Tretinoin Gel Microsphere

Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

Tretinoin Gel Microsphere, 0.1% and 0.04%, is a white to very pale yellow opaque gel for topical treatment of acne vulgaris.

Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds, and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C20H28O2 and the following chemical structure:

Each gram of Tretinoin Gel Microsphere, 0.1% contains 1 mg of tretinoin.

Each gram of Tretinoin Gel Microsphere, 0.04% contains 0.4 mg of tretinoin.

The formulation uses methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dermal carcinogenicity testing has not been performed with Tretinoin Gel Microsphere, 0.1% or 0.04%.

In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of the 0.04% and 0.1% clinical formulations. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day tretinoin, respectively. These doses are two and four times the MRHD based on BSA comparison.

The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose 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 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the MRHD based on BSA comparison). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources [see Warnings and Precautions (5.2)].

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

The components of the microspheres have shown potential for genetic toxicity and teratogenesis. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, and the in vivo mouse micronucleus assay.

In oral fertility studies in rats with tretinoin, the no-observable effect level was 2 mg/kg/day (19 times the MRHD based on BSA comparison).

Tretinoin Gel Microsphere, 0.1%

In two vehicle-controlled trials, Tretinoin Gel Microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

Tretinoin Gel Microsphere, 0.1% was also significantly superior to the vehicle in the investigator’s global evaluation of the clinical response. In Study #1, thirty-five percent (35%) of subjects using Tretinoin Gel Microsphere, 0.1%, achieved an excellent result, as compared to eleven percent (11%) of subjects on the vehicle control. In Study #2, twenty-eight percent (28%) of patients using Tretinoin Gel Microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the subjects on the vehicle control.

Tretinoin Gel Microsphere, 0.04%

In two vehicle-controlled clinical trials, Tretinoin Gel Microsphere, 0.04%, applied once daily, was more effective (p<0.05) than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

Tretinoin Gel Microsphere, 0.04%, was also superior (p<0.05) to the vehicle in the investigator’s global evaluation of the clinical response. In Study #1, fourteen percent (14%) of subjects using Tretinoin Gel Microsphere, 0.04%, achieved an excellent result compared to five percent (5%) of subjects on vehicle control. In Study #2, nineteen percent (19%) of subjects using Tretinoin Gel Microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of subjects on vehicle control.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

The patient should be instructed to:

Cleanse the treatment area thoroughly, before treatment, with a mild, non-medicated cleanser. Do not use more than the recommended amount and do not apply Tretinoin Gel Microsphere more than once daily as this will not produce faster or better results, but may increase irritation.

Minimize exposure to sunlight, including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.

Manufactured by: Valeant Pharmaceuticals International, Inc. Laval, Quebec H7L 4A8, Canada

Distributed by:

Spear Dermatology Products Randolph, NJ 07869 USA

Microsponge is a registered trademark of AMCOL International Corporation. Any other product/brand names are trademarks of their respective owners.

©Valeant Pharmaceuticals North America LLC

9507001
20001075B

NDC 66530-260-20

Tretinoin Gel
Microsphere
0.1%

For Topical Use Only
Rx only

SPEAR
DERMATOLOGY PRODUCTS

Net wt. 20 g