|Clinical Impact:||Simvastatin may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin.|
|Intervention:||In patients taking coumarin anticoagulants, obtain an INR before starting simvastatin and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.|
|Clinical Impact:||Concomitant use of digoxin with simvastatin may result in elevated plasma digoxin concentrations [ see CLINICAL PHARMACOLOGY ( 12.3) ].|
|Intervention:||Monitor digoxin levels in patients taking digoxin when simvastatin is initiated.|
Discontinue simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.
Simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin 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 simvastatin 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 simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m 2) (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.
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% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing 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.
Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits.
Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested.
Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta.
There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including
simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.
Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with simvastatin [see USE IN SPECIFIC POPULATIONS (8.1), CLINICAL PHARMACOLOGY ( 12.1)].
The safety and effectiveness of simvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of simvastatin for this indication is based on a double-blind, placebo-controlled clinical study in 175 pediatric patients (99 boys and 76 girls at least 1 year post-menarche) 10 years of age and older with HeFH. In this limited controlled study, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls.
The safety and effectiveness of simvastatin have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).
Of the total number of simvastatin-treated patients in clinical studies 1,021 (23%) patients, 5,366 (52%) patients, and 363 (15%) patients were ≥65 years old, respectively. In Study HPS, 615 (6%) patients were ≥75 years old [see CLINICAL STUDIES ( 14)] . In a clinical study of patients treated with simvastatin 80 mg daily, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age.
A pharmacokinetic study with simvastatin use showed the mean plasma level of total inhibitors to be approximately 45% higher in geriatric patients between 70-78 years of age compared with patients between 18-30 years of age [see CLINICAL PHARMACOLOGY ( 12.3)] .
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