Carcinogenicity/Tumorigenicity: Statistically significant increases in the incidence of thyroid gland follicular cell adenomas were seen in male mice receiving Quetiapine at daily dosages that were equivalent to 1.5 and 4.5 times the maximum recommended human dose (MRHD) on a mg per square meter of body surface area (mg/m2) basis and in male rats receiving three times the MRHD on a mg/m2 basis, possibly as a result of chronic stimulation of the thyroid gland by thyroid-stimulating hormones (TSH). Although the results were not definitive, Quetiapine toxicity studies in rats and mice showed changes in Thyroxine concentrations, Thyroxine clearance, and TSH concentrations that are consistent with the proposed mechanism of increased Thyroxine clearance leading to increased TSH concentrations and increased thyroid gland stimulation.
Statistically significant increases in the incidence of mammary gland adenocarcinomas were seen in rats receiving Quetiapine at daily dosages that were equivalent to 0.3 to 3 times the MRHD on a mg/m2 basis. In a 1-year Quetiapine toxicity study, median serum prolactin concentrations were increased a maximum of 32-fold in male rats, and 13-fold in female rats. The mammary gland neoplasms seen in rodents are chronic administrationof antipsychotic medications are considered to be prolactin-mediated.
The relevance of these findings to human is unknown.
Mutagenicity: Quetiapine produced a reproducible increase in mutations in one of six strains in in vitro bacterial gene mutation assays in the presence of metabolic activation. An in vitro chromosomal aberration assay in cultured human lymphocytes and an in vivo micronucleus assay in rats found no evidence of clastogenic potential.
Fertility: In male Sprague-Dawley rats, the interval to mate and the number of matings required to produce pregnancy increased at Quetiapine doses equivalent to 0.6 to 1.8 times the MRHD on a mg/m2 basis. These effects were still present 2 weeks after discontinuation of Quetiapine in the rats that had received 1.8 times of MRHD. No effects on estrus, mating, or fertility were seen in female rats receiving ≤ 0.3 times the MRHD on a mg/m2 basis.
In female Sprague-Dawley rats, the interval to mate increased and the number of matings and the number of matings resulting in pregnancy decreased at a Quetiapine dose equivalent to 0.6 times the MRHD on a mg/m2 basis. Irregular estrus cycles increased at doses equivalent to 0.1 and 0.6 times the MRHD on a mg/m2 basis. No effects on estrus, mating, or fertility were seen in female rats receiving ≤0.01 times the MRHD on a mg/m2 basis.
Use in Pregnancy: Adequate and well-controlled studies in humans have not been done.
Quetiapine showed no teratogenic potential in rats and rabbits, dosed at 0.3 to 2.4 and 0.6 to 2.4 times the MRHD on a mg/m2 basis, respectively, during the period of organogenesis. However, in rats, delays in skeletal ossification were seen in fetuses at all doses. Also, reduced fetal body weight and reduced maternal weight gain and/or increased maternal deaths were seen at all doses, delays in skeletal ossification in the fetuses, were seen at doses of 1.2 and 2.4 times the MRHD on a mg/m2 basis, and reduced fetal body weight and an increase incidence of minor soft tissue anomaly in the fetuses were seen at the highest dosage used. In a perinatal/postnatal study in rats receiving 0.01 to 0.24 times the MRHD on a mg/m2 basis, no drug-related effects were observed. However, in a preliminary perinatal/postnatal study in rats receiving three times the MRHD on a mg/m2 basis, increase in fetal and pup deaths and decreases in mean litter weight were found.
FDA Pregnancy Category C.
Use in Lactation: Quetiapine is distributed into the milk of animals. It is not known whether Quetiapine is distributed in breast milk, but breast-feeding while taking Quetiapine is not recommended.
Use in Children: No information is available on the relationship of age to the effects of Quetiapine in pediatric patients. Safety and efficacy have no been established.
Use in Elderly: No geriatrics-specific problems that would limit the usefulness of Quetiapine in the elderly were seen in studies that included subject 65 years of age and older. However, the mean plasma clearance of Quetiapine in elderly patients was 30 to 50% less than in younger patients. Reduced initial and target dosages, and slower dosage titration may be necessary in elderly patients.