Actonel

[Risedronate]

Mutagenesis

Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/ HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (> 675 mcg/ mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.

Impairment of Fertility

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In female rats, ovulation was inhibited at an oral dose of 16 mg/ kg/ day (approximately 5.2 times the 30-mg/ day human dose based on surface area, mg/ m 2 ). Decreased implantation was noted in female rats treated with doses 30-mg/ day human dose based on surface area, mg/ m 2 ). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/ kg/ day (approximately 13 times the 30-mg/ day human dose based on surface area, mg/ m 2 ). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/ kg/ day (approximately 5.2 times the 30-mg/ day human dose based on surface area, mg/ m 2 ). There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/ kg/ day (approximately 8 times the 30-mg/ day human dose based on surface area, mg/ m 2 ). These findings tended to increase in severity with increased dose and exposure time.

Pregnancy

Pregnancy Category C

Survival of neonates was decreased in rats treated during gestation with oral doses -mg/ day human dose based on surface area, mg/ m 2 ). Body weight was decreased in neonates from dams treated with 80 mg/ kg (approximately 26 times the 30-mg/ day human dose based on surface area, mg/ m 2 ). In rats treated during gestation, the number of fetuses exhibiting incomplete ossification of sternebrae or skull was statistically significantly increased at 7. 1 mg/ kg/ day (approximately 2. 3 times the 30-mg/ day human dose based on surface area, mg/ m 2 ). Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses the 30-mg/ day human dose based on surface area, mg/ m 2 ). A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses time the 30-mg/ day human dose based on surface area, mg/ m 2 ). The relevance of this finding to human use of ACTONEL is unclear.

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