarotene 0.05% gel 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 (AUC_0-24h) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 2.4 and 26 times, respectively, 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.

As with other retinoids, 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 2.1 and 52 times, respectively, 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 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 number 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 were reported to be related to treatment. 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.

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. 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).

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.

AVAGE® (tazarotene) Cream 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 AVAGE® (tazarotene) 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 human chorionic gonadotropin (hCG) should be obtained within 2 weeks prior to AVAGE® (tazarotene) Cream therapy, which should begin during a normal menstrual period (See also PRECAUTIONS: Pregnancy: Teratogenic Effects).

AVAGE® (tazarotene) Cream is contraindicated in individuals who have shown hypersensitivity to any of its components.

Clinical Pharmacology

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 RARγand may modify gene expression. The clinical significance of these findings is unknown.

The mechanism of tazarotene action in the amelioration of fine wrinkling, facial mottled hypo- and hyperpigmentation, and benign facial lentigines is unknown. A histological study of tazarotene cream 0.1% applied in subjects with fine wrinkling and mottled hyperpigmentation but otherwise normal skin for 24 weeks showed that tazarotene cream was associated with significantly greater proportions of patients who had an increase from baseline in the number of granular cell layers and in epidermal edema. The clinical significance of these changes is unknown.

Pharmacokinetics

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.

Tazarotene cream 0.1% was topically applied once daily to either the face (6 females and 2 males) or to 15% of body surface area (8 females and 8 males) over four weeks in patients with fine wrinkling and mottled hyperpigmentation. In the “face-only” dosing group, the maximum average Cmax and AUC_0-24 hr values of tazarotenic acid occurred on Day 15 with mean ± SD values of Cmax and AUC_0-24 hr of tazarotenic acid being 0.236 ± 0.255 ng/mL (N = 8) and 2.44 ± 1.38 ng·hr/mL (N = 8), respectively. The mean Cmax and AUC_0-24 hr values of tazarotenic acid from patients in the 15% body surface area dosing group were approximately 10 times higher than those from patients in the face-only dosing group. The single highest Cmax throughout the study period was 3.43 ng/mL on day 29 from patients in the 15% body surface area dosing group. Gender had no influence on the systemic bioavailability of tazarotenic acid.

Blood samples were collected from one of the two phase 3 studies to evaluate the systemic exposure following application of tazarotene cream 0.1% once daily for 24 weeks (double-blind period) followed by 28 weeks (open-label) under clinical conditions. The mean plasma tazarotenic acid concentrations following topical treatment with tazarotene cream 0.1% over 52 weeks ranged between 0.092 ± 0.073 ng/mL and 0.127 ± 0.142 ng/mL. The single highest observed tazarotenic acid concentration throughout the 52-week study was 0.705 ng/mL (observed at week 36). Systemic availability of tazarotenic acid was minimal and remained steady following once daily application of tazarotene cream 0.1% to the faces of patients in the study for up to 52 weeks.

Clinical Studies

In two double-blind controlled studies in which tazarotene cream 0.1% was compared with its vehicle, applications were made once daily for 24 weeks to the facial skin of subjects with mild to severe fine wrinkling, facial mottled hypo- and hyperpigmentation, and benign facial lentigines due to overexposure to the sun. Treatment was as an adjunct to a comprehensive skin care and sun avoidance program which included use of sunscreens, protective clothing, and non-prescription emollient cream. At two to four week intervals the severity of fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines were graded on a scale of 0=none, 1=minimal, 2=mild, 3=moderate, and 4=severe. The results of both studies demonstrate that tazarotene cream 0.1% was significantly superior to its vehicle for fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines expressed as the proportion of subjects with an improvement of at least one grade from baseline.

Approximately 97% of subjects in clinical trials were white (Caucasian) with 80% of subjects in the clinical studies having Fitzpatrick skin type classifications I-III. The distribution of subject skin types were: Type I –12%; Type II – 26%; Type III – 40%; and Type IV 22%. Patients with skin types V and VI were not studied. Insufficient non-white patients (Asian, Hispanic, or other) were studied to make an adequate determination of efficacy of AVAGE® (tazarotene) Cream in such patients.

Percentage of Patients with Improvement in Fine Wrinkling after 24 Weeks of Treatment

	StudyA	StudyB
Taz. 0.1% N=283	Vehicle N=280	Taz. N=284	0.1% N=284
2 or more Grades Improvement	5%	1%	13%	5%
1 Grade Improvement	35%	15%	45%	18%
No Change	59%	83%	42%	76%
Worsened	1%	1%	0%	1%

Fine Wrinkling was graded on a 5-point scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe) using a photonumeric guideline for investigators.

Percentage of Patients with Improvement in Mottled Hyperpigmentation after 24 Weeks of Treatment

	StudyA	StudyB
Taz. 0.1% N=283	Vehicle N=280	Taz. N=284	0.1% N=284
2 or more Grades Improvement	17%	1%	28%	10%
1 Grade Improvement	42%	17%	54%	30%
No Change	41%	80%	18%	59%
Worsened	<1%	3%	<1%	1%

Mottled Hyperpigmentation was graded on a 5-point scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe) using a photonumeric guideline for investigators.

In the 24 week studies, efficacy was also demonstrated in mottled hypopigmentation and benign facial lentigines, which were secondary endpoints in those studies.

The duration of the mitigating effects on facial fine wrinkling, mottled hyper- and hypopigmentation, and benign facial lentigines following discontinuation of AVAGE® (TAZAROTENE) Cream 0.1% has not been studied.