Zocor

Erythromycin, Clarithromycin, and Telithromycin: (See Warnings and Precautions, Measures to reduce the risk of myopathy/rhabdomyolysis caused by drug interactions.)

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250-mL glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, very large quantities (over 1 liter daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

ZOCOR may elevate serum transaminase and creatine phosphokinase levels (from skeletal muscles) (see Adverse Reactions, Laboratory Tests).

The risk of myopathy may also be increased by the following lipid-lowering drugs that are not potent inhibitors of CYP3A4, but which can cause myopathy when given alone (see below and Warnings and Precautions).

• Gemfibrozil: The risk of myopathy/rhabdomyolysis is increased by gemfibrozil (see Dosage and Administration).

  
  

• Other Fibrates (except fenofibrate): These drugs (except fenofibrate) increase the risk of myopathy when given concomitantly with simvastatin, probably because they can produce myopathy when given alone (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent.

  
  

• Niacin (≥1 g/day): Myopathy, including rhabdomyolysis, has occurred in patients who were receiving coadministration of ZOCOR and other HMG-CoA reductase inhibitors with fibric acid derivatives and niacin, particularly in subjects with pre-existing renal insufficiency (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

Bile Acid Sequestrants (Cholestyramine): Preliminary evidence suggests that the cholesterol-lowering effects of ZOCOR and the bile acid sequestrant, cholestyramine, are additive.

When ZOCOR is used concurrently with cholestyramine or any other resin, an interval of at least two hours should be maintained between the two drugs, since the absorption of ZOCOR may be impaired by the resin.

CYP3A4 Interactions: Simvastatin itself is a substrate for CYP3A4. However, simvastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect plasma levels of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 increase the risk of myopathy by increasing the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy. These include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal insufficiency. However, caution should be exercised when ZOCOR is administered to patients with severe renal insufficiency; such patients should be started at 5 mg/day and be closely monitored (see Warnings and Precautions, Muscle Effects and Renal).

Patients should be placed on a standard cholesterol-lowering diet before receiving ZOCOR, and should continue on this diet during treatment with ZOCOR. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with ZOCOR, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

• Patients at high risk of coronary events, because of existing Coronary Heart Disease (CHD) or other occlusive arterial disease, or being over the age of 40 years with a diagnosis of diabetes: The usual starting dose of ZOCOR is 40 mg/day given as a single dose in the evening. Drug therapy can be initiated simultaneously with diet and exercise.

  
  

• Patients with hyperlipidemia (who are not in the risk categories above): The usual starting dose is 10 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg/day given as a single dose in the evening. Patients with mild to moderate hypercholesterolemia can be treated with a starting dose of 5 mg of ZOCOR. Adjustments of dosage, if required, should be made as specified above.

  
  

• Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of ZOCOR if cholesterol levels fall below the desired range.

  
  

• Concomitant therapy with other lipid metabolism regulators: If ZOCOR is used with gemfibrozil, the dose of ZOCOR should not exceed 10 mg/day (see Drug Interactions, Concomitant Therapy with Other Lipid Metabolism Regulators.)

  
  

• In patients taking cyclosporine, danazol, therapy should begin at 5 mg/day and not exceed 10 mg/day.

  
  

• In patients taking amiodarone or verapamil concomitantly with ZOCOR, the dose of ZOCOR should not exceed 20 mg/day (see Warnings and Precautions, Measures to reduce the risk of myopathy/rhabdomyolysis caused by drug interactions and Drug Interactions).

  
  

• The dosage of ZOCOR should be individualized according to baseline LDL-C, total-C/HDL-C ratio and/or TG levels to achieve the recommended desired lipid values at the lowest possible dose and the patient response. Lipid levels should be monitored periodically and, if necessary, the dose of ZOCOR adjusted based on desired lipid levels.

The recommended dose range for most patients is 10 to 40 mg/day. The maximum dose is 80 mg/day, which may be required in a minority of patients unable to achieve the desired reductions with lower doses. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening.

If a tablet is missed at its usual time, it should be taken as soon as possible. But, if it is too close to the time of the next dose: only the prescribed dose should be taken at the appointed time. A double dose should not be taken.

rhabdomyolysis, muscle cramps, myalgia.

vomiting.

anemia, leukopenia, purpura.

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features:

dizziness, paresthesia, peripheral neuropathy. Peripheral neuropathy with muscle weakness or sensory disturbance has been reported. Memory impairment.

In the Scandinavian Simvastatin Survival Study (4S) involving 4444 patients treated with 20-40 mg/day of ZOCOR (n=2221) or placebo (n=2223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study.

hepatitis. Hepatic failure with fatal or liver transplant outcome have been reported. Jaundice, pancreatitis.

erythema multiforme including Stevens-Johnson Syndrome, rash, pruritus, alopecia.

Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported.

Although the following adverse reactions were not observed in clinical studies with ZOCOR, they have been reported following treatment with other HMG-CoA reductase inhibitors: anorexia, psychic disturbances including anxiety, hypospermia and gynecomastia.

See Warnings and Precautions, Ophthalmologic.

The following additional adverse reactions were reported either in uncontrolled clinical studies or in post-marketing experience with ZOCOR, regardless of causality assessment.

depression, insomnia.

ZOCOR is indicated as an adjunct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated total cholesterol (total-C) and Low-Density Lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), and triglycerides (TG) levels in patients with primary hypercholesterolemia (Type IIa){*A disorder of lipid metabolism characterized by elevated serum cholesterol levels in association with normal triglyceride levels (Type IIa) or with increased triglyceride levels (Type IIb). Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins - An integrated approach to mechanisms and disorders. N Engl J Med 1967;276:148-56.}, or combined (mixed) hyperlipidemia (Type IIb)* when the response to diet and other nonpharmacological measures alone has been inadequate. ZOCOR (5-80 mg/day) reduces the levels of total cholesterol (19-36%), LDL-cholesterol (26-47%), apolipoprotein B (19-38%), and triglycerides (12-33%), in patients with mild to severe hyperlipidemia (Fredrickson Types IIa and IIb). ZOCOR also raises HDL-cholesterol (8-16%) and therefore lowers the LDL-C/HDL-C and total-C/HDL-C ratios.

Limited data is available in homozygous familial hypercholesterolemia (FH). In a controlled clinical study with 12 patients, ZOCOR (40 and 80 mg/day) reduced elevated total cholesterol (12% and 23%), LDL-cholesterol (14% and 25%), and apolipoprotein B (14% and 17%), respectively. One patient with absent LDL-cholesterol receptor function had an LDL-cholesterol reduction of 41% with the 80 mg/day dose.

After establishing that the elevation in plasma lipids represents a primary disorder not due to underlying conditions such as poorly-controlled diabetes mellitus, hypothyroidism, the nephrotic syndrome, liver disease, or dysproteinemias, it should ideally be determined that patients for whom treatment with ZOCOR is being considered have an elevated LDL-C level as the cause for an elevated total serum cholesterol. This may be particularly relevant for patients with total triglycerides over 4.52 mmol/L (400 mg/dL) or with markedly elevated HDL-C values, where non-LDL fractions may contribute significantly to total cholesterol levels without apparent increase in cardiovascular risk. In most patients LDL-C may be estimated according to the following equation:

When total triglycerides are greater than 4.52 mmol/L (400 mg/dL) this equation is less accurate. In such patients, LDL-cholesterol may be obtained by ultra centrifugation.

Each buff, oval-shaped biconvex, film-coated tablet, engraved MSD 726 on one side and ZOCOR 5 on the other, contains: simvastatin 5 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide and yellow ferric oxide. Blister packages of 28.

Each brick-red, capsule-shaped, film-coated tablet, engraved 543 on one side and 80 on the other, contains: simvastatin 80 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc and titanium dioxide. Blister packages of 28.

Each tan, oval-shaped biconvex, film-coated tablet, engraved MSD 740 on one side and plain on the other, contains: simvastatin 20 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc, titanium dioxide and yellow ferric oxide. Blister packages of 28. High density polyethylene bottles of 100.

Each brick-red, oval-shaped biconvex, film-coated tablet, engraved MSD 749 on one side and plain on the other, contains: simvastatin 40 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc and titanium dioxide. Blister packages of 28.

Each peach, oval-shaped biconvex, film-coated tablet, engraved MSD 735 on one side and plain on the other, contains: simvastatin 10 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc, titanium dioxide and yellow ferric oxide. Blister packages of 28.

ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously. This recommendation is based on studies with lovastatin (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Higher dosages (40-80 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of simvastatin. Caution should be exercised in such patients who are also significantly renally impaired or are concomitantly administered P-450 inhibitors (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Drug Interactions).

Effects on skeletal muscle such as myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with ZOCOR.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with ZOCOR and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine phosphokinase (CK) values to greater than ten times the upper limit of normal (ULN), should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or a marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. ZOCOR therapy should be immediately discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected. 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 HMG-CoA reductase inhibitory activity in plasma.

In the Scandinavian Simvastatin Survival Study, there was one case of myopathy among 1399 patients taking simvastatin 20 mg and no cases among 822 patients taking 40 mg daily for a median duration of 5.4 years. In two 6-month controlled clinical studies, there was one case of myopathy among 436 patients taking 40 mg and 5 cases among 669 patients taking 80 mg. The risk of myopathy is increased by concomitant therapy with certain drugs, some of which were excluded by the designs of these studies.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with simvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with simvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones (see Drug Interactions,Overview ).

Current long-term data from clinical studies do not indicate an adverse effect of simvastatin on the human lens.

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [Lp(a)] level. Further research is currently ongoing to elucidate the significance of Lp(a) plasma level variations. Therefore, until further experience is obtained, it is suggested, when feasible, that Lp(a) measurements be carried out in patients placed on therapy with ZOCOR.

Limited experience is available in children. However, safety and effectiveness in children have not been established.

ZOCOR is contraindicated during pregnancy.

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to ZOCOR or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking ZOCOR or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with ZOCOR may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, ZOCOR should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with ZOCOR should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see Contraindications).

In clinical studies, marked persistent increases (to more than 3 times the ULN) in serum transaminases have occurred in 1% of adult patients who received ZOCOR (see Adverse Reactions, Laboratory Tests). When the drug 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. Some of these patients had abnormal liver function tests prior to therapy with simvastatin and/or consumed substantial quantities of alcohol.

In the Scandinavian Simvastatin Survival Study (4S), the number of patients with more than one transaminase elevation to >3 times the ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs 12 [0.6%]). The frequency of single elevations of ALT to 3 times the ULN was significantly higher in the simvastatin group in the first year of the study (20 vs 8, p=0.023), but not thereafter. Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2221) and 5 in the placebo group (n=2223). Of the 1986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to >3 times the ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. 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 1105 patients, the 6-month incidence of persistent hepatic transaminase elevations considered drug-related was 0.7% and 1.8% at the 40 and 80 mg dose, respectively.

In HPS (Heart Protection Study), in which 20,536 patients were randomized to receive ZOCOR 40 mg/day or placebo, the incidences of elevated transaminases (>3×ULN confirmed by repeat test) were 0.21% (n=21) for patients treated with ZOCOR and 0.09% (n=9) for patients treated with placebo.

It is recommended that liver function tests be performed at baseline and thereafter when clinically indicated. Patients titrated to the 80 mg dose should receive an additional test prior to titration, 3 months after titration to the 80 mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.

If the transaminase levels show evidence of progression, particularly if they rise to three times the ULN and are persistent, the drug should be discontinued.

ZOCOR, as well as other HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of ZOCOR; if such a condition should develop during therapy, the drug should be discontinued.

Moderate (less than three times the ULN) elevations of serum transaminases have been reported following therapy with ZOCOR (see Adverse Reactions). These changes were not specific to ZOCOR and were also observed with comparative lipid-lowering agents. They generally appeared within the first 3 months after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptom and did not require interruption of treatment.

For patients over the age of 65 years who received simvastatin in controlled clinical studies, efficacy, as assessed by reduction in total and LDL-cholesterol levels, appeared similar to that seen in the population as a whole, and there was no apparent increase in the frequency and severity of clinical or laboratory adverse findings.

Higher dosages (40-80 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of simvastatin. Caution should be exercised in such patients who are also elderly or are concomitantly administered P-450 inhibitors (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Drug Interactions).

Elderly patients may be more susceptible to myopathy (see Warnings and Precautions, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

Use of simvastatin concomitantly with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, danazol, gemfibrozil, or other fibrates (except fenofibrate). The combined use of simvastatin with gemfibrozil should be avoided unless the benefits are likely to outweigh the increased risk of this drug combination. The benefits of the use of simvastatin in patients receiving other fibrates (except fenofibrate), cyclosporine, or danazol should be carefully weighed against the risks of these drug combinations. Caution should be used when prescribing fenofibrate or niacin (≥1 g/day) with simvastatin, as either agent can cause myopathy when given alone. Addition of fibrates to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. Combinations of fibrates or niacin with simvastatin have been used without myopathy in small, short-term clinical studies with careful monitoring.

The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.

Patients on fusidic acid (oral or iv) and simvastatin should be closely monitored for symptoms and/or signs of myopathy. Temporary suspension of simvastatin treatment may be considered.

Before instituting therapy with ZOCOR, an attempt should be made to control hypercholesterolemia with appropriate diet and exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see Indications and Clinical Use). The patient should be advised to inform subsequent physicians of the prior use of ZOCOR or any other lipid-lowering agent.

In primary prevention intervention the effects of simvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortality or total mortality have not been established.

The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are coadministered with drugs that inhibit certain metabolic pathways in the cytochrome P-450 system. Simvastatin is metabolized by the cytochrome P-450 isoform 3A4 and as such may interact with agents which inhibit this enzyme (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Drug Interactions, Overview ).

The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin with the following:

• Potent inhibitors of CYP3A4: e.g., the antifungal azoles itraconazole, and ketoconazole, the antibiotics erythromycin, clarithromycin and telithromycin, the HIV protease inhibitors, or the antidepressant nefazodone, particularly with higher doses of simvastatin (see Drug Interactions).

  
  

Other Drugs:

• Gemfibrozil or other fibrates (except fenofibrate), particularly with higher doses of simvastatin (see Drug Interactions). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent.

  
  

• Cyclosporine or danazol particularly with higher doses of simvastatin (see Drug Interactions).

  
  

• Amiodarone or verapamil with higher doses of simvastatin (see Drug Interactions). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.

  
  

• Diltiazem: Patients on diltiazem treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy is approximately 1% in these patients. In clinical studies, the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltiazem (see Drug Interactions).

  
  

• Fusidic acid (oral or iv): Patients on fusidic acid (oral or iv) treated concomitantly with simvastatin may have an increased risk of myopathy (see Drug Interactions).

  
  

• Niacin (≥1 g/day): Myopathy, including rhabdomyolysis, has occurred in patients who were receiving coadministration of ZOCOR and other HMG-CoA reductase inhibitors with fibric acid derivatives and niacin, particularly in subjects with pre-existing renal insufficiency (see Drug Interactions).

  
  

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41 050 patients were treated with ZOCOR with 24 747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

ZOCOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: personal or family history of hereditary muscular disorders; previous history of muscle toxicity with another HMG-CoA reductase inhibitor; concomitant use of a fibrate or niacin (nicotinic acid); hypothyroidism; alcohol abuse; excessive physical exercise; age >70 years; renal impairment; hepatic impairment; diabetes with hepatic fatty change; surgery and trauma; frailty; situations where an increase in plasma levels of active ingredient may occur (see Drug Interactions).

ZOCOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders, or uncontrolled seizures).

In the differential diagnosis of chest pain in a patient on therapy with ZOCOR cardiac and noncardiac fractions of serum transaminase and creatine phosphokinase levels should be determined.

In few instances eosinophilia and skin eruptions appear to be associated with simvastatin treatment. If hypersensitivity is suspected, ZOCOR should be discontinued.

Significant decreases in circulating CoQ₁₀ levels in patients treated with ZOCOR and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of CoQ₁₀ has not been established.

It is not known whether simvastatin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking ZOCOR should not nurse (see Contraindications).

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with simvastatin 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. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

ZOCOR has complex pharmacokinetic characteristics.

ZOCOR is a lipid-lowering agent derived synthetically from a fermentation product of A. terreus.

After oral ingestion, ZOCOR, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This principal metabolite is a specific 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.

ZOCOR reduces cholesterol production by the liver and induces some changes in cholesterol transport and disposition in the blood and tissues. The mechanism(s) of this effect is believed to involve both reduction of the synthesis of Low-Density Lipoprotein (LDL), and an increase in LDL catabolism as a result of induction of the hepatic LDL receptors.

Simvastatin is metabolized by the microsomal hepatic enzyme system (cytochrome P-450 isoform 3A4). The major active metabolites present in human plasma are the β-hydroxyacid of simvastatin and four other active metabolites.