RiteMED Simvastatin

Simvastatin.

Each tablet contains: Simvastatin 20 mg or 40 mg.

Pharmacology: Simvastatin is a gamma-lactone obtained by chemical modification of lovastatin. Hydrolysis of the lactone by esterases results in the dihydroxy acid known as simvastatin acid or SVA, which is the active form of the compound. This active metabolite is a competitive inhibitor of HMG-CoA reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway, which catalyzes the conversion of HMG-CoA to mevalonate.
The main mechanism of reduction of low density lipoprotein (LDL) cholesterol is that, following inhibition of HMG-CoA reductase activity, the LDL receptor density on the liver cells is increased (up regulation) and this leads to increased removal of LDL cholesterol from plasma and increased catabolism of LDL cholesterol. In addition, there is decreased production of very low-density lipoprotein (VLDL) cholesterol and reduced formation of LDL from VLDL. Inhibition of HMG-CoA reductase does not lead to a build-up of intermediary metabolites since this enzyme is involved early in the synthetic pathway for cholesterol.
Simvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, while increasing HDL. In one head-to-head study of simvastatin versus pravastatin involving 291 patients, simvastatin produced slightly greater improvements in total cholesterol, LDL and HDL cholesterol, and triglycerides after 6 weeks. Both drugs were given in an oral dose of 10 mg once daily. Higher doses can produce more dramatic results. Bedtime administration of the drug is recommended since there is evidence for diurnal variation in the hepatic synthesis of cholesterol.
Pharmacokinetics: Simvastatin is a prodrug and must be activated in the liver. Absorption is about 85%, but bioavailability is 5% due to extensive presystemic metabolism. Absorption is not significantly reduced if taken before a low-fat meal, but to optimize the action of simvastatin, it should be administered at bedtime. Peak plasma concentrations are reached in 1.3-2.4 hours. Both simvastatin and its active metabolite, simvastatin acid, are strongly bound to plasma proteins (98%).
Simvastatin is extensively metabolized in the liver, which is also its main site of action. Sixty percent of an oral dose is excreted in the feces and 13% in the urine. Half-life of simvastatin is 1.9 hours.
Pharmacokinetic studies of single and multiple doses of simvastatin showed no accumulation of simvastatin during multiple dosing.
The effects of liver disease on the kinetics of simvastatin are not known.

Coronary Heart Disease: In patients with coronary heart disease and hypercholesterolemia to decrease the risk of death; decrease the risk of fatal and non fatal myocardial infarction; decrease the incidence of stroke and transient ischemic attacks; decrease the risk of undergoing myocardial revascularization procedures (coronary artery bypass grafting and coronary angioplasty); slow the progression of coronary atherosclerosis.
Hyperlipidemia: To decrease total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride concentrations in the treatment of primary hypercholesterolemia (heterozygous familial and non-familial), homozygous familial hypercholesterolemia and mixed dyslipidemia.

The patient should be placed on a standard cholesterol-lowering diet before receiving simvastatin and should continue on this diet during treatment with Simvastatin.
Coronary Heart Disease: Initial Dose: 20 mg once daily at bedtime.
May be increased at intervals of not less than 4 weeks to a maximum of 80 mg once daily given as a single dose at bedtime.
Hyperlipidemia: Initial Dose: 20 mg once daily at bedtime.
Patients who require only a moderate reduction of LDL-C may be started at 10 mg once daily at bedtime.
Homozygous Familial Hypercholesterolemia: Initial Dose: 40 mg once daily at bedtime or 80 mg/day in 3 divided doses of 20, 20 and 40 mg given in the morning, afternoon and evening, respectively.
Renal Insufficiency: Initial Dose: 5 mg once daily at bedtime with close monitoring.
Initiating therapy in patients with severe renal insufficiency (creatinine clearance <30 mL/min) at a dose above 10 mg/day should be considered carefully and implemented cautiously.
Dose modification should not be necessary in patients with mild to moderate renal impairment because simvastatin does not undergo substantial renal excretion.
Or as prescribed by a physician.

Hypersensitivity to simvastatin or any component of of the preparation; acute liver disease or unexplained persistent elevations of serum transaminases; porphyria; pregnancy and breastfeeding; women of child-bearing potential unless adequately protected by barrier contraceptive methods.

An attempt should be made to lower cholesterol by other methods such as diet, exercise, and weight loss before instituting therapy with simvastatin. Any other medical problems that can cause high cholesterol should also be treated.
About 1 % of patients who took simvastatin in clinical trials developed elevated levels of some liver enzymes. Patients who had these increases usually had no symptoms. Elevated liver enzymes usually returned to normal levels when therapy with simvastatin was stopped.
Measure liver enzymes before starting treatment with simvastatin and periodically thereafter for the first year of treatment or until one year after the last elevation in dose. If enzyme levels increase, more frequent test should be ordered. If liver enzyme levels remain unusually high discontinue simvastatin.
Use simvastatin with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease. Since simvastatin is metabolized predominantly in the liver and potentially may accumulate in the plasma of patients with hepatic impairment, such patients should be monitored closely while receiving simvastatin therapy. Simvastatin is classified as FDA pregnancy category X. Its safe use during pregnancy has not been established. Rare reports of congenital abnormality have been received following intrauterine exposure to HMG-CoA reductase inhibitors. Since there is no apparent benefit to therapy with simvastatin during pregnancy, it should be immediately discontinued as soon as pregnancy is recognized. It should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of potential hazards.

Increased serum creatine kinase concentrations of at least 3 times the upper limit of normal on ≥1 occasions occurred in approximately 5% of patients receiving simvastatin in clinical trials.
Rhabdomyolysis with acute renal failure secondary to myoglobinuria has occurred rarely with simvastatin and has required drug discontinuance.
Simvastatin was extremely well tolerated in controlled clinical trials. Only 1.4% of subjects were discontinued from therapy due to the adverse effects of simvastatin. Adverse reactions tend to be transient and mild. Constipation (2.3%), dyspepsia (1.1%) and flatulence (1.9%) were the only adverse reactions reported at a higher incidence than placebo.
The following adverse reactions were reported in >1% of patients receiving simvastatin during clinical trials: Pain, asthenia, diarrhea, nausea/vomiting and headache.

Coumarin Derivatives: Simvastatin appeared to slightly enhance the anticoagulant effect of warfarin (mean changes in prothrombin time less than 2 s) in normal volunteers maintained in a state of low therapeutic anticoagulation. The clinical importance of these findings for fully anticoagulated patients receiving concomitant chronic therapy with simvastatin is unknown. In patients taking anticoagulants, prothrombin time should be determined prior to starting therapy with simvastatin and then monitored at the intervals usually recommended for patients on coumarin anticoagulants once a stable prothrombin time has been reached.
Digoxin: Concomitant administration of digoxin and simvastatin results in a slight increase (less than 0.3 micrograms per liter) in plasma digoxin levels.
Protease Inhibitors (Lopinavir/Nelfinavir) and Selected Azole Antifungals (Itraconazole/Ketoconazole): These group of drugs are known to inhibit the metabolism of some HMG-CoA reductase inhibitors at the cytochrome P450-3A4 isozyme. Concurrent administration may result in an increased levels of simvastatin, which may result in an increased risk of rhabdomyolysis.
Fibrates, Lipid-Lowering Doses of Niacin, Cyclosporine: Concurrent administration of simvastatin with these drugs has been associated with severe myopathy, rhabdomyolysis and acute renal failure.
Erythromycin: Erythromycin may inhibit the metabolism of HMG-CoA reductase inhibitors and concurrent administration may result in increased levels of simvastatin which may produce rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels and reddish-brown, hemepositive urine.
Verapamil/Diltiazem: Verapamil and diltiazem may increase the serum concentrations of simvastatin, a CYP3A4 substrate. The interaction is presumed to be due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism. In a drug interaction study with simvastatin, verapamil was reported to increase serum concentrations and the AUC.
Grapefruit Juice: Clinicians should be aware that some food products may interact with some HMG-CoA reductase inhibitors. Grapefruit juice contains an unknown compound that inhibits cytochrome P450 3A4 isozymes in the gut wall. Co-administration with grapefruit juice increases the peak serum concentrations and the AUC of simvastatin. Grapefruit juice should be avoided in patients taking these agents to avoid the potential for drug accumulation and toxicity (ie, myopathy and rhabdomyolysis).
Other Significant Interactions: In clinical studies, simvastatin was used concomitantly with beta-blockers, ACE inhibitors, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.

Store at temperatures not exceeding 30°C.

Dyslipidaemic Agents

C10AA01 - simvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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