![]() However, variations in teratogenic doses among various strains of rats have been reported. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. 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 (16 times the human topical dose adjusted for total body surface area). A dermal Segment III study with RETIN-A has not been performed in any species. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area) and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. 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. 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. For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). 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. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. A dose-related incidence of liver tumors in male mice was observed at those same doses. ![]() 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. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.Ĭarcinogenesis, Mutagenesis, Impairment to Fertility If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Topical use may induce severe local erythema and peeling at the site of application. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. 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. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-A, 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. If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued.
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