Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
no guideline followed
Guideline:
other: no data
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat

Administration / exposure

Doses / concentrations
Remarks:
Doses / Concentrations:
25 and 10 mg/kg/day
Basis:
no data
No. of animals per sex per dose:
rats and rabbits

Results and discussion

Results (fetuses)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Developmental and Reproductive Toxicity – Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk2.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation)2. No microscopic changes were observed in the testes of rats from either study2. At 180 mg/kg/day, seminiferous tubule degeneration was observed2. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day2.
Executive summary:

Developmental and Reproductive Toxicity – Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk2. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation)2. No microscopic changes were observed in the testes of rats from either study2. At 180 mg/kg/day, seminiferous tubule degeneration was observed2. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day2.