Avita

AVITA- tretinoin cream
Mylan Pharmaceuticals Inc.

DESCRIPTION

AVITA® Cream, a topical retinoid, contains tretinoin 0.025% by weight in a hydrophilic cream vehicle of stearic acid, polyolprepolymer-2, isopropyl myristate, polyoxyl 40 stearate, propylene glycol, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. Chemically, tretinoin is all-transretinoic acid (C20 H28 02 ; molecular weight 300.44 vitamin A acid) and has the following structural formula:

Avita Cream Structural Formula
(click image for full-size original)

CLINICAL PHARMACOLOGY

Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

Pharmacokinetics

In vitro and in vivo pharmacokinetic studies with AVITA® Cream indicate that less than 0.3% of the topically applied dose is bioavailable. Circulating plasma levels of both tretinoin and isotretinoin are only slightly elevated above those found in healthy normal controls.

CLINICAL STUDIES

In one vehicle-controlled clinical trial, AVITA® (tretinoin cream) Cream 0.025%, applied once daily was more effective than vehicle in the treatment of facial acne vulgaris of mild to moderate severity. Percent reductions in lesion count after treatment for 12 weeks in this study are shown in the following table:

Avita® Cream,0.025%

VehicleCream

N = 75

N = 58

Noninflammatory Lesions

45%

27%

Inflammatory Lesions

46%

32%

Total Lesions

46%

28%

N = Number of Subjects

INDICATIONS AND USAGE

AVITA® Cream is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of this product in the treatment of other disorders have not been established.

CONTRAINDICATIONS

The product should not be used if there is hypersensitivity to any of the ingredients.

PRECAUTIONS

General

If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, or artificial sunlight, should be minimized during the use of AVITA® Cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.

AVITA® (tretinoin cream) Cream, 0.025% should be kept away from the eyes, the mouth, the paranasal creases, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to temporarily use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Efficacy at reduced frequencies of application has not been established. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

Information for Patients

See attached Patient Package Insert.

Drug Interactions

Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with AVITA® Cream. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of AVITA® Cream is begun.

Carcinogenesis, Mutagenesis and Impairment of Fertility

In a life-time dermal study in CD-1 mice with another tretinoin cream, at 100 and 200 times the average recommended human topical clinical dose, a few skin tumors in the female mice and liver tumors in male mice were observed. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when tretinoin was administered topically at a dose five times the average recommended human topical clinical dose. For purposes of comparisons of the animal exposure to human exposure, the “recommended human topical clinical dose” is defined as 1.0 g of 0.025% AVITA® Cream applied daily to a 50 kg person. In a chronic, two-year bioassay of vitamin A acid in mice performed by Tsubura and Yamamoto, generalized amyloid deposition was reported in all vitamin A treated groups in the basal layer of the skin. In CD-1 mice, a similar study reported hyalinization at the treated skin sites and the incidence of this finding was 0/50, 3/50, 3/50, and 2/50 in male mice and 1/50, 0/50, 4/50, and 2/50 in female mice from the vehicle control, 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg groups, respectively.

Studies in hairless albino mice suggest that tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVA/UVB light, the incidence and rate of development of skin tumors were either reduced or no effect was seen. Due to significantly different experimental conditions, no strict comparison of these disparate data is possible at this time. Although the significance of these studies to humans is not clear, patients should minimize exposure to sun.

The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

Dermal Segment I and III studies with AVITA® Cream have not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (> 400 times the average recommended human topical clinical dose).

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