REPAGLINIDE

Fetal Risk Summary

Repaglinide is a nonsulfonylurea oral hypoglycemic agent (meglitinide class) that is used, either alone or in combination with metformin, as an adjunct to diet and exercise in the management of type II diabetes (non-insulin-dependent diabetes mellitus). It is an insulin secretagogue. After absorption from the gastrointestinal tract, repaglinide is rapidly metabolized to inactive metabolites.

In animal reproduction studies, repaglinide was not teratogenic in rats and rabbits at doses 40 and 0.8 times the human clinical exposure based on a body surface area (HCE), respectively (1). However, offspring of rat dams given doses 15 times the HCE in the latter part of gestation and during lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. The no-effect doses were 2.5 times the HCE given throughout pregnancy (through day 22) or higher doses given through gestational day 16 (1). A study published in 2000 found effects similar to those above in pregnant rats (2). Because the toxic effects on long bone development were only observed after organogenesis and only with high doses, the investigators concluded that the toxicity was limited to effects on growth and that repaglinide was not teratogenic (2).

It is not known if repaglinide crosses the human placenta. The molecular weight (about 453) is low enough, however, that transfer to the fetus should be expected.

No reports describing the use of repaglinide during human pregnancy have been located. Insulin is the treatment of choice for pregnant diabetic patients because, in general, other hypoglycemic agents do not provide adequate glycemic control. Moreover, insulin, unlike most oral agents, does not cross the placenta to the fetus, thus eliminating the additional concern that the drug therapy itself will adversely effect the fetus. Carefully prescribed insulin therapy provides better control of the mother's glucose, thereby preventing the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as may occur in diabetes mellitus, are closely associated with a number of maternal and fetal adverse effects, including fetal structural anomalies if the hyperglycemia occurs early in gestation. To prevent this toxicity, most experts, including the American College of Obstetricians and Gynecologists, recommend that insulin be used for types I and II diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (3,4).

Breast Feeding Summary

No reports describing the use of repaglinide during human lactation have been located. The molecular weight (about 453) is low enough that excretion into breast milk should be expected. Consistent with the relatively low molecular weight, repaglinide was detected in the milk of lactating rats (1). Skeletal deformities (see above) were produced in nursing pups who had not been exposed to the drug during gestation (1,2). Because of the unknown potentials for this toxicity and hypoglycemia in a nursing infant, repaglinide should not be used during breast feeding (5).

References

1. Product information. Prandin. Novo Nordisk Pharmaceuticals, 2000.
2. Viertel B, Guttner J. Effects of the oral antidiabetic repaglinide on the reproduction of rats. Arzneim-Forsch/Drug Res 2000;50:425–40.
3. American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200, December 1994.
4. Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:558–64.
5. Guay DRP. Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus. Pharmacotherapy 1998;18:1195–1204.