Antidiabetic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The published human pregnancy experience is limited. No teratogenicity was observed in two animal species but, in one species, exposure during late pregnancy through lactation resulted in adverse effects on long-bone growth. The embryo–fetal risk from exposure to repaglinide cannot be fully assessed but, based on the animal and limited human data, inadvertent exposure early in gestation does not appear to represent a major risk. However, insulin is the treatment of choice for pregestational and gestational control of maternal hyperglycemia because, in general, most hypoglycemic agents do not provide adequate glycemic control. Moreover, insulin, unlike oral agents, does not cross the placenta to the fetus, thus eliminating the additional concern that the drug therapy itself will adversely affect 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, the American College of Obstetricians and Gynecologists recommends that insulin be used for types 1 and 2 diabetes occurring during pregnancy and, if diet and exercise alone are not successful, for gestational diabetes (1,2).
FETAL RISK SUMMARY
Repaglinide is an oral blood glucose–lowering agent that is chemically unrelated to the sulfonylurea insulin secretagogues. It is in the same antidiabetic subclass of meglitinides as nateglinide. Repaglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The drug is completely metabolized to inactive metabolites. Plasma protein binding to albumin is >98% and the mean half-life is 1.0–1.4 hours (range 0.4–8 hours) (3). It is often combined with metformin.
Reproduction studies have been conducted in rats and rabbits. Repaglinide was not teratogenic in these species when given throughout pregnancy at doses that were about 40 and 0.8 times, respectively, the human clinical exposure based on BSA (HCE). When a dose that was 15 times the HCE was given to rats during gestational days 17–22 and during lactation, offspring developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times the HCE given on gestational days 1–22 or at higher doses on gestational days 1–16 (3).
Another study found effects similar to those above in pregnant rats (4). Because the toxic effects on long bone development were observed only 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 (4).
No evidence of carcinogenicity was found in long-term studies in mice and female rats. In male rats there was an increased incidence of benign adenomas of the thyroid and liver. Multiple tests for genotoxicity were negative. No effects on fertility of male and female rats were observed with doses >40 times the HCE (3).
It is not known if repaglinide crosses the human placenta. The molecular weight (about 453) suggests that it will cross, but the extensive metabolism, high plasma protein binding, and short half-life suggest that the embryo–fetal exposure may be limited.
A 2006 report from Italy described the outcomes of two pregnancies treated with repaglinide for type 2 diabetes early in gestation (5). In both patients, the gestational age was confirmed by ultrasound and their therapy was changed to insulin. The first case involved a 38-year-old woman (pregestational body mass index [BMI] 26.2 kg/m2) who had been on long-term repaglinide 1.5 mg/day and metformin 3 g/day when she presented in the 7th week of pregnancy. Her HbA1c values were 6.8% (preconception), 7% (conception), and 5.6% (3rd trimester). Gestational hypertension developed at 29 weeks’ gestation and was treated with methyldopa. At 40 weeks’, she gave birth to a healthy 3690-g female infant with Apgar scores of 9 and 10. The infant developed jaundice that needed phototherapy for 1 day. The second case was a nulliparous 34-year-old woman (pregestational BMI 21.3 kg/m2) who had been taking repaglinide 2.5 mg/day for 2 years when she presented in the 6th gestational week. Her HbA1c values at conception and in the 3rd trimester were 6.4% and 5.1%, respectively. At 39 weeks’, she gave birth by cesarean section to a 2650-g male infant with Apgar scores 9 and 10. The birth weights for both infants were appropriate for gestational age, and no minor or major malformations were noted. Both infants were doing well at 6 weeks of age (5).
A report from England on the safety profile of repaglinide briefly mentioned five pregnancies exposed to the drug during pregnancy (6). The outcomes of the pregnancies were three infants with no abnormalities reported, one stillborn at 26 weeks’ (mother had Fraser syndrome), and one outcome was unknown (no other details provided).
A brief 2007 report described the pregnancy outcome of a 38-year-old woman with type 2 diabetes who was exposed to repaglinide up to the 7th week (7). At that time her therapy was changed to insulin. In the 39th week, she delivered a normal 3350-g infant (sex not specified). The newborn had no evidence of hypoglycemia.
BREASTFEEDING SUMMARY
No reports describing the use of repaglinide during lactation have been located. The molecular weight (about 453) suggests that it will be excreted into breast milk, but the extensive metabolism and high plasma protein binding (>98%) suggest that the amount in milk will be limited. Although the mean half-life (1.0–1.4 hours) also suggests limited exposure, the range might be as great as 8 hours and suggests otherwise. The effect of this exposure on a nursing infant is unknown, but hypoglycemia is a potential complication. Thus, if a woman plans to breastfeed, changing her therapy to other agents, such as insulin or a second-generation sulfonylurea (see Glipizide and Glyburide) might be appropriate. In any case, monitoring the infant’s blood glucose concentrations should be conducted.
References
1.American College of Obstetricians and Gynecologists. Pregestational diabetes mellitus. ACOG Practice Bulletin. No. 60, March 2005.
2.American College of Obstetricians and Gynecologists. Gestational diabetes. ACOG Practice Bulletin. No. 30, September 2001.
3.Product information. Prandin. Novo Nordisk, 2009.
4.Viertel B, Guttner J. Effects of the oral antidiabetic repaglinide on the reproduction of rats. Arzneim-Forsch/Drug Res 2000;50:425–40.
5.Napoli A, Ciampa F, Colatrella A, Fallucca F. Use of repaglinide during the first weeks of pregnancy in two type 2 diabetic women. Diabetes Care 2006;29:2326–7.
6.Marshall V, Wilton L, Shakir S. Safety profile of repaglinide as used in general practice in England: results of a prescription-event monitoring study. Acta Diabetol 2006;43:6–13.
7.Mollar-Puchades MA, Martin-Cortes A, Perez-Calvo A, Diaz-Garcia C. Use of repaglinide on a pregnant woman during embryogenesis. Diabetes Obes Metab 2007;9:146–7.