Antilipemic Agent
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of rosuvastatin in human pregnancy have been located. There was developmental toxicity (growth restriction and/or death) in two animal species at exposures that were close to those obtained in humans, but maternal toxicity also was observed in one of the species. The absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. Because the interruption of cholesterol-lowering therapy during pregnancy should have no apparent effect on the long-term treatment of hyperlipidemia, rosuvastatin should not be used during pregnancy. Moreover, cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (1). Women taking this agent before conception should stop the therapy before becoming pregnant and certainly on recognition of pregnancy. Accidental use of the drug during gestation, though, apparently has no proven consequences for the fetus.
FETAL RISK SUMMARY
Rosuvastatin (a statin) is a lipophilic agent that is used to lower elevated levels of cholesterol. It has the same cholesterol-lowering mechanism (i.e., inhibition of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase) as other agents available in this class: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin (cerivastatin was withdrawn from the market in 2001). Rosuvastatin undergoes little metabolism (about 19%). The main metabolite has some activity but ≤50% than that of the parent compound. Protein binding, mostly to albumin, is about 88%. The primary route of elimination is in the feces with an elimination half-life of about 19 hours (1).
Reproduction studies have been conducted in rats and rabbits. Decreased fetal body weight (female pups) and delayed ossification were observed in the offspring when female rats were given a dose before mating and continuing through day 7 postcoitus that resulted in exposures 10 times the human exposure from 40 mg/day based on AUC (HE-AUC). Decreased pup survival was observed with continuous dosing from day 7 of gestation through lactation day 21 (weaning) at 10 times the HE-AUC or ≥12 times the human exposure based on BSA (HE-BSA). In pregnant rabbits given a dose equivalent to the HE-BSA from gestation day 6 through lactation day 18 (weaning), decreased fetal viability and maternal mortality were observed. Rosuvastatin was not teratogenic in rats or rabbits at systemic exposures equivalent to the HE-AUC or HE-BSA (1).
In 2-year carcinogenicity studies in rats and mice, increased incidences of uterine stromal polyps and hepatocellular adenoma/carcinoma, respectively, were observed at a dose 20 times the HE-AUC. No mutagenic or clastogenic effects were noted in a variety of tests. There also were no effects on fertility in male or female rats at doses up to 10 times the HE-AUC. However, in male dogs and monkeys, doses that were 20 and 10 times, respectively, the HE-BSA caused spermatidic giant cells. In addition, vacuolation seminiferous tubular epithelium was observed in male monkeys (1).
It is not known if rosuvastatin crosses the human placenta. The molecular weight is moderately high (about 966 for the free acid) as is protein binding, but the low metabolism and prolonged elimination half-life suggest that exposure of the embryo–fetus should be expected.
Pregnancy exposures to this class of drugs that had been reported to the FDA were described in 2004 (2). (See Lovastatin.) Twenty of the 178 reported cases involved major congenital malformations. Although none of the cases involved exposure to rosuvastatin (approved by the FDA in August 2003), and the sample was biased because of its voluntary nature and the likely reporting of severe outcomes, some of the defects might be consistent with the inhibition of cholesterol biosynthesis (2). In another 2004 report, among 214 exposures reported to the FDA (none involving rosuvastatin), there were 22 birth defects, 4 infants with intrauterine growth restriction, and 5 cases of fetal death (3). (See Lovastatin.) As in the first report, it was thought that some of the defects might be consistent with inhibition of cholesterol biosynthesis (3).
BREASTFEEDING SUMMARY
No reports describing the use of rosuvastatin during lactation have been located. The excretion of rosuvastatin into breast milk should be expected because of the molecular weight (about 966 for the free acid), low metabolism (10%), and long elimination half-life (about 19 hours). At least two similar agents (fluvastatin and pravastatin) appear in human milk. Because of the potential for adverse effects in the nursing infant, the drug should not be used during lactation.
References
1.Product information. Crestor. AstraZeneca, 2005.
2.Edison RJ, Muenke M. Central nervous system and limb anomalies in case-reports of first trimester statin exposure. New Engl J Med 2004;350:1579–82.
3.Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet 2004;131A:287–98.