Registration Dossier

Administrative data

Key value for chemical safety assessment

Justification for classification or non-classification

In the FDA Pharmacology review, with application number 20-825, for ziprasidone hydrochloride monohydrate the conclusion on "reproduction studies/pregnancy labeliing" are detailed below.

"Although the sponsor has recommended Pregnancy Category C labeling based on increased numbers of rat pups born dead and decreased postnatal survival, there is no mention of teratogenic effects. However, it is the opinion of our reviewers that there is sufficient evidence to consider ziprasidone to be a teratogen in rabbits even though none of the three teratogenicity studies conducted in that species would technically be considered a definitive one. In the first study (doses of 10, 30 and 60 mg/kg/day during organogenesis there were not enough litters/fetuses available to evaluate due to a combination of dam mortality, reduced pregnancy rate and decreased viable litters. The study was repeated twice; once with two dose groups (10 and 30 mg/kg/day) and once with one dose group (30 mg/kg/day) rather than the usual three dose groups. However, in the first of those studies, ventricular septal defects associated with other cardiac defects occurred in 3 high dose fetuses from 3 different litters. In the second study, ectopic kidneys were observed, also in 3 fetuses from 3 different litters. These malformations were not associated with clear evidence for maternal toxicity, indicating a potentially direct effect on the fetus, and the incidences fell outside the historical control range for the particular strain/laboratory/time period.

The fact that the findings were in each case from 3 separate litters adds strength to the signal. We have therefore concluded that ziprasidone is teratogenic in rabbits and have included the findings, which occurred at only 3 times the maximum 'recommended daily human dose on a surface area basis, in the pregnancy section of labeling, retaining the "C" category.

Teratogenicity was not observed in the rat study."

 

However, from the document is not well clear if the malformations observed in rabbits were not associated with clear evidence for maternal toxicity. Moreover, teratogenicity was not observed in the rat study; so an by an overall evaluation on the available information and the criteria of Annex I of CLP Regulation data are inconclusive for the classification of the substance.