Simvastatin 40 mg Tablet, Film Coated, 100-count — NDC 31722-513-01 (Billing 31722-0513-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.2Pharmacodynamics Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of simvastatin is usually achieved by 4 weeks and is maintained after that.

12.3Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid. Pharmacokinetics (PK) of simvastatin and its metabolites was originally characterized using inhibition of HMG-CoA reductase activity following base hydrolysis of plasma samples, as specific bioanalytical methods were not available. Inhibition of the enzyme activity (equivalent to the level of total inhibitors) represented the combination of activities in plasma following administration of simvastatin from both active (simvastatin acid and its metabolites) and latent forms (simvastatin and its metabolites) after conversion to the active forms in the presence of base.

Absorption Following an oral dose of 14 C-labeled simvastatin, plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of simvastatin to the general circulation is low (<5%). PK, assessed as area under the concentrations of total inhibitors – time curve, was apparently linear with doses up to 120 mg.

Effect of Food The plasma profile of total inhibitors concentration was not affected when simvastatin was administered with low fat meal. Distribution Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Elimination Metabolism Simvastatin is metabolized by CYP3A4.

The major active metabolites of simvastatin present in human plasma are simvastatin acid and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Excretion Following an oral dose of 14 C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces.

Specific Populations Geriatric Patients In a study including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18 to 30 years of age [see Use in Specific Populations ( 8.5 )]. Drug Interaction Studies Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of inhibitors of the transport protein OATP1B1 and/or CYP3A4 may lead to increased exposure of simvastatin acid.

Cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see Drug Interactions ( 7 )]. Table 4 displays the effect of coadministered drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions ( 7 )]. Table 4: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect =

1.00AUC C max Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.3Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid. Pharmacokinetics (PK) of simvastatin and its metabolites was originally characterized using inhibition of HMG-CoA reductase activity following base hydrolysis of plasma samples, as specific bioanalytical methods were not available. Inhibition of the enzyme activity (equivalent to the level of total inhibitors) represented the combination of activities in plasma following administration of simvastatin from both active (simvastatin acid and its metabolites) and latent forms (simvastatin and its metabolites) after conversion to the active forms in the presence of base.

Absorption Following an oral dose of 14 C-labeled simvastatin, plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of simvastatin to the general circulation is low (<5%). PK, assessed as area under the concentrations of total inhibitors – time curve, was apparently linear with doses up to 120 mg.

Effect of Food The plasma profile of total inhibitors concentration was not affected when simvastatin was administered with low fat meal. Distribution Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Elimination Metabolism Simvastatin is metabolized by CYP3A4.

The major active metabolites of simvastatin present in human plasma are simvastatin acid and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Excretion Following an oral dose of 14 C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces.

Specific Populations Geriatric Patients In a study including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18 to 30 years of age [see Use in Specific Populations ( 8.5 )]. Drug Interaction Studies Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of inhibitors of the transport protein OATP1B1 and/or CYP3A4 may lead to increased exposure of simvastatin acid.

Cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see Drug Interactions ( 7 )]. Table 4 displays the effect of coadministered drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions ( 7 )]. Table 4: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect =

1.00AUC C max Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 12 8.9 15

5.3Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6

6.2Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 13.1

13.1Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5

11.4Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18

0.91Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3

1.9Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of simvastatin is usually achieved by 4 weeks and is maintained after that.

14 CLINICAL STUDIES 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 to 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 a 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), 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 Cardi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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/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.