SIMVASTATIN: Package Insert and Label Information (Page 4 of 5)


13.1 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 statins. 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/m2), 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.


Adults at High Risk of Coronary Heart Disease Events

In a randomized, double-blind, placebo-controlled, multi-centered study [the Scandinavian Simvastatin Survival Study (Study 4S)], the effect of therapy with simvastatin on total mortality was assessed in 4,444 adult patients with CHD (history of angina and/or a previous myocardial infarction) and baseline total cholesterol (total-C) between 212 and 309 mg/dL who were on a lipid-lowering diet. In Study 4S, patients were treated with standard care, including lipid-lowering diet, and randomized to either simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years.

  • Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 deaths in the simvastatin group vs 189 deaths in the placebo group). There was no statistically significant difference between groups in non-cardiovascular mortality.
  • Simvastatin significantly reduced the risk for the secondary composite endpoint (time to first occurrence of CHD death, definite or probable hospital verified non-fatal MI, silent MI verified by ECG, or resuscitated cardiac arrest) by 34% (p<0.00001, 431 vs 622 patients with one or more events). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. The risk of having a hospital-verified non-fatal MI was reduced by 37%.
  • Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p< 0.00001, 252 vs 383 patients).
  • Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients).
  • Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and triglycerides (TG) of 25%, 35%, and 10%, respectively, and a mean increase in high-density lipoprotein cholesterol (HDL-C) of 8%. In contrast, treatment with placebo led to increases in total-C, LDL-C and TG of 1%, 1%, and 7%, respectively.
  • Because there were only 53 female deaths (approximately 18% of the study population was female), the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly reduced the risk of having major coronary events in women by 34% (60 vs 91 women with one or more event).
  • Simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in geriatric patients (≥65 years) compared with younger adults.

The Heart Protection Study (Study HPS) was randomized, placebo-controlled, double-blind, multi-centered study with a mean duration of 5 years conducted in 10,269 patients on simvastatin 40 mg and 10,267 on placebo).Patients had a mean age of 64 years (range 40 to 80 years old), were 97% were white and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vascular disease (33%), or they were males ≥65 years with hypertension in (6%). At baseline:

  • 3,421 patients (17%) had LDL-C levels below 100 mg/dL, including 953 (5%) below 80 mg/dL; and
  • 10,047 patients (49%) had levels greater than 130 mg/dL.

Patients were randomized to simvastatin or placebo using a covariate adaptive method which considered the distribution of 10 important baseline characteristics of patients already enrolled.

The Study HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; and non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 5).

Table 5: CHD Mortality and Cardiovascular Events in Adult Patients with High Risk of Developing a Major Coronary Event in Study HPS

* n = number of patients with indicated event

Endpoint Simvastatin (N=10,269) n (%)* Placebo (N=10,267) n (%)* Risk Reduction (%) (95% CI) p-Value
Mortality 1,328 (12.9%) 1,507 (14.7%) 13 (6 to 19%) p=0.0003
CHD mortality 587 (5.7%) 707 (6.9%) 18 (8 to 26%) p=0.0005
Non-fatal MI 357 (3.5%) 574 (5.6%) 38 (30 to 46%) p<0.0001
Stroke 444 (4.3%) 585 (5.7%) 25 (15 to 34%) p<0.0001
Coronary revascularization 513 (5%) 725 (7.1%) 30 (22 to 38%) p<0.0001
Peripheral and other non-coronary revascularization 450 (4.4%) 532 (5.2%) 16 (5 to 26%) p=0.006

Two composite endpoints were defined in order to have enough events to assess relative risk reductions across a range of baseline characteristics:

  • Major coronary events (MCE) was comprised of CHD mortality and non-fatal MI. Analyzed by time-to-first event; 898 patients (8.7%) treated with simvastatin had events and 1,212 patients (11.8%) treated with placebo had events.
  • Major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures Analyzed by time-to-first event; 2,033 patients (19.8%) treated with simvastatin had events and 2,585 patients (25.2%) on placebo had events.

Simvastatin use led to significant relative risk reductions for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001) and for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, baseline levels of LDL-C, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, or obesity. Patients with diabetes showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity.

Primary Hyperlipidemia in Adults

The effects of simvastatin on total-C and LDL-C were assessed in controlled clinical studies in adult patients with heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. simvastatin significantly decreased total-C, LDL-C, and TG, and increased HDL-C (see Table 6). Maximal to near maximal response was generally achieved within 4-6 weeks and maintained during chronic therapy.

Table 6:Mean Changes in Lipid Levels in Adult Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)

* median percent change

mean baseline LDL-C =244 mg/dL and median baseline TG =168 mg/dL

mean baseline LDL-C =188 mg/dL and median baseline TG =128 mg/dL

§ mean baseline LDL-C =226 mg/dL and median baseline TG =156 mg/dL

21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded

& mean baseline LDL-C =156 mg/dL and median baseline TG =391 mg/dL

Lower Dose Comparative Study (Mean % Change at Week 6)
Simvastatin 5 mg at night. 109 -19% -26% +10 -12%
Simvastatin 10 mg at night. 110 -23% -30% +12 -15%
Scandinavian Simvastatin Survival Study (Mean % Change at Week 6)
Placebo 2223 -1% -1% 0 -2%
Simvastatin 20 mg at night. 2221 -28% -38% +8 -19%
Upper Dose Comparative Study§ (Mean % Change Averaged at Weeks 18 and 24)
Simvastatin 40 mg at night. 433 -31% -41% +9 -18%
Simvastatin 80 mg at night. 664 -36% -47% +8 -24%
Combined Hyperlipidemia Study# (Mean % Change at Week 6)
Placebo 125 1% 2% +3 -4%
Simvastatin 40 mg at night. 123 -25% -29% +13 -28%
Simvastatin 80 mg at night. 124 -31% -36% +16 -33%

Hypertriglyceridemia in Adults

The results of a subgroup analysis in 74 patients with hypertriglyceridemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in TABLE 6 for the Combined Hyperlipidemia Study. Simvastatin decreased TC, LDL-C, and TG in these patients.

Dysbetalipoproteinemia in Adults

The results of a subgroup analysis in 7 adult patients with dysbetalipoproteinemia (apo E2/2) (very-low-density lipoprotein cholesterol [VLDL-C]/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7. Simvastatin decreased total-C, LDL-C + intermediate[1]density lipoprotein (IDL), VLDL-C + IDL, and TG compared to placebo.

Table 7:Lipid Effects in Adult Patients with Dysbetalipoproteinemia Over Six Weeks [Median Percent Change (min, max) from Baseline]*

* The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291

Placebo 7 -8% (-24, +34) -8% (-27, +23) -2% (-21, +16) +4% (-22, +90) -4% (-28, +78) -8% (-26, -39)
Simvastatin 40 mg/day 7 -50% (-66, -39) -50% (-60, -31) +7% (-8, +23) -41% (-74, -16) -58% (-90, -37) -57% (-72, -44)
Simvastatin 80 mg/day 7 -52% (-55, -41) -51% (-57, -28) +7% (-5, +29) -38% (-58, +2) -60% (-72, -39) -59% (-61, -46)

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia (HoFH) received simvastatin 40 mg/day in a single dose or 80 mg/day in 3 divided doses. In 12 patients the mean LDL-C changes at 9 weeks for the 40- and 80-mg doses were -13.7% (range -22.5% to -4.9%) and -24.6% (range -37.3% to -11.9%), respectively.

Pediatric Patients 10 Years of Age and Older with HeFH

In a double-blind, placebo-controlled study, 175 pediatric patients (99 boys and 76 post-menarchal girls) 10 years of age and older (mean age 14 years old) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). To be included in the study, patients were required to have a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24 week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (ApoB) (see Table 8) in the HeFH study. Results from the extension at 48 weeks were comparable to the results at Week 24.

The safety and effectiveness of dosages above 40 mg daily have not been studied in pediatric patients with HeFH. The long-term efficacy of simvastatin therapy in pediatric patients to reduce morbidity and mortality in adulthood has not been established.

Table 8 :Lipid Effects in Pediatric Patients 10 Years of Age and Older with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)
median percent change
Dosage Duration N Total-C LDL-C HDL-C TG * Apo B
Placebo 24 Weeks 67 % Change from Baseline (95% CI) +1.6% (-2.2, 5.3) +1.1% (-3.4, 5.5) +3.6% (-0.7, 8.0) -3.2% (-11.8, 5.4) -0.5 (-4.7, 3.6)
Mean baseline, mg/dL (SD) 279 (52) 212 (49) 47 (12) 90 (51) 186 (38)
Simvastatin 24 Weeks 106 % Change from Baseline (95% CI) -26.5% (-29.6, -23.3) -36.8 (-40.5, -33.0) +8.3% (4.6, 11.9) -7.9 (-15.8, 0.0) -32.4% (-35.9, -29.0)
Mean baseline, mg/dL (SD) 270 (44) 204 (42) 48 (9) 78 (46) 180 (34) provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

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