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Simvor

Simvastatin Tablets

DESCRIPTION

Simvastatin is an HMG-CoA reductase inhibitor used in the treatment of hypercholesterolemia. Simvastatin is chemically designated as (1S, 3R,7S, 8S, 8aR),1,2,3,7,8,8a-hexahydro-3, 7-dimethyl-8- [2-((2R, 4R) tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthyl 2,2-dimethyl-butyrate. Its empirical formula is C₂₅H₃₈O₅ and its molecular weight is 418.6.

PHARMACOLOGY

Mechanism of Action

HMG-CoA reductase catalyses the conversion of HMG-CoA to mevalonate, which is the major rate limiting step in the cholesterol synthesis pathway. Simvastatin after gastrointestinal absorption, is readily hydrolysed to the open beta-hydroxy acid which is a potent competitive inhibitor of HMG-CoA reductase, as a result cholesterol synthesis is inhibited. The primary site of action of HMG-CoA reductase inhibitors is the liver. Inhibition of cholesterol synthesis in the liver leads to upregulation of LDL-receptors and an increase in LDL- catabolism.

There may also be some reduction of LDL production as a result of inhibition of hepatic synthesis of very low density lipoprotein (VLDL), the precursor of LDL-cholesterol. Simvastatin reduces total cholesterol, LDL cholesterol and triglycerides by 25%, 35% and 10% respectively. The increase in HDL is up to 12%.

PHARMACOKINETICS

Simvastatin, after absorption from gastrointestinal tract, undergoes extensive first pass metabolism in liver – its primary site of action. As a consequence, the availability of drug to the general circulation is low and variable. Less than 5% of the oral dose has been reported to reach the circulation as the active metabolite. It is highly bound to plasma proteins (95%). Time to reach peak concentration is 1.3 to 2.4 hours.

Simvastatin is hydrolysed in liver to its active β-hydroxy acid form. Three other metabolites also have been isolated as 6-hydroxy, 6-hydroxy methyl and 6-exomethylene derivatives.

Simvastatin is eliminated primarily through the faecal route which is mainly the unabsorbed fraction of the drug and forms 60% of the orally administered dose. About 13% of the drug is eliminated by the renal route. The half-life of the active metabolite is 1.9 hour.

{ SIMVOR is indicated as an adjunct to diet inpatients with primary hypercholesterolemia (type IIa and IIb hyperlipoproteinemia) caused by elevated low density lipoprotein (LDL) cholesterol concentrations in patients with a significant risk of coronary artery disease, who have not responded to diet or other measures alone }. SIMVOR is also indicated for reduction of elevated LDL cholesterol levels inpatients with combined hypercholesterolemia and hypertriglyceridemia.

DOSAGE AND ADMINISTRATION

The recommended starting dose is 5 -10 mg per day in the evening. The maximum recommended dose is 80 mg/day. Doses should be individualised according to patient's response. General Recommendations Prior to initiating therapy with simvastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (< 4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = total-C [(0.20xTG) + HDL-C]

For TG levels > 400 mg/dL (> 4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or normal despite elevated total-C. In such cases, simvastatin is not indicated.

Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted according to the patient's response to therapy.

The NCEP Treatment Guidelines are summarized in the Table below :

Summary of NCEP Treatment Gideline

LDL-Cholesterol mg/dL (mmol/L)

* Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease),

** Other risk factors for coronary heart disease (CHD) include: age (males: 45 years; females: 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 60 mg/dL (1.6 mmol/L).

*** In CHD patients with LDL-C levels 100-129 mg/dL, the physician should exercise clinical judgment in deciding whether to initiate drug treatment.

At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is 130 mg/dL (see NCEP Treatment Guidelines, above).

Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy.

Dosage in Patients with Renal Insufficiency

Because simvastatin 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 simvastatin is administered to patients with severe renal insufficiency; such patients should be started at 5 mg/day and be closely monitored.

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