SIMVASTATIN

Fetal Risk Summary

Simvastatin 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 some other agents in this class (e.g., see Fluvastatin, Lovastatin, and Pravastatin) and is structurally similar to lovastatin and pravastatin.

Simvastatin was not teratogenic in rats and rabbits at doses up to 3 times the human exposure based on body surface area (1). A decrease in fertility was observed in male rats dosed for 34 weeks at 4 times the maximum human exposure level based on area under the concentration curve (AUC), but this effect was not observed when the study was repeated for 11 weeks (1). Male dogs given 10 mg/kg/day (about 2 times the human exposure based on AUC at 80 mg/day) demonstrated a drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation (1).

Shepard reviewed four studies involving the administration of simvastatin to pregnant rats and rabbits (2,3,4 and 5). Although maternal weight was reduced compared with controls, no teratogenicity, adverse effects on fertility, or interference with postnatal behavior or fertility were observed.

Five cases of fetal loss were reported to the FDA in 1995, but additional data on these cases are not available (F. Rosa, personal communication, FDA, 1995).

A 1996 report described the outcomes of simvastatin-exposed pregnancies gathered from a worldwide postmarketing surveillance by the manufacturer (6). A total of 187 cases of inadvertent exposure to simvastatin had been identified, among which the outcomes of 15 (8%) were still pending, 46 (25%) had been lost to follow-up, and 40 (21%) underwent elective abortions. None of the products of conception from the elective abortions underwent morphologic and/or chromosomal evaluations (7). In the remaining 86 cases, there were 64 (74.4%) normal outcomes, 13 (15.1%) spontaneous abortions, 5 (5.8%) congenital malformations, 1 (1.2%) fetal death, and 3 (3.5%) miscellaneous adverse outcomes. In at least 59 (92%) of the 64 normal outcomes, the mother had been taking the drug before conception so that exposure had occurred from the start of the pregnancy. In three cases, exposure occurred from the 10th week through term, and in two cases the mother took the drug during the 1st trimester, but the exact timing during this period was unknown. The one fetal death occurred at 23 weeks' gestation in a pregnancy exposed to simvastatin (10 mg/day) during the first 3–4 weeks of gestation, but specific details on the case were not available. Congenital anomalies after 1st-trimester exposure to simvastatin occurred in five infants, one of which was a twin. Four reports were prospective and one was retrospective. The defects were (maternal dose and exposure in weeks from last menstrual period): polydactyly with small, boneless, outgrowth from hand (10 mg/day, 3–5 weeks); unilateral cleft lip without cleft palate, amniocentesis normal (10 mg/day, 0–6 weeks); balanic hypospadias (10 mg/day, 0–6 weeks); trisomy 18, multiple malformations in a dead fetus, other twin normal (5 mg/day, 0–7 weeks); and club foot, mother also treated for hypertension (10 mg/day, 0–12 weeks). The cases of polydactyly and hypospadias were thought not to be drug induced because the time of drug exposure in both cases occurred before the critical periods for these defects (6). The trisomy was also dismissed as drug induced because of the lack of evidence that this defect could be caused by drugs. The miscellaneous adverse effects were patent ductus arteriosus in a 1814-g premature infant delivered from a hypertensive mother (10 mg/day, 0–10 weeks); respiratory distress, cardiac arrhythmia, anemia, and infection in a 1900-g premature infant delivered from a hypertensive mother (10 mg/day, 0–7 weeks); and bilateral hydrocele, hyperbilirubinemia in a 1720-g premature infant (20 mg/day, 0–9 weeks). All three cases were thought to be possibly related to prematurity (6).

In summary, based on the animal data and limited human experience, exposure to simvastatin during early pregnancy does not appear to present a significant risk to the fetus. The outcomes reported above are within those expected in a nonexposed population. However, because the interruption of cholesterol-lowering therapy during pregnancy should have no apparent effect on the long-term treatment of hyperlipidemia, simvastatin should not be used during pregnancy. Women taking this agent before conception should ideally stop the therapy before becoming pregnant and certainly on recognition of pregnancy. Accidental use of the drug during gestation, though, apparently has no known consequences for the fetus.

Breast Feeding Summary

No published reports describing the use of simvastatin during lactation have been located, and it is not known whether the agent is excreted into milk. However, the passage of simvastatin into milk should be expected because at least two other 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. Zocor. Merck, 2000.
2. Wise LD, Minsker DH, Robertson RT, Bokelman DL, Akutsu S, Fujii T. Simvastatin (mk-0733): oral fertility study in rats. Oyo Yakuri 1990;39:127–41. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:359–60.
3. Wise LD, Majka JA, Robertson RT, Bokelman DL. Simvastatin (mk-0733): oral teratogenicity study in rats pre- and postnatal observation. Oyo Yakuri 1990;39:143–58. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:359–60.
4. Wise LD, Prahalada S, Robertson RT, Bokelman DL, Akutsu S, Fujii T. Simvastatin (mk-0733): oral teratogenicity study in rabbits. Oyo Yakuri 1990;39:159–67. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:359–60.
5. Minsker DH, Robertson RT, Bokelman DL. Simvastatin (mk-0733): oral late gestation and lactation study in rats. Oyo Yakuri 1990;39:169–79. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:359–60.
6. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 1996;10:439–46.
7. Manson JM. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 1997;11:641–2.