Drugs Details

Drugs Info of Zocor
Drugs Details
  • Drugs Type  : Multum
  • Date : 17th Jul 2015 05:51 am
  • Brand Name : Zocor
  • Generic Name : simvastatin (Pronunciation: SIM va sta tin)
Descriptions

ZOCOR (simvastatin) is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4hydroxy-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:

 

ZOCOR (simvastatin) Structural Formula Illustration

 

Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Tablets ZOCOR for oral administration contain either 5 mg, 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.

 

What are the possible side effects of simvastatin (Zocor)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using simvastatin and call your doctor at once if you have:

  • unexplained muscle pain, tenderness, or weakness;
  • confusion, memory problems;
  • fever, unusual tiredness, and dark colored urine;
  • pain or burning when you urinate;
  • swelling, weight gain, little or no urinating;
  • increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin,...

Read All Potential Side Effects and See Pictures of Zocor »

What are the precautions when taking simvastatin (Zocor)?

Before taking simvastatin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, kidney disease, alcohol use.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Limit alcoholic beverages. Daily use of alcohol may increase your risk for liver problems, especially when combined with simvastatin. Ask your doctor or pharmacist for more information.

Older adults may be...

Read All Potential Precautions of Zocor »

Indications

Therapy with lipid-altering agents should be only one component of multiplerisk factor intervention in individuals at significantly increased risk foratherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted insaturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, ZOCOR® can be started simultaneously with diet.

Reductions In Risk Of CHD Mortality And Cardiovascular Events

In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or othercerebrovascular disease, ZOCOR is indicated to:

  • Reduce the risk of total mortality by reducing CHD deaths.
  • Reduce the risk of non-fatal myocardial infarction and stroke.
  • Reduce the need for coronary and non-coronary revascularization procedures.

Hyperlipidemia

ZOCOR is indicated to:

  • Reduce elevated total cholesterol (total-C), low-density lipoproteincholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
  • Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).
  • Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).
  • Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Adolescent Patients With Heterozygous Familial Hypercholesterolemia (HeFH)

ZOCOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:

  1. LDL cholesterol remains ≥ 190 mg/dL; or
  2. LDL cholesterol remains ≥ 160 mg/dL and
  • There is a positive family history of premature cardiovascular disease(CVD) or
  • Two or more other CVD risk factors are present in the adolescent patient.

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C < 130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CADhas not been determined.

Limitations Of Use

ZOCOR has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

Dosage Administration

Recommended Dosing

The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, ZOCOR can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.

Restricted Dosing For 80 mg

Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of ZOCOR should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [seeWARNINGS AND PRECAUTIONS].

Patients who are currently tolerating the 80-mg dose of ZOCOR who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.

Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of ZOCOR, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

Coadministration With Other Drugs

Patients taking Verapamil, Diltiazem, or Dronedarone
  • The dose of ZOCOR should not exceed 10 mg/day [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
Patients taking Amiodarone, Amlodipine or Ranolazine
  • The dose of ZOCOR should not exceed 20 mg/day [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Patients With Homozygous Familial Hypercholesterolemia

The recommended dosage is 40 mg/day in the evening [see Restricted Dosing for 80 mg]. ZOCOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ZOCOR should be reduced by 50% if initiating lomitapide. ZOCOR dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken ZOCOR 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.

Adolescents (10-17 years of age) With Heterozygous Familial Hypercholesterolemia

The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines1 and Clinical Studies]. Adjustments should be made at intervals of 4 weeks or more.

1National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents.Pediatrics. 89(3):495-501. 1992.

Patients With Renal Impairment

Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when ZOCOR is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see WARNINGS ANDPRECAUTIONS and CLINICAL PHARMACOLOGY].

Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) Of Niacin-Containing Products

Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [SeeWARNINGS AND PRECAUTIONS]

How Supplied

Dosage Forms And Strengths

  • Tablets ZOCOR 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and ZOCOR 5 on the other.
  • Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other.
  • Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other.
  • Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other.
  • Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other.

Storage And Handling

No. 8360 — Tablets ZOCOR 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and ZOCOR 5 on the other. They are supplied as follows:

NDC 0006-0726-31 unit of use bottles of 30.

No. 8146 — Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other. They are supplied as follows:

NDC 0006-0735-31 unit of use bottles of 30
NDC 0006-0735-54 unit of use bottles of 90.

No. 8147 — Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other. They are supplied as follows:

NDC 0006-0740-31 unit of use bottles of 30
NDC 0006-0740-54 unit of use bottles of 90.

No. 8148 — Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other. They are supplied as follows:

NDC 0006-0749-31 unit of use bottles of 30
NDC 0006-0749-54 unit of use bottles of 90.

No. 6577 — Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other. They are supplied as follows:

NDC 0006-0543-31 unit of use bottles of 30
NDC 0006-0543-54 unit of use bottles of 90.

Storage

Store between 5-30°C (41-86°F).

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. By: Merck Sharp & Dohme Ltd. Cramlington, Northumberland, UK NE23 3JU. Revised: Feb 2015

Side Effects

Clinical Trials Experience

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 the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥ 5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).

Scandinavian Simvastatin Survival Study

In 4S involving 4,444 (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of ZOCOR (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2.

Table 2: Adverse Reactions Reported Regardless of Causality by ≥ 2% of Patients Treated with ZOCOR and Greater than Placebo in 4S

  ZOCOR
(N = 2,221) %
PLACEBO
(N = 2,223) %
Body as a Whole
  Edema/swelling 2.7 2.3
  Abdominal pain 5.9 5.8
Cardiovascular System Disorders
  Atrial fibrillation 5.7 5.1
Digestive System Disorders
  Constipation 2.2 1.6
  Gastritis 4.9 3.9
Endocrine Disorders
  Diabetes mellitus 4.2 3.6
Musculoskeletal Disorders
  Myalgia 3.7 3.2
Nervous System/ Psychiatric Disorders
  Headache 2.5 2.1
  Insomnia 4.0 3.8
  Vertigo 4.5 4.2
Respiratory System Disorders
  Bronchitis 6.6 6.3
  Sinusitis 2.3 1.8
Skin / Skin Appendage Disorders
  Eczema 4.5 3.0
Urogenital System Disorders
  Infection, urinary tract 3.2 3.1

 

Heart Protection Study

In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with ZOCOR 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with ZOCOR compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysiswas < 0.1% in patients treated with ZOCOR.

Other Clinical Studies

In a clinical trial in which 12,064 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 serumcreatine kinase [CK] > 10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

Other adverse reactions reported in clinical trials were: diarrhea, rash,dyspepsia, flatulence, and asthenia.

Laboratory Tests

Marked persistent increases of hepatic transaminases have been noted [seeWARNINGS AND PRECAUTIONS]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. [SeeWARNINGS AND PRECAUTIONS]

Adolescent Patients (ages 10-17 years)

In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familialhypercholesterolemia (n=175), treated with placebo or ZOCOR (10-40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations and Clinical Studies].

Postmarketing Experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see WARNINGS AND PRECAUTIONS].

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupuserythematous-like syndrome, polymyalgia rheumatica, dermatomyositis,vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positiveANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermalnecrolysis, erythema multiforme, including Stevens-Johnson syndrome.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for allstatins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Interactions

Strong CYP3A4 Inhibitors, Cyclosporine, Or Danazol

Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see CONTRAINDICATIONS]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole,erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated [seeCONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

Gemfibrozil

Contraindicated with simvastatin [see CONTRAINDICATIONS andWARNINGS AND PRECAUTIONS].

Other fibrates

Caution should be used when prescribing with simvastatin [see WARNINGS AND PRECAUTIONS].

Amiodarone, Dronedarone, Ranolazine, Or Calcium Channel Blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS, and Table 3 inCLINICAL PHARMACOLOGY].

Niacin

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses ( ≥ 1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. [See WARNINGS AND PRECAUTIONS andCLINICAL PHARMACOLOGY]

Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated [seeCLINICAL PHARMACOLOGY].

Coumarin Anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increasedprothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Myopathy/Rhabdomyolysis

Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysiswith or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age ( ≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment.

The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with ZOCOR, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which 12,064 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 creatine kinase [CK] > 10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of ZOCOR should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see DOSAGE AND ADMINISTRATION, Restricted Dosing for 80 mg]. If, however, a patient who is currently tolerating the 80-mg dose of ZOCOR needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Liver Dysfunction]

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients starting therapy with ZOCOR, or whose dose of ZOCOR is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ZOCOR. ZOCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with ZOCOR or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. ZOCOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. ZOCOR therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis;hypotension; major surgery; trauma; severe metabolic, endocrine, orelectrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolideantibiotics erythromycin and clarithromycin, and the ketolide antibiotictelithromycin, HIV protease inhibitors, boceprevir, telaprevir, theantidepressant nefazodone, cobicistat-containing products, or grapefruit juice [see CLINICAL PHARMACOLOGY]. Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See CONTRAINDICATIONS and DRUG INTERACTIONS]

The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see CONTRAINDICATIONS and DRUG INTERACTIONS].

Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see DRUG INTERACTIONS].

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see DRUG INTERACTIONS].

The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: otherlipid-lowering drugs (other fibrates, ≥ 1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see DRUG INTERACTIONS and Table 3 inCLINICAL PHARMACOLOGY] [also see DOSAGE AND ADMINISTRATION,Patients with Homozygous Familial Hypercholesterolemia].

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses ( ≥ 1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomizedcardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see DRUG INTERACTIONS].

Prescribing recommendations for interacting agents are summarized in Table 1 [see also DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS,CLINICAL PHARMACOLOGY].

Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

INTERACTING AGENTS PRESCRIBING RECOMMENDATIONS
Strong CYP3A4 Inhibitors, e.g.: Contraindicated with simvastatin
  Itraconazole
  Ketoconazole
  Posaconazole
  Voriconazole
  Erythromycin
  Clarithromycin
  Telithromycin
  HIV protease inhibitors
  Boceprevir
  Telaprevir
  Nefazodone
  Cobicistat-containing products
Gemfibrozil
Cyclosporine
Danazol
Verapamil Do not exceed 10 mg simvastatin daily
Diltiazem
Dronedarone
Amiodarone Do not exceed 20 mg simvastatin daily
Amlodipine
Ranolazine
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice Avoid grapefruit juice
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide

 

Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. W hen drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated withjaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies], the number of patients with more than one transaminase elevation to > 3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to > 3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40-and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.

It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ZOCOR, promptly interrupt therapy. If an alternate etiology is not found do not restart ZOCOR. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Myopathy/Rhabdomyolysis].

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.

Moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including ZOCOR.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid-and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid-and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid-and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivochromosomal 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 microscopicchanges 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), seminiferoustubule 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.

Use In Specific Populations

Pregnancy

Pregnancy Category X [See CONTRAINDICATIONS]

ZOCOR is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development.Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with ZOCOR during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZOCOR may cause fetal harm when administered to a pregnant woman. If ZOCOR is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

There are rare reports of congenital anomalies following intrauterineexposure to statins. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3-to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m² surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.

Women of childbearing potential, who require treatment with ZOCOR for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of ZOCOR should be considered. If pregnancy occurs, ZOCOR should be immediately discontinued.

Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see CONTRAINDICATIONS].

Pediatric Use

Safety and effectiveness of simvastatin in patients 10-17 years of age withheterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies.] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see CONTRAINDICATIONS and Use In Specific Populations]. Simvastatin has not been studied in patients younger than 10 years of age, nor in premenarchal girls.

Geriatric Use

Of the 2,423 patients who received ZOCOR in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received ZOCOR, 363 (15%) and 5,366 (52%), respectively were ≥ 65 years old. In HPS, 615 (6%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age ( ≥ 65 years) is a predisposing factor for myopathy, ZOCOR should be prescribed with caution in the elderly. [See CLINICAL PHARMACOLOGY]

A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and ZOCOR significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.

Because advanced age ( ≥ 65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ZOCOR should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥ 65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients < 65 years of age. [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]

Renal Impairment

Caution should be exercised when ZOCOR is administered to patients with severe renal impairment.

[See DOSAGE AND ADMINISTRATION]

Hepatic Impairment

ZOCOR is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [seeCONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

2 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.

OverDose

Significant lethality was observed in mice after a single oral dose of 9 g/m². No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m², respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with ZOCOR have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

ContrainDications

ZOCOR is contraindicated in the following conditions:

  • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV proteaseinhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [seeWARNINGS AND PRECAUTIONS].
  • Concomitant administration of gemfibrozil, cyclosporine, or danazol [seeWARNINGS AND PRECAUTIONS].
  • Hypersensitivity to any component of this medication [see ADVERSE REACTIONS].
  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see WARNINGS AND PRECAUTIONS].
  • Women who are pregnant or may become pregnant. Serum cholesteroland triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZOCOR may cause fetal harm when administered to a pregnant woman. 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 primaryhypercholesterolemia. There are no adequate and well-controlled studies of use with ZOCOR during pregnancy; however, in rare reportscongenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. ZOCOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ZOCOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].
  • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with ZOCOR should not breastfeed their infants [see Use In Specific Populations].

Clinical Pharamacology

Mechanism Of Action

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

Pharmacodynamics

Epidemiological studies have demonstrated that elevated levels of total-C,LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. 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 the drug to the general circulation is low ( < 5%).

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatinderived radioactivity crossed the blood-brain barrier.

The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin 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. W hile the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.

In a study including 16 elderly patients between 70 and 78 years of age who received ZOCOR 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use In Specific Populations].

Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, 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.

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Table 3: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

View Enlarged Table

 

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. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, 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.

Animal Toxicology And/Or Pharmacology

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (W allerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrindeposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Clinical Studies

Clinical Studies In Adults

Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either ZOCOR 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with ZOCOR led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. ZOCOR significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the ZOCOR group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. ZOCOR significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent nonfatal myocardial infarction [MI]) by 34% (p < 0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. ZOCOR significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting orpercutaneous transluminal coronary angioplasty) by 37% (p < 0.00001, 252 vs 383 patients). ZOCOR significantly reduced the risk of fatal plus non-fatalcerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). ZOCOR reduced the risk of major coronary events to a similar extent across the range of baseline total andLDL cholesterol levels. Because there were only 53 female deaths, the effect of ZOCOR on mortality in women could not be adequately assessed. However, ZOCOR significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of ZOCOR on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, ZOCOR resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients ( ≥ 65 years), compared with younger patients.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on ZOCOR 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method3 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40-80 years), were 97% Caucasian 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 vessel disease (33%), or hypertension in males ≥ 65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that ZOCOR 40 mg/day significantly reduced: total and CHD mortality; nonfatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).

Table 4: Summary of Heart Protection Study Results

ENDPOINT ZOCOR 
(N=10,269) N (%)*
PLACEBO
(N=10,267) N (%)*
RISK REDUCTION (%) (95% CI) P-VALUE
Primary
  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
Secondary
  Non-fatal 357 (3.5) 574 (5.6) 38 (30-46) p < 0.0001
  MI Stroke 444 (4.3) 585 (5.7) 25 (15-34) p < 0.0001
Tertiary
  Coronary revascularization 513 (5) 725 (7.1) 30 (22-38) p < 0.0001
  Peripheral and other noncoronary revascularization 450 (4.4) 532 (5.2) 16 (5-26) p=0.006
* n = number of patients with indicated event

 

Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with ZOCOR had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with ZOCOR had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p < 0.0001). Treatment with ZOCOR produced significant relative risk reductions 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 diseaserelated 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, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to ZOCOR treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD.

3D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453

Figure 1 : The Effects of Treatment with ZOCOR on Major Vascular Events and Major Coronary Events in HPS

View Enlarged Table

 

N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.

Angiographic Studies

In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. ZOCOR significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.

Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type IIa and IIb)

ZOCOR has been shown to be effective in reducing total-C and LDL-C inheterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4-6 weeks and maintained during chronic therapy. ZOCOR significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; ZOCOR also decreased TG and increased HDL-C (see Table 5).

Table 5: Mean Response in 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 †(Mean % Change at Week 6)
ZOCOR 5 mg q.p.m. 109 -19 -26 10 -12
ZOCOR 10 mg q.p.m. 110 -23 -30 12 -15
Scandinavian Simvastatin Survival Study ‡ (Mean % Change at Week 6) Placebo 2223 -1 -1 0 -2
ZOCOR 20 mg q.p.m. 2221 -28 -38 8 -19
Upper Dose Comparative Study § (Mean % Change Averaged at Weeks 18 and 24)
ZOCOR 40 mg q.p.m. 433 -31 -41 9 -18
ZOCOR 80 mg q.p.m. ¶ 664 -36 -47 8 -24
Multi-Center Combined Hyperlipidemia Study # (Mean % Change at Week 6)
Placebo 125 1 2 3 -4
ZOCOR 40 mg q.p.m. 123 -25 -29 13 -28
ZOCOR 80 mg q.p.m. 124 -31 -36 16 -33
* median percent change 
† mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL 
‡ mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL 
§ mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL 
¶ 21% and 36% median reduction in TG in patients with TG ≤ 200 mg/dL and TG > 200 mg/dL, respectively. Patients with TG > 350 mg/dL were excluded 
# mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.

 

Hypertriglyceridemia (Fredrickson type lV)

The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.

Table 6: Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline*

TREATMENT N TOTAL-C LDL-C HDL-C TG VLDL-C NON-HDL-C
Placebo 74 +2
(-7, +7)
+1
(-8, +14)
+3
(-3, +10)
-9
(-25, +13)
-7 
(-25, +11)
+1
(-9, +8)
ZOCOR 40 mg/day 74 -25
(-34, -19)
-28
(-40, -17)
+11
(+5, +23)
-29
(-43, -16)
-37
(-54, -23)
-32
(-42, -23)
ZOCOR 80 mg/day 74 -32
(-38, -24)
-37
(-46, -26)
+15
(+5, +23)
-34
(-45, -18)
-41
(-57, -28)
-38
(-49, -32)
* The median baseline values
(mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.

 

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG > 0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7.

Table 7: Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia 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)
ZOCOR 40 mg/day 7 -50
(-66, -39)
-50
(-60, -31)
+7
(-8, +23)
-41
(-74, -16)
-58
(-90, -37)
-57
(-72, -44)
ZOCOR 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 15-39 years of age with homozygousfamilial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40-and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose.

Endocrine Function

In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acidsequestrant cholestyramine. There was no effect on plasma gonadotropinlevels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20-40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown.

Clinical Studies In Adolescents

In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required 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.

ZOCOR significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study.

Table 8: Lipid-Lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)

View Enlarged Table

 

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the ZOCOR 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

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

Patient Information

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP) recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

Patients should be advised about substances they should not take concomitantly with simvastatin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking ZOCOR.

Muscle Pain

All patients starting therapy with ZOCOR should be advised of the risk ofmyopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing ZOCOR. Patients using the 80-mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80-mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of ZOCOR is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.

Liver Enzymes

It is recommended that liver function tests be performed before the initiation of ZOCOR, and thereafter when clinically indicated. All patients treated with ZOCOR should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using ZOCOR. Discuss future pregnancy plans with your patients, and discuss when to stop taking ZOCOR if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking ZOCOR and call their healthcare professional.

Breastfeeding

Women who are breastfeeding should not use ZOCOR. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

SIMVASTATIN - ORAL

 

(SIM-va-STAT-in)

 

COMMON BRAND NAME(S): Zocor

 

USES: Simvastatin is used along with a proper diet to help lower "bad" cholesterol and fats (such as LDL, triglycerides) and raise "good" cholesterol (HDL) in the blood. It belongs to a group of drugs known as "statins." It works by reducing the amount of cholesterol made by the liver. Lowering "bad" cholesterol and triglycerides and raising "good" cholesterol decreases the risk of heart disease and helps prevent strokes and heart attacks.

In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.

 

HOW TO USE: Take this medication by mouth with or without food as directed by your doctor, usually once daily in the evening.

Dosage is based on your medical condition, response to treatment, age, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Chinese patients taking niacin may require lower doses of simvastatin. Ask your doctor for more details.

The usual maximum dose for this medication is 40 milligrams a day. If you have been instructed by your doctor to take more than 40 milligrams, continue on that same dose. However, promptly talk with him or her about the risks and benefits of your higher dose.

Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details.

Take this medication regularly in order to get the most benefit from it. Remember to take it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high cholesterol or triglycerides do not feel sick.

It is very important to continue to follow your doctor's advice about diet and exercise. It may take up to 4 weeks before you get the full benefit of this drug.

Consumer Overview Side Effect

SIDE EFFECTS: Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very small number of people taking simvastatin may have mild memory problems or confusion. If these rare effects occur, talk to your doctor.

Rarely, statins may cause or worsen diabetes. Talk to your doctor about the benefits and risks.

This drug may infrequently cause muscle problems (which can rarely lead to very serious conditions called rhabdomyolysis and autoimmune myopathy). Tell your doctor right away if you develop any of these symptoms during treatment and if these symptoms persist after your doctor stops this drug: muscle pain/tenderness/weakness (especially with fever or unusual tiredness), change in the amount of urine.

This medication may rarely cause liver problems. If you notice any of the following rare but serious side effects, tell your doctor immediately: yellowing eyes/skin, dark urine, severe stomach/abdominal pain, persistent nausea/vomiting.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Zocor (simvastatin) Side Effects Center for a complete guide to possible side effects

Learn More »
 

PRECAUTIONS: Before taking simvastatin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, kidney disease, alcohol use.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Limit alcoholic beverages. Daily use of alcohol may increase your risk for liver problems, especially when combined with simvastatin. Ask your doctor or pharmacist for more information.

Older adults may be more sensitive to the side effects of this drug, especially muscle problems.

This medication must not be used during pregnancy. Simvastatin may harm an unborn baby. Therefore, it is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control (such as condoms, birth control pills) while taking this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is unknown if this medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: See also How to Use section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: "blood thinners" (such as warfarin), cyclosporine, danazol, gemfibrozil.

Other medications can affect the removal of simvastatin from your body, which may affect how simvastatin works. Examples include certain azole antifungals (such as itraconazole, ketoconazole, posaconazole, voriconazole), boceprevir, cobicistat, colchicine, delavirdine, macrolide antibiotics (such as clarithromycin, erythromycin), nefazodone, HIV protease inhibitors (such as nelfinavir, ritonavir), telaprevir, telithromycin, among others.

Do not take any red yeast rice products while you are taking simvastatin because some red yeast rice products may also contain a statin called lovastatin. Taking simvastatin and red yeast rice products together can increase your risk of serious muscle and liver problems.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as blood cholesterol/triglyceride levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature away from light and moisture. Storage temperature ranges differ according to different manufacturers, so consult your pharmacist for more information. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

Information last revised November 2014. Copyright(c) 2014 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Zocor

Generic Name: simvastatin (Pronunciation: SIM va sta tin)

  • What is simvastatin (Zocor)?
  • What are the possible side effects of simvastatin (Zocor)?
  • What is the most important information I should know about simvastatin (Zocor)?
  • What should I discuss with my healthcare provider before taking simvastatin (Zocor)?
  • How should I take simvastatin (Zocor)?
  • What happens if I miss a dose (Zocor)?
  • What happens if I overdose (Zocor)?
  • What should I avoid while taking simvastatin (Zocor)?
  • What other drugs will affect simvastatin (Zocor)?
  • Where can I get more information?

What is simvastatin (Zocor)?

 

Simvastatin is in a group of drugs called HMG CoA reductase inhibitors, or "statins." Simvastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

Simvastatin is used to lower cholesterol and triglycerides (types of fat) in the blood.

Simvastatin is also used to lower the risk of stroke, heart attack, and other heart complications in people with diabetes, coronary heart disease, or other risk factors

Simvastatin is used in adults and children who are at least 10 years old.

Simvastatin may also be used for purposes not listed in this medication guide.

Simvastatin 10 mg-INT

oval, red, imprinted with S4

What are the possible side effects of simvastatin (Zocor)?

 

Get emergency medical help if you have any of thesesigns of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using simvastatin and call your doctor at once if you have:

  • unexplained muscle pain, tenderness, or weakness;
  • confusion, memory problems;
  • fever, unusual tiredness, and dark colored urine;
  • pain or burning when you urinate;
  • swelling, weight gain, little or no urinating;
  • increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss; or
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

  • headache;
  • joint pain, mild muscle pain;
  • constipation, stomach pain or indigestion, mild nausea;
  • mild skin rash;
  • sleep problems (insomnia); or
  • cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Zocor (simvastatin) Side Effects Center for a complete guide to possible side effects

Learn More »
 

What is the most important information I should know about simvastatin (Zocor)?

 

In rare cases, simvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Never take simvastatin in larger amounts, or for longer than recommended by your doctor. Follow your doctor's dosing instructions very carefully. Taking too much of this medication may cause serious or life-threatening side effects.

Many other drugs can interact with simvastatin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Before taking simvastatin, tell your doctor if you have ever had liver or kidney disease, diabetes, or a thyroid disorder, if you are of Chinese descent, or if you drink more than 2 alcoholic beverages daily.

Simvastatin can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

Grapefruit and grapefruit juice may interact with simvastatin and lead to potentially dangerous effects. Do not consume grapefruit products while taking this medication.

Patient Detailed How Take

What should I discuss with my healthcare provider before taking simvastatin (Zocor)?

 

You should not take simvastatin if you are allergic to it, if you have liver disease, or if you are pregnant or breast-feeding.

In rare cases, simvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid). You may also be more likely to develop this condition if you are of Chinese descent and you take high-dose simvastatin while also taking medication that contains niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others).

Some medicines can cause unwanted or dangerous effects when used with simvastatin. Your doctor may need to change your treatment plan if you use any of the following drugs:

  • cyclosporine;
  • danazol;
  • gemfibrozil;
  • nefazodone;
  • the antibiotics clarithromycin, erythromycin, and telithromycin;
  • the antifungal medications itraconazole, ketoconazole, and posaconazole;
  • the hepatitis C medications boceprevir and telaprevir; or
  • the HIV/AIDS medications atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

Before you start taking simvastatin, tell your doctor if you are already using any of these other medicines:

  • amiodarone;
  • diltiazem;
  • amlodipine;
  • ranolazine; or
  • verapamil.

To make sure simvastatin is safe for you, tell your doctor if you have:

  • history of liver disease;
  • history of kidney disease;
  • diabetes;
  • a thyroid disorder; or
  • if you drink more than 2 alcoholic beverages daily.

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not take simvastatin if you are pregnant.Stop taking this medication and tell your doctor right away if you become pregnant. Use effective birth control to avoid pregnancy while you are taking simvastatin.

Simvastatin may pass into breast milk and could harm a nursing baby. Do not breast-feed while you are taking simvastatin.

How should I take simvastatin (Zocor)?

 

Follow all directions on your prescription label. Never take this medicine in larger amounts, or for longer than prescribed. Taking too much of this medication may cause serious or life-threatening side effects.

Simvastatin is usually taken at bedtime or with an evening meal. If you take simvastatin more than once daily, take it with meals. Your doctor may occasionally change your dose to make sure you get the best results.

While using simvastatin, you may need frequent blood tests at your doctor's office.

You may need to take simvastatin on a long-term basis for the treatment of high cholesterol. You may need to stop using simvastatin for a short time if you have surgery or a medical emergency. Do not stop taking this medication unless your doctor tells you to.

Simvastatin is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture, heat, and light.

Patient Detailed Avoid Taking

What happens if I miss a dose (Zocor)?

 

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Zocor)?

 

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking simvastatin (Zocor)?

 

Grapefruit and grapefruit juice may interact with simvastatin and lead to potentially dangerous effects. Do not consume grapefruit products while taking this medication.

Avoid eating foods that are high in fat or cholesterol. Simvastatin will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

What other drugs will affect simvastatin (Zocor)?

 

Many drugs can interact with simvastatin. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with simvastatin, especially:

  • colchicine;
  • digoxin, digitalis;
  • a blood thinner such as warfarin, Coumadin;
  • fenofibric acid or fenofibrate;
  • antifungal medications such as fluconazole or voriconazole;
  • other medicines that contain niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others);
  • drugs that weaken your immune system, such as steroids, cancer medicine, or medicines used to prevent organ transplant rejection, such as sirolimus or tacrolimus; or
  • any other "statin" medication such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or other medication that contains simvastatin (Simcor, Vytorin).

This list is not complete and many other drugs can interact with simvastatin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Where can I get more information?

 

Your pharmacist can provide more information about simvastatin.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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