Simvastatin as a HMG-Co A reductase inhibitor, prevents conversion of HMG–Co A to mevalonate, the rate–limiting step in cholesterol biosynthesis. Inhibition of cholesterol synthesis in the liver leads to upregulation of LDL receptors and an increase in catabolism of LDL cholesterol. There may also be some reduction in LDL production as a result of inhibition of hepatic synthesis of VLDL , the precursor of LDL . Simvastatin reduces LDL cholesterol , VLDL cholesterol , and to a lesser extent , plasma triglyceride concentrations , and slightly increase HDL concentrations.

Hyperlipidemia (treatment) – Simvastatin is indicated as an adjunct to diet in the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial ) and mixed dyslipidemia (type IIa and IIb hyperlipoproteinemia ) caused by elevated LDL – cholesterol concentrations in patient with a significant risk of coronary artery disease , who have not responded to diet or other measures alone . Simvastatin may also be useful for the reduction of elevated LDL- C concentrations in patients with combined hypercholesterolemia and hypertriglyceridemia . Simvastatin is indicated as adjunctive therapy with other lipid lowering treatments in homozygous familial hypercholesteromia to reduce total cholesterol ( total – C ) and LDL – C
Coronary heart disease (prophylaxis) – Simvastatin is indicated to reduce the risk of total mortality by reducing the incidence of coronary death in patients without symptomatic cardiovascular disease . Simvastatin is indicated to reduce the risk of myocardial infarction and the risk of undergoing myocardical revascularization procedures .
Stroke or transient ischemic attack (prophylaxis) – Simvastatin is indicated to reduce the risk of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia.

a– 1% to 10%: Constipation ; Dyspepsia ; Flatulence ; CPK elevation ( > 3x normal on one or more occasions ) ; Upper respiratory infection .
b- < 1%: Depression ; Lichen planus ; Photosensitivity ; Thrombocytopenia ; Vertigo .
c- Additional class – related events: Alopecia ; Anaphylaxis ; Angioedema ; Impotence ; Myalgia , myositis , or rhabdomyolysis ; Headache ; Nausea ; skin rash ; Insomnia ; Hepatitis ; Pancreatitis ; Hemolytic anemia ; Leukopenia ; Peripheral neuropathy

Hypersensitivity to simvastatin or any component of the formulation ; Acute liver disease ; Unexplained persistent elevations of serum transaminases ; Pregnancy ; Breast – feeding.

Secondary causes of hyperlipidemia should be ruled out prior to therapy . Liver function must be monitored by laboratory assessment . Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis . Use with caution in patients who consume large amounts of ethanol or have a history of liver disease.

Amiodarone, clofibrate, fenofibrate, cyclosporine, gemfibrozil and niacin may increase the risk of myopathy and rhabdomyolysis . Cholestyramine reduces absorption of simvastatin ; separate administration times by at least 4 hours . Atazanavir , clarithromycin . cyclosporine , danazole , diltiazem , fluconazole , fluvoxamine , erythromycin , indinavir , itraconazole , ketoconazole , miconazole , nefazodone , nelfinavir , ritonavir , saquinavir , amprenavir, and verapamil increase simvastatin blood level and may increase the risk of myopathy and rhabdomyolysis. Grapefruit juice may inhibit metabolism of simvastatin ; avoid high dietary intakes of grapefruit juice. Cholesterol – lowering effects of bile acid sequestrants (cholestyramine and colestipol ) and simvastatin are additive . Concurrent use of simvastatin with digoxin may cause an elevation in serum digoxin concentrations.

Monitor creatine phosphokinase levels and serum cholesterol. Patients titrated to the 80 mg dose should be tested for liver function tests prior to initiation and 3 months after initiating the 80 mg dose . Thereafter , periodic monitoring (ie , semiannually ) is recommended for the first year of treatment. Patients with elevated transaminase levels should have a second (confirmatory) test and frequent monitoring until values normalize. Discontinue if increase in ALT/AST is persistently > 3 times upper limit of normal.