SIMVASTATIN- simvastatin_tablet, film coated

Simvastatin is a prodrug and is hydrolyzed to its active beta-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. 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. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding beta-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 14C-labeled simvastatin, plasma concentrations of total radioactivity (simvastatin plus 14C-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 en dash 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 beta-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. 4 hours postdose. Excretion Following an oral dose of 14C-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. 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 * dagger double dagger section paragraph 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 AUC C max Telithromycin dagger 200 mg QD for 4 days 80 mg simvastatin acid double dagger 12 8. 3 Nelfinavir dagger 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid double dagger 6 6. 2 Itraconazole dagger 200 mg QD for 4 days 80 mg simvastatin acid double dagger 13. 1 Posaconazole 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. 4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2. 91 Grapefruit Juice section 200 mL of double-strength TID paragraph 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice section 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1. 9 Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2. 1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2. 88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4. 6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1. 75 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1. 79 Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1. 47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2. 75 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1. 6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1. 7 Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0. 83 Niacin extended-release 2 g single dose 20 mg single dose simvastatin acid simvastatin 1. 08 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0. 79 down arrow from 33. 1 ng·eq/mL down arrow from 7 to 4. 7 ng·eq/mL Simvastatin’s Effect on the Pharmacokinetics of Other Drugs In a study of 12 healthy volunteers, simvastatin at the 80 mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. Simvastatin is not an inhibitor of CYP3A4 and is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. [see DRUG INTERACTIONS (7.

Simvastatin tablets are indicated: Simvastatin tablets are an HMG-CoA reductase inhibitor indicated: (1).

Important Dosage and Administration Information: (2. 1) Adults: Pediatric Patients Aged 10 Years and Older with HeFH: Take simvastatin tablets orally once daily in the evening. The recommended dosage range of simvastatin tablets are 20 mg to 40 mg once daily. The recommended dosage range of simvastatin tablets are 10 mg to 40 mg daily. For patients with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min], the recommended starting dosage [see Warnings and Precautions (5. 1) and Use in Specific Populations (8. Concomitant use of simvastatin tablets with the following drugs requires dosage modification of simvastatin tablets [see Warnings and Precautions (5. 1) and Drug Interactions (7. Patients taking Lomitapide [see Dosage and Administration (2. Patients taking Verapamil, Diltiazem, or Dronedarone Patients taking Amiodarone, Amlodipine, or Ranolazine.

The following important adverse reactions are described below and elsewhere in the labeling: [see Warnings and Precautions (5. 1)] [see Warnings and Precautions (5. 2)] [see Warnings and Precautions (5. 3)] [see Warnings and Precautions (5. 4)] Most common adverse reactions (incidence >=5%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. 1) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. [see CLINICAL STUDIES (14)]; Table 1: Adverse Reactions Reported >=2% of Patients Treated with Simvastatin and Greater than Placebo in Study 4S % Placebo (N = 2,223) % Simvastatin (N = 2,221) Bronchitis 6. 6 Abdominal pain 5. 9 Atrial fibrillation 5. 7 Gastritis 3. 5 Vertigo 4. 5 Diabetes mellitus 3. 2 Insomnia 3. 0 Myalgia 3. 7 Urinary tract infection 3. 2 Edema/swelling 2. 7 Headache 2. 5 Sinusitis 1. 3 Constipation 1. 2 Myopathy/Rhabdomyolysis In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received simvastatin, the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0. 61% for the simvastatin 20 mg, 40 mg, and 80 mg daily groups, respectively. In a clinical outcomes study in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6. 7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10x [1200 U/L] ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0. 9%, respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients on simvastatin 20 mg and 80 mg daily was approximately 0% and 0. 4%, respectively. The incidence of myopathy and rhabdomyolysis were highest during the first year and then decreased during the subsequent years of treatment. In another clinical outcomes study in which 10,269 adult patients were treated with simvastatin 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0. 1% in patients treated with simvastatin. Elevations in Liver Enzyme Tests Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of simvastatin. Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have occurred with simvastatin. Elevated alkaline phosphatase and gamma-glutamyl transpeptidase have also been reported. In Study 4S, with a median follow-up of 5. 4 years, 1,986 adult patients were treated with simvastatin 20 mg once daily, of whom 37% titrated to 40 mg once daily. The percentage of patients with one or more occurrences of transaminase elevations to >3xULN was 0. 7% in patients taking simvastatin compared with 0. 6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0. 4% of patients taking simvastatin and 0. 2% of patients taking placebo. The majority of elevated transaminases leading to treatment discontinuation occurred within in the first year. Adverse Reactions in Pediatric Patients with Heterozygous Familial Hypercholesterolemia In a 48-week clinical study in pediatric patients 10 years of age and older (43% female, 97. 7% Caucasians, 1. 7% Hispanics, 0. 6% Multiracial) with HeFH (n=175), treated with placebo or simvastatin (10 to 40 mg daily), the most common adverse reactions were upper respiratory infection, headache, abdominal pain, and nausea [see USE IN SPECIFIC POPULATIONS (8. 4) and CLINICAL STUDIES (14)]. The following adverse reactions have been identified during post-approval use of simvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as whole: Blood and Lymphatic System Disorders: Gastrointestinal Disorders: Hepatic and Pancreatic Disorders: Immune System Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Skin and Subcutaneous Tissue Disorders: Respiratory and Thoracic: Reproductive System Disorders:.

Simvastatin tablets are contraindicated in the following conditions: [see Drug Interactions (7. [see Drug Interactions (7. [see Warnings and Precautions (5. [see Adverse Reactions (6. .

Pregnancy: Lactation: See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 02/2024 Risk Summary 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. 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 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/m2) ( see The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Data Human Data 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 en dash including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use en dash 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. 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. Animal Data Simvastatin was given to pregnant rats at doses of 6. 5 and 25 mg/kg/day (0. 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 to 17 and to pregnant rabbits from gestation days 6 to 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. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6. 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. Risk Summary 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. 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)]. A pharmacokinetic study with simvastatin use showed the mean plasma level of total inhibitors to be approximately 45% higher in geriatric patients between 70 to 78 years of age compared with patients between 18 to 30 years of age [see CLINICAL PHARMACOLOGY (12. Advanced age (>=65 years) is a risk factor for simvastatin-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving simvastatin for the increased risk of myopathy [see WARNINGS AND PRECAUTIONS (5. Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment (CLcr 15 to 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see DOSAGE AND ADMINISTRATION (2. 4), WARNINGS AND PRECAUTIONS (5. Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5. In a clinical study in which patients at high risk of CVD were treated with simvastatin 40 mg/day (median follow-up 3. 9 years), the incidence of myopathy was approximately 0. 05% for non-Chinese patients (n=7367) compared with 0. 24% for Chinese patients (n=5468). In this study, the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1. Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of simvastatin with lipid-modifying doses of niacin-containing products (>=1 g/day niacin) is not recommended in Chinese patients [see WARNINGS AND PRECAUTIONS (5. 1), DRUG INTERACTIONS (7.

Coumarin Anticoagulants: Digoxin: Simvastatin is a substrate of CYP3A4 and of the transport protein OATP1B1. Simvastatin exposure can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1. Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with simvastatin and instructions for preventing or managing them [see WARNINGS AND PRECAUTIONS (5. 1) and CLINICAL PHARMACOLOGY (12. Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with simvastatin increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher simvastatin dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated [see CONTRAINDICATIONS (4)]. Examples: Select azole anti-fungals (e. , itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e. , erythromycin and clarithromycin), select HIV protease inhibitors (e. , nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e. , boceprevir and telaprevir), cobicistat-containing products, and nefazodone. Cyclosporine, Danazol, or Gemfibrozil Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin. Gemfibrozil may cause myopathy when given alone. Intervention: oncomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin is contraindicated [see CONTRAINDICATIONS (4)]. Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with simvastatin. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed simvastatin 10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed simvastatin 20 mg daily [see DOSAGE AND ADMINISTRATION (2. Lomitapide Clinical Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased. Intervention: Reduce the dose of simvastatin by 50% if initiating lomitapide. Do not exceed simvastatin 20 mg daily (or simvastatin 40 mg daily for patients who have previously taken an 80 mg daily dosage of simvastatin chronically) while taking lomitapide [see DOSAGE AND ADMINISTRATION (2. Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Intervention: If treatment with daptomycin is required, consider temporarily suspending simvastatin during the course of daptomycin treatment. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (>=1 gram/day niacin) with simvastatin. The risk of myopathy is greater in Chinese patients. In a clinical study (median follow-up 3. 9 years) of patients at high risk of CVD and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses of niacin. Intervention: Concomitant use of simvastatin with lipid-modifying dosages of niacin is not recommended in Chinese patients [see USE IN SPECIFIC POPULATIONS (8. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with simvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with simvastatin. Intervention: Consider if the benefit of using colchicine concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. Grapefruit Juice Clinical Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid grapefruit juice when taking simvastatin. Table 3 presents simvastatin’s effect on other drugs and instructions for preventing or managing them. Table 3: Simvastatin Effects on Other Drugs Coumarin Anticoagulants 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. 8 in healthy subjects and from 2. 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. Digoxin Clinical Impact: Concomitant use of digoxin with simvastatin may result in elevated plasma digoxin concentrations [see CLINICAL PHARMACOLOGY (12. Intervention: Monitor digoxin levels in patients taking digoxin when simvastatin is initiated.

OVERDOSAGE
No specific antidotes for simvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations.
NONCLINICAL TOXICOLOGY
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 vitro in vitro in vivo 2
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. 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: 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 Endpoint Simvastatin (N=10,269) n (%)* Placebo (N=10,267) n (%)* Risk Reduction (%)(95% CI) p-Value Primary Mortality CHD mortality 1,328 (12.9) 587 (5.7) 1,507 (14.7) 707 (6.9) 13 (6 to 19) 18 (8 to 26) p=0.0003 p=0.0005 Secondary Non-fatal MI Stroke 357 (3.5) 444 (4.3) 574 (5.6) 585 (5.7) 38 (30 to 46) 25 (15 to 34) p<0.0001 p<0.0001 Tertiary Coronary revascularization Peripheral and other non-coronary revascularization 513 (5) 450 (4.4) 725 (7.1) 532 (5.2) 30 (22 to 38) 16 (5 to 26) p<0.0001 p=0.006 * Two composite endpoints were defined to have enough events to assess relative risk reductions across a range of baseline characteristics: 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 to 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) TREATMENT N TOTAL-C LDL-C HDL-C TG* Lower Dose Comparative Study dagger (Mean % Change at Week 6) Simvastatin 5 mg once at night Simvastatin 10 mg once at night 109 110 -19 -23 -26 -30 10 12 -12 -15 Scandinavian Simvastatin Survival Study double dagger (Mean % Change at Week 6) Placebo 2223 -1 -1 0 -2 Simvastatin 20 mg once at night 2221 -28 -38 8 -19 Upper Dose Comparative Study section (Mean % Change Averaged at Weeks 18 and 24) Simvastatin Simvastatin paragraph 433 664 -31 -36 -41 -47 9 8 -18 -24 Combined Hyperlipidemia Study # (Mean % Change at Week 6) Placebo Simvastatin Simvastatin 125 123 124 1 -25 -31 2 -29 -36 3 13 16 -4 -28 -33 * median percent change dagger double dagger section paragraph # Hypertriglyceridemia in Adults The results of a subgroup analysis in 74 adult patients with hypertriglyceridemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are similar to those 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-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]* TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C + IDL Non-HDL-C 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) * 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. 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) Dosage Duration N Total-C LDL-C HDL-C TG* ApoB 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) -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) +8.3% (4.6, 11.9) -7.9% (-15.8, 0) -32.4% (-35.9, -29) Mean baseline, mg/dL (SD) 270 (44) 204 (42) 48 (9) 78 (46) 180 (34) * median percent change

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