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Renova (Tretinoin) - Description and Clinical Pharmacology

 
 



FOR TOPICAL USE ON THE FACE. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.

DESCRIPTION

RENOVA® (tretinoin cream) 0.02% contains the active ingredient tretinoin in a cream base. Tretinoin is a yellow- to light-orange crystalline powder having a characteristic floral odor. Tretinoin is soluble in dimethylsulfoxide, slightly soluble in polyethylene glycol 400, octanol, and 100% ethanol. It is practically insoluble in water and mineral oil, and it is insoluble in glycerin. The chemical name for tretinoin is (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. Tretinoin is also referred to as all-trans-retinoic acid and has a molecular weight of 300.44. The structural formula is represented below.

TRETINOIN

TRETINOIN

Tretinoin is available as RENOVA® at a concentration of 0.02% w/w in an oil-in-water emulsion formulation consisting of benzyl alcohol, butylated hydroxytoluene, caprylic/capric triglyceride, cetyl alcohol, edetate disodium, fragrance, methylparaben, propylparaben, purified water, stearic acid, stearyl alcohol, steareth 2, steareth 20, and xanthan gum.

CLINICAL PHARMACOLOGY

Tretinoin is an endogenous 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 retinoic 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 such as irritation, or both.

The effect of tretinoin on skin with chronic photodamage has not been evaluated in animal studies. When hairless albino mice were treated topically with tretinoin shortly after a period of UVB irradiation, new collagen formation was demonstrated only in photodamaged skin. However, in human skin treated topically, adequate data have not been provided to demonstrate any increase in desmosine, hydroxyproline, or elastin mRNA. Application of 0.1% tretinoin cream to photodamaged human forearm skin was associated with an increase in antibody staining for procollagen I propeptide. No correlation was made between procollagen I propeptide staining with collagen I levels or with observed clinical effects. Thus, the relationships between the increased collagen in rodents, increased procollagen I propeptide in humans, and the clinical effects of tretinoin have not yet been clearly defined.

Tretinoin was shown to enhance UV-stimulated melanogenesis in pigmented mice. Generalized amyloid deposition in the basal layer of tretinoin-treated skin was noted in a two-year mouse study. In a different study, hyalinization at tretinoin-treated skin sites was noted at doses beginning at 0.25 mg/kg in CD-1 mice.

The transdermal absorption of tretinoin from various topical formulations ranged from 1% to 31% of applied dose, depending on whether it was applied to healthy skin or dermatitic skin. No percutaneous absorption study was conducted with RENOVA® (tretinoin cream) 0.02% in human volunteers. When percutaneous absorption of the oil-in-water emulsion formulation at 0.05% concentration was assessed in healthy male subjects with radiolabeled cream after a single application (n=7), as well as after repeated daily applications (n=7) for 28 days, the absorption of tretinoin was less than 2% and the extent of bioavailability was less after repeated application. No significant difference in endogenous concentrations of tretinoin was observed between single and repeated daily applications.

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