(i) ROUTE OF ADMINISTRATION
Oral

DOSAGE AND ADMINISTRATION

The patient should be started on a standard cholesterol-lowering diet before receiving Simvastatin and should continue this diet during treatment.
The recommended starting dose is 5-10 mg once a day in the evening. The recommended dosing range is 5-40 mg/day as a single dose in the evening; the maximum recommended dose is 40 mg/day. Doses should be individualised according to baseline LDL-C levels, the recommended goal of therapy [see National Cholesterol Education Program (NCEP) guidelines] and the patient's response.
Patients requiring reductions in LDL cholesterol of 20% or more to achieve their goal should be started on 10 mg/day. A starting dose of 5 mg should be considered for patients requiring smaller reductions in LDL cholesterol, for the elderly and in patients with severe renal insufficiency. Adjustments of dosage should be made at intervals of 4 weeks or more.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of Simvastatin if cholesterol falls significantly below the targeted range.
The NCEP guidelines for initiation and goal of drug therapy are summarized below:

LDL-cholesterol (mmol/L) LDL-mg/dl (mmol/L) LDL-cholesterol mg/dl
Definite athero-sclerotic disease* Two or more other risk factors** Initiation level Goal
NO NO >=190(>=4.9) <160(<4.1)
NO YES >=160(>=4.1) <130(<3.4)
YES YES OR NO >=130(>=3.4) <=100(<=2.6)

* Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
** Other risk factors for coronary heart disease (CHD) include: age (males:³ 45 years; females: ³ 55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C < 35 mg/dl (< 0.91 mmol/L); and diabetes mellitus. Subtract one risk factor if HDL-C is ³ 60mg/dl (³ 1.6 mmol/L).
In the elderly Maximum reductions in LDL cholesterol may be achieved with daily doses of 20 mg simvastatin or less.

Patients with renal insufficiency Modification of dosage is not necessary in patients with mild to moderate renal insufficiency. However, caution should be exercised when simvastatin is administered to patients with severe renal insufficiency; such patients should be started at 5 mg/day and be closely monitored.

Concomitant therapy
In patients taking immunosuppressive drugs concomitantly with simvastatin, therapy should begin with 5 mg of simvastatin and should not exceed 10 mg/day

(ii) THERAPEUTIC / DIAGNOSTIC CLAIMS

Simvastatin is indicated in patients with coronary heart disease and hypercholesterolaemia, to reduce the risk of total mortality by reducing coronary death, to reduce the risk of non-fatal myocardial infarction and to reduce the risk for undergoing myocardial revascularization procedures.
Simvastatin is also indicated for the reduction of elevated total and LDL cholesterol in patients with primary hypercholesterolaemia (type IIa and IIb hyperlipoproteinemia).
Simvastatin is also indicated for reduction of elevated LDL cholesterol levels in patients with combined hypercholesterolaemia and hypertriglyceridaemia where hypercholes-terolaemia is the major abnormality (Type IIb hyperlipoproteinemia).

(iii) DESCRIPTION OF DOSAGE FORM

Simvastatin, a cholesterol lowering agent, is a specific inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin has been shown to reduce both normal and elevated low-density lipoprotein (LDL) cholesterol concentrations. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of very-low-density lipoprotein (VLDL) cholesterol, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL cholesterol. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin modestly reduces VLDL cholesterol and plasma triglycerides and can produce increases of variable magnitude in HDL cholesterol.

(iv) CONTRAINDICATIONS

Hypersensitivity, Active liver disease or unexplained persistent elevations of serum transaminases, Pregnancy and lactation.

WARNING AND PRECAUTIONS

DRUG INTERACTIONS
Immunosuppressive drugs, Gemfibrozil, Niacin (Nicotinic acid), Cyclosporine, Erythromycin: Rhabdomyolysis has been associated with other HMG-CoA reductase inhibitors when they were administered alone or concomitantly with these drugs.

Physicians contemplating combined therapy with simvastatin and gemfibrozil or lipid-lowering doses (=1g/day) of nicotinic acid, or with immunosuppressive drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Because of an apparent relationship between increased plasma levels of active metabolites derived from other HMG-CoA reductase inhibitors and myopathy, in patients taking cyclosporine, the daily dosage should not exceed 10 mg/day.

Itraconazole: The HMG-CoA reductase inhibitors and the azole derivative antifungal agents inhibit cholesterol biosynthesis at different points in the biosynthetic pathway. In patients receiving cyclosporine, simvastatin should be temporarily discontinued if systemic azole derivative antifungal therapy is required; patients not taking cyclosporine should be carefully monitored if systemic azole derivative antifungal therapy is required.

Cholestyramine or colestipol: Concurrent use may decrease the bioavailability of simvastatin.It is recommended that simvastatin be given four hours after administration of cholestyramine or colestipol.

Digoxin: Concomitant administration of digoxin and simvastatin may result in slight elevations in digoxin plasma concentrations. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.
Warfarin: Simvastatin may modestly potentiate the effect of coumarin anticoagulants. Hence in these patients, prothrombin time should be determined before starting simvastatin and during simvastatin therapy to ensure that no significant alteration of prothrombin time occurs.

PREGNANCY
Simvastatin may cause fetal harm when administered to a pregnant woman. Therefore, simvastatin is contraindicated during pregnancy. Simvastatin 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, simvastatin should be discontinued and the patient apprised of the potential hazard to the foetus.

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, simvastatin is contraindicated in nursing mothers. Women taking simvastatin should not nurse their infants.

PEDIATRIC USE Safety and effectiveness in children and adolescents have not been established. Hence treatment of children or adolescents with simvastatin is not recommended.

LIVER DYSFUNCTION Simvastatin may cause persistent increases in serum transaminases. It is recommended that liver function tests be performed before the initiation of treatment and periodically thereafter (e.g. semiannually). Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of therapy with simvastatin is recommended.
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.
Patients with renal insufficiency Caution should be exercised when simvastatin is administered to patients with severe renal insufficiency (See Dosage and administration)

OTHERS
Skeletal muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been associated with simvastatin therapy. Simvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Simvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

Elevation of creatine phosphokinases and transaminase levels
Simvastatin may cause elevation of creatine phosphokinase and transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with simvastatin.

Homozygous Familial Hypercholesterolaemia Simvastatin is less effective in patients with the rare homozygous familial hypercholestero-laemia, possibly because these patients have few functional LDL receptors.

Endocrine function HMG-CoA reductase inhibitors interfere with cholesterol synthesis and might blunt adrenal and/or gonadal steroid production; this has not been demonstrated clinically with simvastatin. Patients treated with simvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.

(v) SIDE EFFECTS

The drug is generally well tolerated. Adverse reactions have usually been mild and transient.Occasional undesirable effects include abdominal pain, asthenia, constipation, diarrhoea, dyspnea, flatulence, nausea, headache and upper respirator infections.

(vii) TOXIC EFFECTS

TERATOGENICITY
Animal studies showed increased incidences of foetal resorption at dosages of 50 mg/kg/day in rats and 15 mg/kg/day in rabbits. In another study, an increased incidence of skeletal malformations was observed in foetuses of rats dosed with the active metabolite of simvastatin, L-654, 969, at a dose level of 60 mg/kg/day. The no-effect dose level of this teratogenic activity has not been established. Other inhibitors of HMG-CoA reductase have also been shown to induce skeletal malformations in rats, and the teratogenic effects may be due to the enzyme inhibitory activity of such drugs. The relevance of these findings to humans is not known.

CARCINOGENICITY
In rats, the incidence of thyroid follicular adenoma was increased in females at doses greater than 5 mg/kg/day and in males at doses greater than 25 mg/kg/day. These thyroid tumours were associated with focal cystic follicular hyperplasia, and may be a secondary effect reflective of a simvastatin-mediated enhancement of thyroid hormone clearance by the liver.

MUTAGENICITY
Genetic toxicology studies of simvastatin showed no evidence of mutagenic activity in bacteria or in mammalian cells in vitro, or of clastogenic activity in vitro or in mice in vivo. In vitro and in vivo assays showed that simvastatin does not cause DNA damage in rat hepatocytes.Fertility of male and female rats was unaffected at oral doses up to 25 mg/kg/day.