Zocor

Pregnancy category: X

Lactation: Contraindicated; potentially unsafe

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

• Pregnant women should not use simvastatin because the developing fetus requires cholesterol for development, and simvastatin reduces the production of cholesterol. Simvastatin should only be administered to women of child bearing age if they are not likely to become pregnant.
• Because of the risk of adverse effects to the developing infant, simvastatin should not be administered to nursing mothers.

Zocor tablets come in 5 milligrams (mg), 10, 20, 40 and 80 mg.

Usually, the starting dose is 10 or 20 mg once a day, in the evening. If you are at high risk of heart disease, the starting dose is 40 mg daily.

The 80-mg dose is linked with an increased risk of muscular problems, so its use should be only for those who have been taking Zocor in that strength for 12 months or longer without muscle problems.

The recommended starting dose for teens with familial high cholesterol is 10 mg a day, and only 40mg a day maximum.

Zocor Overdose

If you have taken too much Zocor, call your doctor right away or go to the emergency department. A few cases of overdose have been reported.

Missed Dose of Zocor

If you miss a dose, take it as soon as you remember it. However, if it's close to the time for your next scheduled dose, skip the forgotten dose. Simply continue with your regular dosing schedule, and never double up.

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.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Zocor falls into category X. It has been shown that women taking Zocor during pregnancy may have babies with problems. There are no situations where the benefits of the medication for the mother outweigh the risks of harm to the baby. These medicines should never be used by pregnant women.

Take Zocor exactly as prescribed.

Zocor comes in tablet form and is given once a day at bedtime, with or without food.

Your doctor may start you on a low dose of Zocor and gradually increase your dose. Do not increase or decrease your dose or stop taking it without first talking to your doctor.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Zocor at the same time.

Prevention of Cardiovascular Events

ACC/AHA cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults; extensive evidence demonstrates that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients).336 337 338 350 Relative reduction in ASCVD risk is correlated with degree of LDL-cholesterol lowering; therefore, use maximum tolerated statin intensity to achieve optimum ASCVD benefits.350 According to ACC/AHA, simvastatin may be used for primary† or secondary prevention in adults when moderate-intensity statin therapy is indicated.350 (See Prevention of Cardiovascular Events under Dosage and Administration.)

Adjunct to nondrug therapies (i.e., lifestyle modifications350 ) in patients with CHD or CHD risk equivalents (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease) to reduce the risk of total mortality by reducing CHD death, to reduce the risk of nonfatal MI and stroke, and to reduce the need for coronary and non-coronary revascularization procedures.1 350 Unless contraindicated, statins are considered first-line therapy in patients 21–75 years of age with clinical ASCVD (i.e., acute coronary syndromes [ACS]; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin).350

Slows the progression and/or induces regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness.1 48 51 53

In the IMPROVE-IT study, addition of ezetimibe to simvastatin therapy further reduced LDL cholesterol and improved cardiovascular outcomes in post-ACS patients.309

Addition of niacin to statin-based therapy (i.e., simvastatin with or without ezetimibe) in patients with established cardiovascular disease not shown to provide incremental ASCVD risk reduction benefit beyond that provided by statin monotherapy.350 354

In the SHARP study, fixed-combination preparation of simvastatin and ezetimibe was found to reduce risk of major vascular and atherosclerotic events in patients with chronic kidney disease.103 308

Current recommendations from ACC/AHA regarding prevention of ASCVD and lifestyle modifications to reduce cardiovascular risk are available at or .352

Dyslipidemias

Adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hyperlipidemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIa or IIb).1 3 4 18

May use in combination or fixed combination with ezetimibe for additive antilipemic effects.89 103

Also used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are on optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that provided by statin monotherapy.105 353

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in boys and girls (≥1 year postmenarchal) 10–17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of ≥190 mg/dL or a serum LDL-cholesterol concentration of ≥160 mg/dL and either a family history of premature cardiovascular disease or ≥2 other cardiovascular risk factors.1

Reduction of elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1 May use in combination or fixed combination with ezetimibe for additive antilipemic effects.89 103

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride and VLDL-cholesterol concentrations in the management of primary dysbetalipoproteinemia (Fredrickson type III).1

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride concentrations in the management of hypertriglyceridemia (Fredrickson type IV).1 However, fibric acid derivatives provide greater benefit in patients with elevated triglyceride concentrations compared with statins.356

Also has been used to reduce total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus† (diabetic dyslipidemia),13 55 58 59 74 cardiac†76 or renal† transplantation,77 or nephrotic syndrome†.63 64

Contraindications

• Concomitant use with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, clarithromycin, erythromycin, telithromycin, nefazodone, cobicistat-containing preparations), gemfibrozil, cyclosporine, or danazol.1 (See Specific Drugs and Foods under Interactions.)

• Active liver disease, including unexplained, persistent elevations of serum aminotransferases.1

• Pregnancy or lactation.1 Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards.1

• Known hypersensitivity to simvastatin or any ingredient in the formulation.1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm.1 Congenital anomalies following intrauterine exposure to statins reported rarely.1

Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards.1 If the patient becomes pregnant while taking the drug, immediately discontinue therapy and apprise the patient of the potential hazard to the fetus.1

Musculoskeletal Effects

Myopathy (manifested as muscle pain, tenderness, or weakness and serum CK [CPK] concentration increases >10 times the ULN) reported.1

Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [>10 times the ULN] in serum CK concentrations and increases in Scr [usually accompanied by brown urine and urinary myoglobinuria])257 with or without acute renal failure secondary to myoglobinuria also reported; rare fatalities have occurred.1

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins.1 Characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.1

Incidence of myopathy, including rhabdomyolysis, reportedly highest during first year and then notably decreased during subsequent years of treatment.1

Risk of myopathy is increased in patients receiving higher dosages of statins; risk also may be increased in geriatric patients (≥65 years of age), women, and patients with renal impairment or uncontrolled hypothyroidism.1

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.1 90 91 92 93 103 (See Contraindications under Cautions and also see Interactions.)

Risk of myopathy, including rhabdomyolysis, is greater with 80-mg daily dosage compared with lower daily dosages or compared with other statins with similar or greater LDL-cholesterol lowering efficacy.1 Restrict use of 80-mg daily dosage.1 (See Prescribing Limits under Dosage and Administration.)

May consider periodic monitoring of CK concentrations when initiating therapy or increasing dosage; however, there is no assurance that such monitoring will prevent myopathy.1

ACC/AHA cholesterol management guideline does not recommend routine monitoring of CK concentrations in adults; however, may obtain CK concentrations before initiating therapy in adults at increased risk of developing adverse musculoskeletal effects (e.g., patients with personal or family history of statin intolerance or muscle disease, patients receiving concomitant therapy with myotoxic drugs).350 During statin therapy, may measure CK concentrations in adults with muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).350

National Heart, Lung, and Blood Institute (NHLBI) expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents recommends obtaining CK concentrations in pediatric patients before initiating statin therapy and routinely monitoring for muscle toxicity during therapy.357

Discontinue if serum CK concentrations increase markedly or if myopathy is diagnosed or suspected.1

Temporarily withhold therapy 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, or electrolyte disorders; uncontrolled seizures).1

Hepatic Effects

Associated with increases in serum aminotransferase (AST, ALT) concentrations.1

Pancreatitis,1 hepatitis,1 jaundice,1 increased serum alkaline phosphatase concentrations,1 increased serum γ-glutamyl transpeptidase concentrations,1 and fatal and nonfatal hepatic failure1 reported.1

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage201 ).1 Although manufacturers previously recommended more frequent monitoring,104 FDA concluded that serious statin-related liver injury is rare and unpredictable, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.200 ACC/AHA cholesterol management guideline recommends obtaining liver function tests in adults with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera).350 However, NHLBI expert panel on cardiovascular health and risk reduction in children and adolescents strongly recommends routine monitoring of hepatic function in children and adolescents receiving statins.357

ALT may emanate from muscle; therefore, concurrent increases in ALT and CK concentrations may indicate myopathy.1 (See Musculoskeletal Effects under Cautions.)

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt simvastatin therapy.1 If an alternate etiology is not found, do not restart simvastatin.1

Also see Hepatic Impairment under Cautions.

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported.1 200 Possible increased risk of developing diabetes.200 May need to monitor glucose concentrations following initiation of statin therapy.201

FDA states that cardiovascular benefits of statins outweigh these small increased risks.200

ACC/AHA cholesterol management guideline recommends evaluating patients for new-onset diabetes mellitus according to current diabetes screening guidelines.350

If diabetes mellitus develops during statin therapy, encourage patients to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD.350

Endogenous Steroid Production

No substantial effects on adrenal reserve or basal plasma cortisol concentration observed with simvastatin.1

Small reductions from baseline in basal plasma testosterone concentrations observed in men; however, unlikely to be clinically important since no substantial effects on plasma gonadotropin concentrations, plasma testosterone response to human chorionic gonadotropin, spermatogenesis, or incidence of male adverse sexual effects observed.1

Effects on pituitary-gonadal axis in premenopausal women unknown.1

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.1

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy).1 200 Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline.200 Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.200

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.200

If manifestations consistent with cognitive impairment occur, National Lipid Association (NLA) statin safety assessment task force recommends evaluating and managing patients appropriately.202

If patients present with confusion or memory impairment, ACC/AHA cholesterol management guideline recommends evaluating patient for statin as well as nonstatin causes (e.g., other drugs, systemic or neuropsychiatric causes).350

Role as Adjunct Therapy

Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality.1

Risk of Cancer

Findings from the SEAS study suggested a possible increased risk of cancer with use of the fixed combination of simvastatin and ezetimibe.304 306 The results of 2 subsequent randomized trials (SHARP and IMPROVE-IT) found no such association.305 307 308 309 Based on currently available evidence, FDA has concluded that the fixed-combination preparation of ezetimibe and simvastatin (Vytorin) is not likely to increase the risk of cancer.307

Use of Fixed Combinations

When used in fixed combination with ezetimibe, consider the cautions, precautions, and contraindications associated with ezetimibe.103

Specific Populations

Category X.1 (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Not known whether simvastatin is distributed into milk;1 however, a small amount of another statin is distributed into milk.1 Use is contraindicated in nursing women; women who require simvastatin therapy should not breast-feed their infants.1 Discontinue nursing or the drug.1

Safety and efficacy of simvastatin not established in children <10 years of age or in premenarchal girls.1 Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.1

Safety and efficacy of simvastatin in fixed combination with ezetimibe not established in children <10 years of age or in premenarchal girls.103 In patients 10–17 years of age, combination of simvastatin and ezetimibe associated with higher discontinuance rate and higher incidence of elevated aminotransferase or CK concentrations compared with simvastatin monotherapy.103

Simvastatin: No overall differences in safety or efficacy relative to younger adults.1 However, increased sensitivity cannot be ruled out; higher dosages (i.e., 80 mg daily) associated with increased risk of myopathy, including rhabdomyolysis, in patients ≥65 years of age.1 Use with caution, since age ≥65 years is a predisposing factor for myopathy.1 In patients >75 years of age, consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.350

Simvastatin/ezetimibe fixed combination: No overall differences in safety or efficacy relative to younger patients; however, increased sensitivity cannot be ruled out.103 Use with caution, since age ≥65 years is a predisposing factor for myopathy.1

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1

Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.1

Because many patients who have developed rhabdomyolysis during simvastatin therapy have had complicated medical histories, including renal impairment secondary to chronic diabetes mellitus, closely monitor such patients.1

Use with caution in patients with severe renal impairment; dosage adjustments necessary in such patients.1 (See Renal Impairment under Dosage and Administration.)

In patients with moderate to severe renal impairment receiving simvastatin 20 mg/ezetimibe 10 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.103 Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy.103 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Upper respiratory tract infections, headache, abdominal pain, constipation, nausea.1

• Prodrug requiring hydrolysis in vivo for activity.1

• Inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol synthesis.1 Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, and triglycerides.1

• Statins may slow progression and/or induce regression of atherosclerosis in coronary and/or carotid arteries,1 48 51 53 113 115 116 117 118 119 120 121 122 123 modulate BP in hypercholesterolemic patients with hypertension,124 125 and possess anti-inflammatory activity.126 127

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Dizziness
• fainting
• fast or irregular heartbeat

• Bladder pain
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chills
• cough
• dark-colored urine
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• dry mouth
• ear congestion
• fever
• flushed, dry skin
• frequent urge to urinate
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• increased urination
• joint pain
• loss of consciousness
• lower back or side pain
• muscle cramps, spasms, or stiffness
• muscular pain, tenderness, wasting, or weakness
• nasal congestion
• nausea
• runny nose
• sneezing
• sore throat
• stomachache
• sweating
• swelling
• swollen joints
• troubled breathing
• unexplained weight loss
• unusual tiredness or weakness
• vomiting

• Blistering, peeling, or loosening of the skin
• bloating
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• constipation
• diarrhea
• difficulty with swallowing
• general tiredness and weakness
• indigestion
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• loss of appetite
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• red skin lesions, often with a purple center
• red, irritated eyes
• skin rash, hives, or itching
• sores, ulcers, or white spots in the mouth or on the lips
• tightness in the chest
• troubled breathing with exertion
• unusual bleeding or bruising
• upper right abdominal or stomach pain
• weakness in the arms, hands, legs, or feet
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• burning feeling in the chest or stomach
• dizziness or lightheadedness
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• full feeling
• heartburn
• lack or loss of strength
• pain or tenderness around the eyes and cheekbones
• passing gas
• sensation of spinning
• skin rash, encrusted, scaly, and oozing
• stomach discomfort, upset, or pain
• tenderness in the stomach area
• trouble sleeping

• Being forgetful
• depression
• discoloration of the skin
• hair loss or thinning of the hair
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• A heartbeat that does not feel normal.
• Not able to pass urine or change in how much urine is passed.
• This medicine may cause muscle pain, tenderness, or weakness. Sometimes, a very bad muscle problem may happen that may lead to kidney problems. Rarely, deaths have happened in people who get these problems when taking drugs like this one. Call your doctor right away if you have muscle pain, tenderness, or weakness that is not normal (with or without fever or feeling out of sorts). Call your doctor right away if you have muscle signs that last after your doctor has told you to stop taking this medicine.
• Liver problems have happened with drugs like this one. Sometimes, this has been deadly. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

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 rhabdomyolysis with 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 (2.2)]. 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 Warnings and Precautions (5.2).]

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, or electrolyte 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 isoform 3A4. 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 macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice [see Clinical Pharmacology (12.3)]. 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 (4) and Drug Interactions (7.1).]

The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].

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 (7.2)].

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 (7.7)].

The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-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 (7.3) and Table 3 in Clinical Pharmacology (12.3)] [also see Dosage and Administration, Patients with Homozygous Familial Hypercholesterolemia (2.4)].

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, randomized cardiovascular 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 (7.4)].

Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3, 2.4), Drug Interactions (7), Clinical Pharmacology (12.3)].

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. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)], 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 Warnings and Precautions (5.1)].

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.

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, simvastatin-derived 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. While 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 (8.5)].

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 (5.1) and Drug Interactions (7.1)].

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

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

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

There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

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 (Wallerian 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 fibrin deposits 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).

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 (4) and Warnings and Precautions (5.1)]. 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 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 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.

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

For patent information: www.merck.com/product/patent/home.html

Copyright © 1999-2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk0733-t-1503r065

PRINCIPAL DISPLAY PANEL - 5 mg Bottle Label

NDC 0006-0726-31

Zocor®
(Simvastatin) Tablets

5 mg

Each tablet contains 5 mg of simvastatin.

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL - 10 mg Bottle Label

NDC 0006-0735-31

Zocor®
(Simvastatin) Tablets

10 mg

Each tablet contains 10 mg of simvastatin.

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL - 20 mg Bottle Label

NDC 0006-0740-31

Zocor®
(Simvastatin) Tablets

20 mg

Each tablet contains 20 mg of simvastatin.

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL - 40 mg Bottle Label

NDC 0006-0749-31

Zocor®
(Simvastatin) Tablets

40 mg

Each tablet contains 40 mg of simvastatin.

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL - 80 mg Bottle Label

NDC 0006-0543-31

Zocor®
(Simvastatin) Tablets

80 mg

Each tablet contains 80 mg of simvastatin.

Rx only

30 Tablets

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

The following drugs can increase your risk of serious muscle problems if you take them together with Zocor. These drugs should not be used while you are taking Zocor:

• cyclosporine;

• danazol;

• gemfibrozil;

• nefazodone;

• an antibiotic--clarithromycin, erythromycin, telithromycin;

• antifungal medication--itraconazole, ketoconazole, posaconazole, voriconazole;

• hepatitis C medications--boceprevir, telaprevir; or

• HIV/AIDS medication--atazanavir, cobicistat (Stribild, Tybost), darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir.

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

• lomitapide; or

• heart medication--amiodarone, amlodipine, diltiazem, dronedarone, ranolazine, verapamil.

To make sure Zocor 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.

Zocor 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).

FDA pregnancy category X. This medicine can harm an unborn baby or cause birth defects. Do not take Zocor 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 this medicine.

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