ZOCOR by is a Prescription medication manufactured, distributed, or labeled by Organon LLC. Drug facts, warnings, and ingredients follow.
ZOCOR is an HMG-CoA reductase inhibitor indicated: (1)
Tablets: 10 mg; 20 mg; 40 mg; 80 mg (3)
Most common adverse reactions (incidence ≥5%) are upper respiratory infection, headache, abdominal pain, constipation, and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
ZOCOR® is indicated:
There are no dosage adjustment recommendations for patients with mild or moderate renal impairment.
Patients taking Lomitapide
Reduce the dosage of ZOCOR by 50%. Do not exceed ZOCOR 20 mg once daily (or 40 mg once daily for patients who have previously taken ZOCOR 80 mg daily chronically while taking lomitapide) [see Dosage and Administration (2.1)].
Patients taking Verapamil, Diltiazem, or Dronedarone
Do not exceed ZOCOR 10 mg once daily.
Patients taking Amiodarone, Amlodipine, or Ranolazine
Do not exceed ZOCOR 20 mg once daily.
The 5 mg strength of ZOCOR is no longer being marketed.
ZOCOR is contraindicated in the following conditions:
Risk Factors for Myopathy
Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
The concomitant use of strong CYP3A4 inhibitors with ZOCOR is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend ZOCOR during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of ZOCOR with gemfibrozil, cyclosporine, or danazol is also contraindicated [see Contraindications (4) and Drug Interactions (7.1)].
ZOCOR dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see Dosage and Administration (2.5)]. ZOCOR use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].
Use the 80 mg daily dosage of ZOCOR only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see Dosage and Administration (2.1)]. If patients treated with ZOCOR 80 mg are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [see Drug Interactions (7.1)].
Discontinue ZOCOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if ZOCOR is discontinued. Temporarily discontinue ZOCOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ZOCOR dosage and advise patients receiving ZOCOR 80 mg of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.
The following important adverse reactions are described below and elsewhere in the labeling:
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.
In clinical studies, 2,423 adult patients were exposed to ZOCOR with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these ZOCOR clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued ZOCOR due to adverse reactions. The most common adverse reactions that led to discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%).
In a Cardiovascular Outcomes Study (the Scandinavian Simvastatin Survival Study [Study 4S]), adult patients (age range 35-71 years, 19% women, 100% Caucasians) were treated with 20-40 mg per day of ZOCOR or placebo over a median of 5.4 years [see Clinical Studies (14)]; adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 1.
(N = 2,223)
(N = 2,221)
|Urinary tract infection||3.1||3.2|
In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received ZOCOR , the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the ZOCOR 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 ZOCOR (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 ZOCOR 20 mg and 80 mg daily was approximately 0.02% and 0.9%, respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients on ZOCOR 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 ZOCOR 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with ZOCOR.
Elevations in Liver Enzyme Tests
Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of ZOCOR.
Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving ZOCOR in clinical studies. Marked persistent increases of hepatic transaminases have occurred with ZOCOR. Elevated alkaline phosphatase and γ-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 ZOCOR 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 ZOCOR compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking ZOCOR 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 ZOCOR (10-40 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 ZOCOR. 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: fever, chills, malaise, asthenia
Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia
Gastrointestinal Disorders: pancreatitis, vomiting
Hepatic and Pancreatic Disorders: hepatitis/jaundice, fatal and non-fatal hepatic failure
Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis
Musculoskeletal and Connective Tissue Disorders: muscle cramps, immune-mediated necrotizing myopathy, polymyalgia rheumatica, arthritis
Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Skin and Subcutaneous Tissue Disorders: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome
Respiratory and Thoracic: interstitial lung disease, dyspnea
Reproductive System Disorders: erectile dysfunction
ZOCOR is a substrate of CYP3A4 and of the transport protein OATP1B1. ZOCOR 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 ZOCOR and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
|Strong CYP3A4 inhibitors|
|Clinical Impact:||Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with ZOCOR increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher ZOCOR dosages.|
|Intervention:||Concomitant use of strong CYP3A4 inhibitors with ZOCOR is contraindicated [see Contraindications (4)]. If treatment with a CYP3A4 inhibitor is unavoidable, suspend ZOCOR during the course of strong CYP3A4 inhibitor treatment.|
|Examples:||Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., 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 ZOCOR. Gemfibrozil may cause myopathy when given alone.|
|Intervention:||Concomitant use of cyclosporine, danazol, or gemfibrozil with ZOCOR 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 ZOCOR.|
|Intervention:||For patients taking verapamil, diltiazem, or dronedarone, do not exceed ZOCOR 10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed ZOCOR 20 mg daily [see Dosage and Administration (2.5)].|
|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 ZOCOR by 50% if initiating lomitapide. Do not exceed ZOCOR 20 mg daily (or ZOCOR 40 mg daily for patients who have previously taken ZOCOR 80 mg daily chronically) while taking lomitapide [see Dosage and Administration (2.1, 2.5)].|
|Clinical Impact:||Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both ZOCOR 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 ZOCOR during the course of daptomycin treatment.|
|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 ZOCOR. 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 ZOCOR with lipid-modifying dosages of niacin is not recommended in Chinese patients [see Use in Specific Populations (8.8)]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with ZOCOR 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.|
|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 ZOCOR.|
|Intervention:||Consider if the benefit of using fibrates concomitantly with ZOCOR 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.|
|Clinical Impact:||Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with ZOCOR.|
|Intervention:||Consider if the benefit of using colchicine concomitantly with ZOCOR 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.|
|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 ZOCOR.|
Table 3 presents ZOCOR’s effect on other drugs and instructions for preventing or managing them.
|Clinical Impact:||ZOCOR may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of ZOCOR (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 ZOCOR 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 ZOCOR may result in elevated plasma digoxin concentrations [see Clinical Pharmacology (12.3)].|
|Intervention:||Monitor digoxin levels in patients taking digoxin when ZOCOR is initiated.|
Discontinue ZOCOR when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.
ZOCOR decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ZOCOR 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 ZOCOR 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/m2) (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 ZOCOR, 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 ZOCOR [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].
The safety and effectiveness of ZOCOR 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 ZOCOR 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 ZOCOR 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 ZOCOR-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 ZOCOR 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 ZOCOR 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)].
Advanced age (≥65 years) is a risk factor for ZOCOR-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 ZOCOR for the increased risk of myopathy [see Warnings and Precautions (5.1)].
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 – 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. ZOCOR is not available in a 5 mg strength. Use another simvastatin product to initiate dosing in such patients.
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 1.24%.
Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of ZOCOR 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 (7.1)].
ZOCOR (simvastatin) is a prodrug of 3-hydoroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is derived synthetically from a fermentation product of Aspergillus terreus.
Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57. Its structural formula is:
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
ZOCOR tablets for oral use contain 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and titanium dioxide. Butylated hydroxyanisole is added as a preservative.
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.
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 ZOCOR is usually achieved by 4 weeks and is maintained after that.
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.
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 – 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.
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins.
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.
Following an oral dose of 14C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces.
In a study including 16 geriatric patients between 70 and 78 years of age who received ZOCOR 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18-30 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)].
|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 = 1.00
|Telithromycin†||200 mg QD for 4 days||80 mg||simvastatin acid‡
|Nelfinavir†||1250 mg BID for 14 days||20 mg QD for 28 days||simvastatin acid‡
|Itraconazole†||200 mg QD for 4 days||80 mg||simvastatin acid‡
|Posaconazole||100 mg (oral suspension) QD for 13 days||40 mg||simvastatin acid|
|200 mg (oral suspension) QD for 13 days||40 mg||simvastatin acid|
|Gemfibrozil||600 mg BID for 3 days||40 mg||simvastatin acid|
| Grapefruit Juice§
|200 mL of double-strength TID¶||60 mg single dose||simvastatin acid|
| Grapefruit Juice§
|8 oz (about 237 mL) of single-strength#||20 mg single dose||simvastatin acid|
|Verapamil SR||240 mg QD Days 1-7 then 240 mg BID on Days 8-10||80 mg on Day 10||simvastatin acid|
|Diltiazem||120 mg BID for 10 days||80 mg on Day 10||simvastatin acid|
|Diltiazem||120 mg BID for 14 days||20 mg on Day 14||simvastatin||4.6||3.6|
|Dronedarone||400 mg BID for 14 days||40 mg QD for 14 days||simvastatin acid|
|Amiodarone||400 mg QD for 3 days||40 mg on Day 3||simvastatin acid|
|Amlodipine||10 mg QD × 10 days||80 mg on Day 10||simvastatin acid |
|Ranolazine SR||1000 mg BID for 7 days||80 mg on Day 1 and Days 6-9||simvastatin acid|
|Lomitapide||60 mg QD for 7 days||40 mg single dose||simvastatin acid|
|Lomitapide||10 mg QD for 7 days||20 mg single dose||simvastatin acid|
|Fenofibrate||160 mg QD × 14 days||80 mg QD on Days 8-14||simvastatin acid|
|Niacin extended-release||2 g single dose||20 mg single dose||simvastatin acid simvastatin||1.6|
|Propranolol||80 mg single dose||80 mg single dose||total inhibitor||0.79||↓ from 33.6 to 21.1 ng∙eq/mL|
↓ from 7.0 to 4.7 ng∙eq/mL
ZOCOR’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.
Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL [see Drug Interactions (7.2)].
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 ZOCOR 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 ZOCOR 20-40 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 ZOCOR 40 mg and 10,267 on placebo. Patients had a mean age of 64 years (range 40-80 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 ZOCOR 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 ZOCOR 40 mg/day significantly reduced: total and CHD mortality; and non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 5).
(%) (95% CI)
|Mortality||1,328 (12.9%)||1,507 (14.7%)||13% (6-19%)||p=0.0003|
|CHD mortality||587 (5.7%)||707 (6.9%)||18% (8-26%)||p=0.0005|
|Non-fatal MI||357 (3.5%)||574 (5.6%)||38% (30-46%)||p<0.0001|
|Stroke||444 (4.3%)||585 (5.7%)||25% (15-34%)||p<0.0001|
|Coronary revascularization||513 (5%)||725 (7.1%)||30% (22-38%)||p<0.0001|
|Peripheral and other non-coronary revascularization||450 (4.4%)||532 (5.2%)||16% (5-26%)||p=0.006|
Two composite endpoints were defined to have enough events to assess relative risk reductions across a range of baseline characteristics:
ZOCOR 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 ZOCOR 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 ZOCOR treatment regardless of baseline HbA1c levels or obesity.
Primary Hyperlipidemia in Adults
The effects of ZOCOR 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. ZOCOR 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.
|Lower Dosage Comparative Study† (Mean % Change at Week 6)|
|ZOCOR 5 mg once at night||109||-19%||-26%||+10%||-12%|
|ZOCOR 10 mg once at night||110||-23%||-30%||+12%||-15%|
|Scandinavian Simvastatin Survival Study‡ (Mean % Change at Week 6)|
|ZOCOR 20 mg once at night||2221||-28%||-38%||+8%||-19%|
|Upper Dosage Comparative Study§ (Mean % Change Averaged at Weeks 18 and 24)|
|ZOCOR 40 mg once at night||433||-31%||-41%||+9%||-18%|
|ZOCOR 80 mg once at night¶||664||-36%||-47%||+8%||-24%|
|Combined Hyperlipidemia Study# (Mean % Change at Week 6)|
|ZOCOR 40 mg once at night||123||-25%||-29%||+13%||-28%|
|ZOCOR 80 mg once at night||124||-31%||-36%||+16%||-33%|
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. ZOCOR 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. ZOCOR decreased total-C, LDL-C + intermediate-density lipoprotein (IDL), VLDL-C + IDL, and TG compared to placebo.
|TREATMENT||N||Total-C||LDL-C + IDL||HDL-C||TG||VLDL-C + IDL||Non-HDL-C|
|ZOCOR 40 mg/day||7||-50% |
|ZOCOR 80 mg/day||7||-52% |
Homozygous Familial Hypercholesterolemia
In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolemia (HoFH) received ZOCOR 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 ZOCOR (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 ZOCOR (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 ZOCOR 40 mg or placebo.
ZOCOR 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 ZOCOR therapy in pediatric patients to reduce morbidity and mortality in adulthood has not been established.
|Placebo||24 Weeks||67||% Change from Baseline (95% CI)||+1.6%|
|Mean baseline, mg/dL |
|ZOCOR||24 Weeks||106||% Change from Baseline (95% CI)||-26.5%|
|Mean baseline, mg/dL |
ZOCOR tablets are supplied as follows:
|Strength*||How Supplied||NDC||Tablet Description|
|10 mg||unit of use bottles of 30||78206-180-01||peach, oval, marked MSD 735 on one side and plain on the other|
|unit of use bottles of 90||78206-180-02|
|20 mg||unit of use bottles of 30||78206-181-01||tan, oval, marked MSD 740 on one side and plain on the other|
|unit of use bottles of 90||78206-181-02|
|40 mg||unit of use bottles of 30||78206-182-01||brick red, oval, marked MSD 749 on one side and plain on the other|
|unit of use bottles of 90||78206-182-02|
|80 mg||unit of use bottles of 30||78206-179-01||brick red, capsule-shaped, marked 543 on one side and 80 on the other|
|unit of use bottles of 90||78206-179-02|
Myopathy and Rhabdomyolysis
Advise patients that ZOCOR may cause myopathy and rhabdomyolysis. Inform patients taking the 80 mg daily dose of ZOCOR that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking ZOCOR. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)].
Inform patients that ZOCOR may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].
Increases in HbA1c and Fasting Serum Glucose Levels
Inform patients that increases in HbA1c and fasting serum glucose levels may occur with ZOCOR. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].
Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if ZOCOR should be discontinued [see Use in Specific Populations (8.1)].
Advise patients that breastfeeding is not recommended during treatment with ZOCOR [see Use in Specific Populations (8.2)].
Manuf. for: Organon LLC, a subsidiary of
ORGANON & Co.,
Jersey City, NJ 07302, USA
Organon Pharma (UK) Limited.
Cramlington, Northumberland, UK NE23 3JU
For patent information: www.organon.com/our-solutions/patent/
© 2022 Organon group of companies. All rights reserved.
PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Label
Each tablet contains 10 mg of simvastatin.
PRINCIPAL DISPLAY PANEL - 20 mg Tablet Bottle Label
Each tablet contains 20 mg of simvastatin.
PRINCIPAL DISPLAY PANEL - 40 mg Tablet Bottle Label
Each tablet contains 40 mg of simvastatin.
PRINCIPAL DISPLAY PANEL - 80 mg Tablet Bottle Label
Each tablet contains 80 mg of simvastatin.
simvastatin tablet, film coated
simvastatin tablet, film coated
simvastatin tablet, film coated
simvastatin tablet, film coated
|Labeler - Organon LLC (117494753)|