Antidiabetic Agent
PREGNANCY RECOMMENDATION: No Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
No reports describing the use of insulin glulisine in human pregnancy have been located. The animal data suggest that the risk to the embryo or fetus is low. Although there are no human data, there are no reasons to believe that insulin glulisine would pose a risk to the embryo or fetus different from that of other insulins. Older forms of insulin, whether of human or of porcine origin, are considered compatible with pregnancy. Insulin glulisine probably can be classified similarly. As with all insulins, the primary concern is severe maternal hypoglycemia.
FETAL RISK SUMMARY
Insulin glulisine is a rapid-acting human insulin analog that differs from regular human insulin by a single substitution of the amino acid asparagine by lysine at position B3. It is produced by recombinant DNA technology. Insulin glulisine is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. It may be given by SC injection or as an SC infusion by an external insulin pump. The mechanism of action of insulin glulisine is similar to human insulin, in that it binds to receptors in muscle and fat cells to facilitate the cellular uptake of glucose and, at the same time, inhibits glucose release from the liver. The apparent elimination half-life of insulin glulisine is 42 minutes, compared with 86 minutes for human regular insulin (1).
Reproduction studies have been conducted in rats and rabbits using regular human insulin as a comparator. In pregnant rats given daily SC doses up to twice the average human dose based on BSA (HD) throughout gestation, no embryo or fetal toxicity different from that observed with human insulin was noted. In pregnant rabbits, daily SC doses up to 0.5 times the HD were associated with developmental toxicity, but only at doses that induced maternal toxicity (hypoglycemia). At the highest dose, increased postimplantation losses and skeletal defects were observed, as was maternal mortality. The no-effect SC dose in rabbits was 0.1 times the HD. The embryo–fetal toxicity in rabbits did not differ from that observed with human insulin at the same dose (1).
In a 12-month carcinogenicity study, rats were given daily SC doses of 1–20 times the HD. A non-dose-dependent increased incidence of mammary gland tumors was observed in female rats compared with untreated controls. However, the incidence of mammary gland tumors was similar to that noted in female rats given human regular insulin. Insulin glulisine was not mutagenic or clastogenic in tests. In male and female rats given daily SC doses up to twice the HD, no clear evidence of impaired fertility or reproductive performance was observed (1).
It is not known if insulin glulisine crosses the human placenta. Human insulin does not cross the placenta in clinically significant amounts (2). Because of the close similarity between insulin glulisine and human insulin, and its high molecular weight (5823), insulin glulisine probably does not cross either. However, there may be endogenous carrier proteins that allow passage of insulin, including insulin glargine, to the embryo early in gestation. After that period, the fetus produces its own insulin as insulin-secreting cells in the fetal pancreas become differentiated near the end of the 1st trimester (3).
BREASTFEEDING SUMMARY
No reports describing the use of insulin glulisine during human lactation have been located. Insulin is a natural component of the blood and is excreted into breast milk (1). Insulin glulisine probably also is present in milk.
References
1.Product information. Apidra. Sanofi-Aventis, 2007.
2.Schardein JL. Insulin and oral hypoglycemic agents. In: Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:458.
3.Buchanan TA, Kjos SL. Diabetes in women. Early detection, prevention, and management. Clin Updates Women’s Health Care. 2002;1(4/Fall):47.