ry of Tumor Occurrence at the Multiples of the Human Dose on a mg/m2 (mg/kg) Basis with Oral Risperidone Dosing
Multiples of Maximum Human Dose in mg/m2 (mg/kg)
Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level
Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4)
Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4)
Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none
rat Female 0.4 (2.4) none
rat Male 6.0 (37.5) 1.5 (9.4)
Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila.
No evidence of mutagenic potential was observed with risperidone subcutaneous injectable suspension or its delivery system alone at doses of 150 mg/kg risperidone or 943 mg/kg delivery system in an in vivo micronucleus test in rats. The safety margins of risperidone were 12 to 19 times the maximum monthly plasma risperidone concentration observed for humans at the monthly MRHD of 120 mg risperidone based on plasma exposure, and 13 times the delivery system amount present in monthly 120 mg risperidone.
Impairment of Fertility
No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the maximum recommended human dose (MRHD), of 16 mg/day based on mg/m2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.
Subcutaneous administration of the delivery system to rats had no effect on fertility parameters in either sex up to a dose that is 17 (delivery system), and 23 (NMP) times the amount present in monthly 120 mg risperidone subcutaneous injectabl |
