Carcinogenesis Mutagenesis and Impairment of Fertility
In a life-time dermal study in CD-1 mice with another tretinoin cream, at 100 and 200 times the average recommended human topical clinical dose, a few skin tumors in the female mice and liver tumors in male mice were observed. 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. There was no evidence of carcinogenic potential when tretinoin was administered topically at a dose five times the average recommended human topical clinical dose. For purposes of comparisons of the animal exposure to human exposure, the "recommended human topical clinical dose" is defined as 1.0 g of 0.025% AVITA® Cream applied daily to a 50 kg person. In a chronic, two-year bioassay of vitamin A acid in mice performed by Tsubura and Yamamoto, generalized amyloid deposition was reported in all vitamin A treated groups in the basal layer of the skin. In CD-1 mice, a similar study reported hyalinization at the treated skin sites and the incidence of this finding was 0/50, 3/50, 3/50, and 2/50 in male mice and 1/50, 0/50, 4/50, and 2/50 in female mice from the vehicle control, 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg groups, respectively.
Studies in hairless albino mice suggest that tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVA/UVB light, the incidence and rate of development of skin tumors were either reduced or no effect was seen. Due to significantly different experimental conditions, no strict comparison of these disparate data is possible at this time. Although the significance of these studies to humans is not clear, patients should minimize exposure to sun.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.
Dermal Segment I and III studies with AVITA® Cream have not been performed in any species. 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 (> 400 times the average recommended human topical clinical dose).
Pregnancy Category C.
Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. It was teratogenic and fetotoxic in rats when given orally in doses 1000 times the average recommended human topical clinical dose. However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than other species examined, fetal malformations were reported at oral doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (1000 times the average recommended human topical clinical dose), although increased skeletal variations were observed at all doses. Dose-related increased embryolethality and abortion were reported. Similar results have also been reported in pigtail macaques.
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (200 times the recommended human topical clinical dose). Anomalies (humerus: short 13%, bent 6%; os parietal incompletely ossified 14%) have also been reported in rats when 10 mg/kg/day was dermally applied.
Topical tretinoin (AVITA® Cream, 0.1%) has been shown to be teratogenic in rabbits when given in doses 91 times the topical human dose for cream (assuming a 50 kg adult applies 1.0 g of 0.1% cream topically). In this study, increased incidence of cleft palate and hydrocephaly was reported in the tretinoin-treated animals.
There are other reports, in New Zealand White rabbits with doses of approximately 80 times the recommended human topical clinical dose, of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
When given subcutaneously to rabbits, tretinoin was teratogenic at 2 mg/kg/day but not at 1 mg/kg/day. These doses are approximately 400 and 200 times, respectively, the human topical dose of tretinoin cream, 0.025% (assuming a 50 kg adult applies 1.0 g of 0.025% cream topically).
In contrast, several well-controlled animal studies have shown that dermally applied tretinoin was not teratogenic at doses of 100 and 200 times the recommended human topical clinical dose, in rats and rabbits, respectively.
With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin (Retin-A). Although no definite pattern of teratogenicity and no causal association have been established from these cases, five of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 100 times the recommended topical human clinical dose. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 500 times the recommended topical human clinical dose. There are, however, no adequate and well-controlled studies in pregnant women. AVITA® Cream should not be used during pregnancy.