Zocor

[simvastatin]

PRECAUTIONS

General

Simvastatin may cause elevation of CK and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy
with simvastatin.

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Information for Patients

Patients should be advised about substances they should not take concomitantly with simvastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/ Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking ZOCOR.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/ kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid-and high-dose males with a maximum incidence of 90% in males.

The incidence of adenomas of the liver was significantly increased in mid-and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid-and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/ kg/ day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/ kg/ day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/ kg/ day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/ kg/ day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/ kg/ day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/ kg/ day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other HMG-CoA reductase inhibitors. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in
an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/ kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/ day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/ kg/ day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/ day based on surface area, mg/ m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/ kg/ day, (approximately 2 times the human exposure, based on AUC, at 80 mg/ day). The clinical significance of these findings is unclear.

Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS. Safety in pregnant women has not been established.

Simvastatin was not teratogenic in rats at doses of 25 mg/ kg/ day or in rabbits at doses up to 10 mg/ kg daily. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/ m 2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review 5 of approximately 100 prospectively followed pregnancies in women exposed to ZOCOR or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/ stillbirths did not exceed what would be expected in the general population.

The number of cases is adequate only to exclude a 3-to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with ZOCOR during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. ZOCOR should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.

Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants (see CONTRAINDICATIONS).

Pediatric Use

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or
sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical Studies in Adolescents; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescents (10-17 years of age) with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy).

Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.

Geriatric Use

A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. In 4S, lipid-lowering efficacy was at least as great in elderly patients compared with younger patients. In this study, ZOCOR significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD.

There were no overall differences in safety between older and younger patients in 4S. In HPS, 52% of patients were elderly (4, 891 patients 65-69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients (see CLINICAL PHARMACOLOGY). In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/ rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/ rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75.

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