Retin-A Micro (Tretinoin Topical) - Description and Clinical Pharmacology

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.

DESCRIPTION

Retin-A Micro^® (tretinoin gel) microsphere, 0.1% and 0.04%, is a formulation containing 0.1% or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE^® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components of this formulation are purified water, carbomer 974P (0.04% formulation), carbomer 934P (0.1% formulation), glycerin, disodium EDTA, propylene glycol, sorbic acid, PPG-20 methyl glucose ether distearate, cyclomethicone and dimethicone copolyol, benzyl alcohol, trolamine, and butylated hydroxtoluene.

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 family of compounds, and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44. Tretinoin has the following structure:

CLINICAL PHARMACOLOGY

Tretinoin is a retinoid metabolite of Vitamin A that binds to intracellular receptors in the cytosol and nucleus, but cutaneous levels of tretinoin in excess of physiologic concentrations occur following application of a tretinoin-containing topical drug product.

Although tretinoin activates three members of the retinoid acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms, or both.

Mode of Action

Although the exact mode of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced.

Additionally, tretinoin acts by modulating the proliferation and differentiation of epidermal cells. These effects are mediated by tretinoin's interaction with a family of nuclear retinoic receptors. Activation of these nuclear receptors causes changes in gene expression. The exact mechanisms whereby tretinoin-induced changes in gene expression regulate skin function are not understood.

Pharmacokinetics

Tretinoin is a metabolite of Vitamin A metabolism in man.

Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy men and women. Estimates of in vivo bioavailability, mean (SD)%, following both single and multiple daily applications, for a period of 28 days with the 0.1% gel, were 0.82 (0.11)% and 1.41 (0.54)%, respectively. The plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid, generally ranged from 1 to 3 ng/mL and were essentially unaltered after either single or multiple daily applications of Retin-A Micro^® (tretinoin gel) microsphere, 0.1%, relative to baseline levels. Clinical pharmacokinetic studies have not been performed with Retin-A Micro^® (tretinoin gel) microsphere, 0.04%.

CLINICAL STUDIES

Retin-A Micro^® (tretinoin gel) microsphere, 0.1%

In two vehicle-controlled studies, Retin-A Micro^® (tretinoin gel) microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the severity of acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

Mean Percent Reduction in Lesion Counts Retin-A Micro^® (tretinoin gel) microsphere, 0.1%

	Retin-A Micro® (tretinoin gel) microsphere, 0.1%		Vehicle Gel
	Study #1 72 pts	Study #2 71 pts	Study #1 72 pts	Study #2 67 pts
Non-inflammatory lesion counts	49%	32%	22%	3%
Inflammatory lesion counts	37%	29%	18%	24%
Total lesion counts	45%	32%	23%	16%

Retin-A Micro^® (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 patients using Retin-A Micro^® (tretinoin gel) microsphere, 0.1%, achieved an excellent result, as compared to eleven percent (11%) of patients on the vehicle control. In Study #2, twenty-eight percent (28%) of patients using Retin-A Micro^® (tretinoin gel) microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the patients on the vehicle control.

Retin-A Micro^® (tretinoin gel) microsphere, 0.04%

In two vehicle-controlled clinical studies, Retin-A Micro^® (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:

Mean Percent Reduction in Lesion Counts Retin-A Micro^® (tretinoin gel) microsphere, 0.04%

	Retin-A Micro® (tretinoin gel) microsphere, 0.04%		Vehicle Gel
	Study #1 108 pts	Study #2 111 pts	Study #1 110 pts	Study #2 103 pts
Non-inflammatory lesion counts	37%	29%	-2% 1	14%
Inflammatory lesion counts	44%	41%	13%	30%
Total lesion counts	40%	35%	8%	20%

Retin-A Micro^® (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 patients using Retin-A Micro^® (tretinoin gel) microsphere, 0.04%, achieved an excellent result compared to five percent (5%) of patients on vehicle control. In Study #2, nineteen percent (19%) of patients using Retin-A Micro^® (tretinoin gel) microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of patients on vehicle control.

No studies were conducted comparing the efficacy of Retin-A Micro^® 0.04% to Retin-A Micro^® 0.1%. There is no evidence that Retin-A Micro^® 0.1% is more efficacious than Retin-A Micro^® 0.04% or that Retin-A Micro^® 0.04% is safer than Retin-A Micro^® 0.1%.