Nextstellis: genotox, carcinogenicity and repro: done or skipped?

“Weight of evidence indicates that E4 is not considered genotoxic in a full battery of in vitro and in vivo assays (Ames assay, in vitro mouse lymphoma assay, an in vivo rat micronucleus assay, and in vivo rat Comet assay).”

“E4 doses of up to 0.8 mg/kg/day were administered orally to female rats for 104 weeks. At the high-dose of 0.8 mg/kg/day E4 (0.7x the MRHD on an AUC basis), there was an increased incidence of mammary neoplasms”

“The observed fetal growth retardation and developmental effects were likely consequences of maternal toxicity in the pregnant female rat and rabbit. There are no indications for intrinsic teratogenic properties of E4 or DRSP in either rat or rabbit.”

“E4 did not alter the cardiovascular function of telemetered monkeys and did not affect the respiratory functions of rats up to the highest dose tested (100 mg/kg in monkeys and 150 mg/kg in rats), with safety margins of approximately 115 times and 830 times the MRHD on an AUC basis, respectively.”