Pregnancy & Lactation : הריון/הנקה

Use in Pregnancy

Category B3
Risedronate has not been studied in pregnant women. Risedronate should only be used during pregnancy if the potential benefit justifies the potential risk to mother and foetus. If administration during pregnancy is contemplated, serum calcium levels should be monitored and calcium supplementation provided in late gestation. Animal studies suggest that periparturient maternal hypocalcaemia and foetal ossification effects may occur.
Animal studies have shown that risedronate sodium crosses the placenta to a minimal extent in rats. The drug had no teratogenic activity in rats or rabbits at oral doses up to 80 and 10 mg/kg/day respectively.
However, suppression of foetal growth and retardation of ossification were observed at the highest dose level in rats. When administered to rats during late gestation, maternal deaths and parturition failure were observed at oral dose levels greater than 2 mg/kg/day. These effects were probably secondary to maternal hypocalcaemia. Systemic exposure (AUC 0-24 h) at the no-effect level in rats was similar to that in patients with Paget’s disease, and about 6 times higher than that in patients with corticosteroid-induced osteoporosis.
Systemic exposure in rabbits was not measured.
Use in Lactation
Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether risedronate is excreted in human milk.
Due to the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
As with other bisphosphonates in preclinical models, foetuses from risedronate treated dams showed ossification changes in sternebrae and/or skull at doses as low as 3.2 mg/kg/day. This is equivalent to the human 30 mg dose and 6 times the human 5 mg dose based on surface area, mg/m2. Treatment with risedronate during mating and gestation with doses of 3.2 mg/kg/day has resulted in periparturient hypocalcaemia and mortality in rats allowed to deliver.
Genotoxicity
Risedronate did not cause gene mutations in bacterial or mammalian cells in vitro, nor did it cause DNA damage in rat hepatocytes in vitro. In clastogenicity assays, risedronate was positive in an in vitro assay using Chinese hamster ovary cells at cytotoxic concentrations (7-18% cell survival), but there was no evidence of chromosomal damage when the assay was repeated at concentrations leading to 48-74% cell survival. Risedronate was negative at oral doses up to 1336 mg/kg in an in vivo assay (chromosomal aberrations in rat bone marrow).
Carcinogenicity
No evidence of carcinogenicity was observed in either rats (treated for 104 weeks with up to 24 mg/kg/day) or mice (treated for 80 weeks with up to 32 mg/kg/day). Systemic exposure (serum AUC 0-24h) at the high dose in rats was 160 times greater than that in humans dosed at 30 mg/day. Systemic exposure was not assessed in mice, but the highest dose in the carcinogenicity study was at least 30 times higher than the dose required for pharmacological effects on bone. Thus, risedronate sodium appears to have no carcinogenic potential at therapeutic dose levels.


Effect on Laboratory Tests
Bisphosphonates are known to interfere with the use of bone-imaging agents. However specific studies with risedronate have not been performed.
Small asymptomatic decreases in serum calcium and phosphorus levels have been observed in some patients 


Renal impairment

Enteric-coated Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance  30 mL/min).