ATORVASTATIN

Fetal Risk Summary

Atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is indicated as an adjunct to diet to reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B, and triglyceride levels in patients with primary hypercholesterolemia and mixed dyslipidemia (1). It has the same mechanism of action as cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The parent drug and some of the metabolites are pharmacologically active in humans (1).

In reproduction studies with pregnant rats and rabbits, doses that were about 30 and 20 times, respectively, the human exposure based on body surface area, were not teratogenic (1). With maternal dosing in rats from gestation day 7 through to lactation day 21 (weaning), at a dose 22 times the human exposure based on area under the plasma concentration curve (HE-AUC), there was decreased pup survival at birth, during the neonatal period, at weaning, and at maturity, and decreased pup weight at birth, during nursing, and at maturity. In addition, pup development was inhibited at this dose. At a dose 6 times the HE-AUC, decreased pup body weight occurred during nursing. A 1994 report described developmental toxicity of atorvastatin at maternally toxic doses in pregnant rats and rabbits (2). There was evidence, however, of teratogenicity in either species (2).

It is not known if atorvastatin crosses the human placenta. The relatively high molecular weight (about 1161 for the non-hydrated form) suggests that transfer of this drug across the human placenta would be inhibited. In pregnant rats, however, fetal liver levels of atorvastatin are equivalent to maternal levels (1).

No published cases involving the use of atorvastatin during human pregnancy have been located. The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, because cholesterol and products synthesized by cholesterol are important during fetal development, the use of atorvastatin is contraindicated during pregnancy.

Breast Feeding Summary

No reports describing the use of atorvastatin in human lactation have been located. The relatively high molecular weight (about 1161 for the non-hydrated form) suggests that excretion into milk would be inhibited. However, the drug is excreted into the milk of lactating rats, resulting in plasma and liver levels that were 50% and 40%, respectively, of the mother's milk (1). Thus, some excretion into human breast milk should be expected. Because of the potential for adverse effects in a nursing infant, women who are taking atorvastatin should not breast feed.

References

1. Product information. Lipitor. Parke-Davis, 2001.
2. Dostal LA, Schardein JL, Anderson JA. Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 1994;50:387–94.