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.
Four adequate and well-controlled multi-center trials and one single-center randomized, controlled trial were conducted involving a total of 324 evaluable patients treated with RENOVA® (tretinoin cream) 0.02% and 332 evaluable patients treated with the vehicle cream on the face for 24 weeks with a comprehensive skin care and sun avoidance program, to assess the effects on fine and coarse wrinkling, mottled hyperpigmentation, tactile skin roughness, and laxity. Patients were evaluated at baseline on a 10 unit scale and changes from the baseline rating were categorized as follows:
Worsening: Increase of 1 unit or more.
No improvement: No change.
Minimal improvement: Reduction of 1 unit.
Mild improvement: Reduction of 2 units.
Moderate improvement: Reduction of 3 units or more.
In these trials, the fine and coarse wrinkling, mottled hyperpigmentation, tactile roughness, and laxity of the facial skin were thought to be caused by multiple factors which included intrinsic aging or environmental factors, such as chronic sunlight exposure.
Two of the five trials provided adequate demonstration of efficacy for mitigation of fine facial wrinkling. No two of the five trials adequately demonstrated efficacy for mitigation of coarse wrinkling, mottled hyperpigmentation, tactile skin roughness, and laxity. Data for fine wrinkling (the indication for which RENOVA® (tretinoin cream) 0.02% demonstrated efficacy) from all five trials (four studies in lightly pigmented subjects with Fitzpatrick Skin Types I-III and one study in darkly pigmented subjects with Fitzpatrick Skin Types IV-VI) is provided below:
FINE WRINKLING IN LIGHTLY PIGMENTED SUBJECTS
|Subjects using RENOVA® (tretinoin cream) 0.02% + CSP*
|Vehicle + CSP*
A single-center study (N=107) in darkly pigmented, mostly African-American, subjects with Fitzpatrick Skin Types IV-VI demonstrated minimal or mild improvement in fine facial wrinkling in 43% of patients using Vehicle + CSP* compared to 29% of subjects using RENOVA® (tretinoin cream) 0.02% + CSP*. Although fewer darkly pigmented subjects improved with RENOVA® (tretinoin cream) 0.02% than with vehicle, these findings may reflect the small size of this study.
*CSP = Comprehensive skin protection and sunlight avoidance programs including use of sunscreens, protective clothing, and non-prescription emollient creams.
Self-assessment of fine wrinkles after 24 weeks of treatment with either RENOVA® (tretinoin cream) 0.02% or Vehicle from the four studies in lightly pigmented patients showed the following:
No studies have been conducted comparing the facial irritation or efficacy of RENOVA® (tretinoin cream) 0.02% to RENOVA® (tretinoin cream) 0.05% (older marketed formulation).
Patients may lose some of the mitigating effects of RENOVA® (tretinoin cream) 0.02% after 12 weeks of discontinuation of RENOVA® (tretinoin cream) 0.02% from their comprehensive skin care and sunlight avoidance program.
Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.
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