ROSIGLITAZONE

Fetal Risk Summary

Rosiglitazone, a thiazolidinedione antidiabetic agent, is used as an adjunct to diet and exercise to improve glycemic control in patients with type II diabetes (non-insulin-dependent diabetes mellitus). It is used either alone or in combination with metformin. Rosiglitazone is not an insulin secretagogue, but acts to decrease insulin resistance in the periphery and in the liver (i.e., decreases insulin requirements). Rosiglitazone undergoes extensive metabolism to inactive metabolites.

Reproduction studies with rosiglitazone have been conducted in rats and rabbits at doses up to 20 and 75 times, respectively, the human area under the plasma concentration curve at the maximum recommended human daily dose (MRHD) (1). No teratogenicity or adverse effects on implantation or the embryo were observed in either species, but placental pathology was noted in rats. Moreover, dosing during mid- to late gestation was associated with fetal death and growth retardation in both rats and rabbits. Treatment extending through the lactation period in rats was associated with reduced litter size and decreased neonatal viability and postnatal growth. Growth retardation was reversible after puberty. For effects on the placenta, embryo, fetus, and offspring, the no-effect dose levels were approximately 4 times the MRHD for both species.

It is not known if rosiglitazone crosses the human placenta, but the molecular weight of the free base (about 357) is low enough that transfer to the fetus should be expected.

No reports describing the use of rosiglitazone 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 rosiglitazone during human lactation have been located. The molecular weight of the free base (about 357) is low enough, however, that excretion into breast milk should be expected. Either the parent drug or its metabolites have been detected in the milk of lactating rats (1). The effects on a nursing infant from exposure to the drug in milk are unknown.

References

1. Product information. Avandia. SmithKline Beecham Pharmaceuticals, 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.