PIOGLITAZONE

Fetal Risk Summary

Pioglitazone, a thiazolidinedione antidiabetic agent, is used as an adjunct to diet and exercise to improve glycemic control in patients with type II diabetes mellitus. It is used either alone or in combination with other antidiabetic agents (insulin, metformin, or sulfonylureas). Pioglitazone is not an insulin secretagogue, but acts to decrease insulin resistance in the periphery and in the liver (i.e., decreases insulin requirements). Thus, it requires the presence of insulin for its action. Pioglitazone undergoes extensive metabolism by hydroxylation and oxidation, and at least three of the metabolites are pharmacologically active (1).

Reproduction studies with pioglitazone have been conducted in rats and rabbits at doses up to 17 and 40 times, respectively, the maximum recommended human dose on a body surface area basis (MRHD) (1). In pregnant rats, at 10 or more times the MRHD, pioglitazone was embryotoxic as evidenced by increased postimplantation losses, delayed development, and reduced fetal weights. At 2 or more times the MRHD during late gestation and in the lactation period, delayed development was observed that was attributed to decreased body weights. Embryotoxicity was observed in rabbits dosed at 40 times the MRHD (1).

It is not known if pioglitazone or its active metabolites cross the placenta to the fetus. The molecular weight of the parent compound (about 393 for the hydrochloride salt) is low enough, however, that transfer to the fetus should be expected.

No reports describing the use of pioglitazone 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 (2,3).

Breast Feeding Summary

No reports describing the use of pioglitazone during human lactation have been located. The molecular weight of pioglitazone (about 393 for the hydrochloride salt) is low enough, however, that secretion into breast milk should be expected. Pioglitazone has been detected in the milk of lactating rats (1). In addition, at least three active metabolites have been identified and these also may be transferred into milk. The effects on a nursing infant from exposure to the drug in milk are unknown.

References

1. Product information. Actos. Takeda Pharmaceuticals America, 2000.
2. American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200, December 1994.
3. Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:558–64.