Risk Summary

Discontinue fluvastatin sodium extended-release tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Fluvastatin sodium extended-release tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, fluvastatin sodium extended-release tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. 

Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with fluvastatin sodium extended-release tablets use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data).

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered fluvastatin during the period of organogenesis at doses that resulted in 2 and 5 times, respectively, the human exposure at the maximum recommended human dosage of 40 mg/day, based on body surface area (mg/m2) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 

Data

Human Data

A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders, including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% CI: 0.85 to 1.37) after controlling for confounders, particularly preexisting diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. 

Animal Data 

Fluvastatin sodium given to rats during organogenesis at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day produced delays in skeletal development. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced significant maternal toxicity. A study in which female rats were given fluvastatin during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. Rats were given fluvastatin from Gestation Day 15 to Lactation Day 21 at doses of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on Days 0 and 7 postpartum.