Apidra (insulin glulisine) - Sanofi Canada

TOXICOLOGY
Single and Repeated Dose Toxicity
Single- and repeated-dose toxicity studies were conducted in mice, rats and dogs in order to
predict the safety profile for the therapeutic use of insulin glulisine in humans; all studies used
normoglycemic animals. After a single injection of insulin glulisine, the approximate LD50 was
>1000 U/kg in rats and mice and 40 U/kg in dogs. After repeated once daily subcutaneous
injection of insulin glulisine, the No Observable Adverse Effect Level (NOAEL) in rats were 50
U/kg after 1 month and 5 U/kg after 6 months. The NOAEL in dogs were 1 U/kg in both the 1month
and 6-month studies.
The toxicological profile of insulin glulisine was limited to the effects resulting from excessive
hypoglycemia attributed to the exaggerated pharmacodynamic action of the compound after high
doses in normoglycemic animals. Repeated-dose toxicity studies in rats and dogs did not reveal
any unexpected findings different from human regular insulin.
Insulin glulisine-related effects in toxicity studies were dose-dependent, reversible and restricted
to toxic dose levels. Clinical observations and pathological findings obtained in these studies
were similar or comparable to those in human beings observed after hyperinsulinemia/
hypoglycemia. In some cases, excessive hypoglycemia caused the deaths of animals. These
findings in healthy, non-diabetic animals are not indicative of any specific toxicity on insulin
glulisine in patients, where it is used for controlled glucose-lowering effects at therapeutic doses.
Carcinogenesis
In Sprague Dawley rats, a 12-month repeat dose toxicity study was conducted with insulin
glulisine at doses of 2.5, 5, 20 or 50 U/kg twice daily (dose resulting in an exposure equivalent to
approximately 26, 54, 258, 662 times the human Cmax at the average human dose, respectively).
The incidence of mortality increased dose dependently in 2x20 and 2x50 U/kg insulin glulisine
or IU/kg human insulin treated groups respectively. Generally, males were more severely
affected than females and mortality at the comparable dose levels was always higher in the
human insulin treated groups.
In this study, the effects of insulin glulisine on cellular proliferation in mammary glands were
evaluated using Ki-67 immunohistochemistry. There were no significant differences in
mammary cell proliferation between insulin glulisine, regular human insulin and control groups.
Page 33 of 61