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Indications/Uses
Used to reduce LDL-cholesterol, apolipoprotein B and triglycerides and to increase HDL-cholesterol in the treatment of hyperlipidemias including hypercholesterolemias, combined hyperlipidemia (type IIa or IIb), hyperlipoproteinemias, hypertriglyceridemia (type IV) and primary dysbetalipoproteinemia (type III).
Also used as an adjunct therapy in patients with homozygous familial hypercholesterolemia who have some residual LDL-receptor activity.
It also slows down the development of atherosclerosis in coronary arteries thus, preventing coronary events, strokes and reduce death caused by coronary heart disease (CHD).
Also used as an adjunct therapy in patients with homozygous familial hypercholesterolemia who have some residual LDL-receptor activity.
It also slows down the development of atherosclerosis in coronary arteries thus, preventing coronary events, strokes and reduce death caused by coronary heart disease (CHD).
Dosage/Direction for Use
Before the onset and during the duration of treatment with simvastatin, the patient must be on a standard cholesterol-lowering diet.
The dosage of simvastatin should be adjusted based on individual requirement, target treatment outcome and the response of the patient.
Initial Dose: 10-20 mg once a day in the evening, with a maximum of 40 mg/day for patients who have high cardiovascular risk. The dose is adjusted at intervals of at least 4 weeks after the start of therapy with simvastatin up to a maximum of 80 mg/day in the evening.
Heterozygous Familial Hypercholesterolemia: Treatment in boys and postmenarchal girls 10-17 years is initiated at 10 mg with a maximum dose of 40 mg/day to be taken in the evening. The dosage may be increased based on the patient's response to Cholestrol.
Homozygous Familial Hypercholesterolemia: Recommended Dose: 40 mg/day in the evening or 80 mg/day given in 3 divided doses (20 mg, 20 mg and an evening dose of 40 mg).
CHD or Corresponding CHD Risks: Initial Dose: 20 mg/day.
In patients with CHD, CHD risks and would require a reduction of >45% LDL-cholesterol, the initial dose is 40 mg with a maximum of 80 mg/day in the evening as a single dose. The dosage may be adjusted at intervals of at least 4 weeks until the desired plasma level of lipoprotein is reached. Maintenance dose is 5-80 mg/day and ≤20 mg for the elderly.
Concomitant Therapy: Simvastatin is useful alone or with bile acid-binding resins in lowering elevated plasma levels of LDL. If given with niacin and bile acid-binding resins eg, cholestyramine, simvastatin should be administered for ≥1 hr before or 2-4 hrs after the resin to ensure absorption (see Adverse Reactions).
Concomitant use of simvastatin with cyclosporine requires that the patient receives an initial dose of 5 mg/day and should not exceed 10 mg/day.
With danazol, niacin and fibric acid derivatives (except fenofibrate), dose of simvastatin should not exceed 10 mg/day.
With amiodarone or verapamil, dose of simvastatin should not exceed 20 mg/day.
Renal Impairment: The dosage of simvastatin in patients with renal impairment need not to be adjusted, since Cholestrol does not undergo substantial renal excretion. However, for patients with severe renal impairment and increased risk of myopathy and rhabdomyolysis, simvastatin 5 mg is recommended to be given initially to the patient. Doses of simvastatin >10 mg should be administered with caution in patients who consume large amounts of alcohol, since simvastatin is metabolized mainly in the liver (see also Precautions).
Hepatic Impairment: Simvastatin should not be given to patients with active liver disease or in patients with unexplained persistent increase in concentrations of serum transaminases. It should also be used with caution in patients who consume large amounts of alcohol since simvastatin is metabolized mainly in the liver (see also Precautions).
Administration: For optimal efficacy in lowering LDL-cholesterol, it is advised that simvastatin be administered orally in the evening because the rate of cholesterol synthesis by the liver is greatest at night. Although absorption in the GIT is not affected to a large extent, simvastatin may be taken with food to enhance the absorption of Cholestrol by the body.
The dosage of simvastatin should be adjusted based on individual requirement, target treatment outcome and the response of the patient.
Initial Dose: 10-20 mg once a day in the evening, with a maximum of 40 mg/day for patients who have high cardiovascular risk. The dose is adjusted at intervals of at least 4 weeks after the start of therapy with simvastatin up to a maximum of 80 mg/day in the evening.
Heterozygous Familial Hypercholesterolemia: Treatment in boys and postmenarchal girls 10-17 years is initiated at 10 mg with a maximum dose of 40 mg/day to be taken in the evening. The dosage may be increased based on the patient's response to Cholestrol.
Homozygous Familial Hypercholesterolemia: Recommended Dose: 40 mg/day in the evening or 80 mg/day given in 3 divided doses (20 mg, 20 mg and an evening dose of 40 mg).
CHD or Corresponding CHD Risks: Initial Dose: 20 mg/day.
In patients with CHD, CHD risks and would require a reduction of >45% LDL-cholesterol, the initial dose is 40 mg with a maximum of 80 mg/day in the evening as a single dose. The dosage may be adjusted at intervals of at least 4 weeks until the desired plasma level of lipoprotein is reached. Maintenance dose is 5-80 mg/day and ≤20 mg for the elderly.
Concomitant Therapy: Simvastatin is useful alone or with bile acid-binding resins in lowering elevated plasma levels of LDL. If given with niacin and bile acid-binding resins eg, cholestyramine, simvastatin should be administered for ≥1 hr before or 2-4 hrs after the resin to ensure absorption (see Adverse Reactions).
Concomitant use of simvastatin with cyclosporine requires that the patient receives an initial dose of 5 mg/day and should not exceed 10 mg/day.
With danazol, niacin and fibric acid derivatives (except fenofibrate), dose of simvastatin should not exceed 10 mg/day.
With amiodarone or verapamil, dose of simvastatin should not exceed 20 mg/day.
Renal Impairment: The dosage of simvastatin in patients with renal impairment need not to be adjusted, since Cholestrol does not undergo substantial renal excretion. However, for patients with severe renal impairment and increased risk of myopathy and rhabdomyolysis, simvastatin 5 mg is recommended to be given initially to the patient. Doses of simvastatin >10 mg should be administered with caution in patients who consume large amounts of alcohol, since simvastatin is metabolized mainly in the liver (see also Precautions).
Hepatic Impairment: Simvastatin should not be given to patients with active liver disease or in patients with unexplained persistent increase in concentrations of serum transaminases. It should also be used with caution in patients who consume large amounts of alcohol since simvastatin is metabolized mainly in the liver (see also Precautions).
Administration: For optimal efficacy in lowering LDL-cholesterol, it is advised that simvastatin be administered orally in the evening because the rate of cholesterol synthesis by the liver is greatest at night. Although absorption in the GIT is not affected to a large extent, simvastatin may be taken with food to enhance the absorption of Cholestrol by the body.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to simvastatin or any component of Cholestrol. It should not be given to patients who have active liver disease, rhabdomyolysis, severe hypotension and infection, trauma or major surgery, uncontrolled epilepsy, myopathy with CPK elevation and severe renal disease.
Simvastatin should not be administered to patients with history or presence of active liver disease or with unexplained persistent increase in serum aminotransferase concentrations. If marked or persistent increase in serum aminotransferase is observed, treatment with simvastatin should be discontinued.
Use in Pregnancy & Lactation: Pregnant and lactating mothers should not be given Cholestrol, as it may harm the fetus or infant.
US FDA Pregnancy Category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience and the risks involved in the use of Cholestrol in pregnant women clearly outweigh potential benefits.
Simvastatin should not be given to women who are pregnant or are likely to become pregnant, since it slows down the production of cholesterol and possibly other products of the cholesterol biosynthesis pathway, which are needed for the proper development of the fetus. For pregnant women with dyslipidemia, dietary management is advised.
If the patient becomes pregnant while on treatment with simvastatin, Cholestrol should be discontinued. The physician should see to it that the patient understand the potential harm of simvastatin to the fetus.
There is no available data yet confirming the excretion of simvastatin in breast milk. Still, simvastatin should not be given to lactating women as it may be harmful to nursing infants.
Simvastatin should not be administered to patients with history or presence of active liver disease or with unexplained persistent increase in serum aminotransferase concentrations. If marked or persistent increase in serum aminotransferase is observed, treatment with simvastatin should be discontinued.
Use in Pregnancy & Lactation: Pregnant and lactating mothers should not be given Cholestrol, as it may harm the fetus or infant.
US FDA Pregnancy Category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience and the risks involved in the use of Cholestrol in pregnant women clearly outweigh potential benefits.
Simvastatin should not be given to women who are pregnant or are likely to become pregnant, since it slows down the production of cholesterol and possibly other products of the cholesterol biosynthesis pathway, which are needed for the proper development of the fetus. For pregnant women with dyslipidemia, dietary management is advised.
If the patient becomes pregnant while on treatment with simvastatin, Cholestrol should be discontinued. The physician should see to it that the patient understand the potential harm of simvastatin to the fetus.
There is no available data yet confirming the excretion of simvastatin in breast milk. Still, simvastatin should not be given to lactating women as it may be harmful to nursing infants.
Special Precautions
Patients with Hepatic Impairment: Simvastatin is mainly metabolized in the liver. Concentrations of Cholestrol in the plasma may accumulate in the liver of patients with hepatic impairment, history of liver disease and those who consume large amounts of alcohol. It is advised that monitoring of liver function tests (LFTs) should be done prior to initiation of simvastatin therapy. This should be repeated semi-annually on the 1st year of treatment or until 1 year after the last dose of Cholestrol is increased. Liver function test monitoring may be done with periodic serum lipoprotein concentration monitoring.
Further, if the patient is taking a daily dose of 80 mg/day, LFTs should be checked after the first 3 months of treatment. When the LFTs are observed to increase, the test should be repeated until the values return to normal. If the LFTs are 3 times more than the upper limit of normal, simvastatin must be discontinued.
Use in Children: In general, simvastatin should not be given to children except those with homozygous familial hypercholesterolemia with residual LDL-receptor activity. There is limited information available regarding the effectivity of simvastatin in lowering total cholesterol and LDL-cholesterol in children >10 years.
Use in Elderly: Clinical trials reveal that safety and efficacy outcomes of simvastatin in elderly patients ≥65 years are found similar to those in younger adults.
Use in Elderly Patients with Renal Impairment: In the presence of severe renal impairment, dosage of simvastatin to geriatric patients ≥70 years, should be adjusted. Close monitoring of the renal function of patients should be done (see Dosage & Administration).
Further, if the patient is taking a daily dose of 80 mg/day, LFTs should be checked after the first 3 months of treatment. When the LFTs are observed to increase, the test should be repeated until the values return to normal. If the LFTs are 3 times more than the upper limit of normal, simvastatin must be discontinued.
Use in Children: In general, simvastatin should not be given to children except those with homozygous familial hypercholesterolemia with residual LDL-receptor activity. There is limited information available regarding the effectivity of simvastatin in lowering total cholesterol and LDL-cholesterol in children >10 years.
Use in Elderly: Clinical trials reveal that safety and efficacy outcomes of simvastatin in elderly patients ≥65 years are found similar to those in younger adults.
Use in Elderly Patients with Renal Impairment: In the presence of severe renal impairment, dosage of simvastatin to geriatric patients ≥70 years, should be adjusted. Close monitoring of the renal function of patients should be done (see Dosage & Administration).
Use In Pregnancy & Lactation
Pregnant and lactating mothers should not be given Cholestrol, as it may harm the fetus or infant.
US FDA Pregnancy Category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience and the risks involved in the use of Cholestrol in pregnant women clearly outweigh potential benefits.
Simvastatin should not be given to women who are pregnant or are likely to become pregnant, since it slows down the production of cholesterol and possibly other products of the cholesterol biosynthesis pathway, which are needed for the proper development of the fetus. For pregnant women with dyslipidemia, dietary management is advised.
If the patient becomes pregnant while on treatment with simvastatin, Cholestrol should be discontinued. The physician should see to it that the patient understand the potential harm of simvastatin to the fetus.
There is no available data yet confirming the excretion of simvastatin in breast milk. Still, simvastatin should not be given to lactating women as it may be harmful to nursing infants.
US FDA Pregnancy Category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience and the risks involved in the use of Cholestrol in pregnant women clearly outweigh potential benefits.
Simvastatin should not be given to women who are pregnant or are likely to become pregnant, since it slows down the production of cholesterol and possibly other products of the cholesterol biosynthesis pathway, which are needed for the proper development of the fetus. For pregnant women with dyslipidemia, dietary management is advised.
If the patient becomes pregnant while on treatment with simvastatin, Cholestrol should be discontinued. The physician should see to it that the patient understand the potential harm of simvastatin to the fetus.
There is no available data yet confirming the excretion of simvastatin in breast milk. Still, simvastatin should not be given to lactating women as it may be harmful to nursing infants.
Adverse Reactions
The adverse effects associated with the use of simvastatin are usually mild and transient. The most common side effects experienced are GI problems (ie, flatus, diarrhea, abdominal pain or cramps, constipation and heartburn). Other adverse effects include headache, dizziness, blurred vision, insomnia, dysgeusia, rash or pruritus and other hypersensitivity reactions to include angioedema and anaphylaxis. Hepatitis and pancreatitis were also reported.
Simvastatin may elevate levels of creatinine phosphokinase (CPK) mildly. This increase in CPK levels is significant to patients with myalgia or myopathy and patients who are taking simvastatin concurrently with cyclosporine, fibric acid derivatives or nicotinic acid.
Levels of creatinine kinase should be measured before treatment with simvastatin and every 4 months, thereafter. Further, if the patient experiences significant weakness, myalgia or myopathy, creatinine kinase activity must be obtained. If CPK activity exceeds twice its normal value, then Cholestrol should be discontinued. Upon cessation of Cholestrol, myopathy immediately disappears.
Increased risk of rhabdomyolysis with acute renal failure is associated with the use of simvastatin.
As reversible increase in levels of serum aminotransferases may occur, liver function of the patient must be assessed before the start of the treatment with simvastatin.
Other adverse effects associated with the use of simvastatin, which in most cases are improved with discontinuance of Cholestrol are thrombocytopenic purpura, cataract (with concurrent erythromycin use), alopecia, proteinuria, reduction in measures of cognitive functions, neuropathy and impotence.
Simvastatin may elevate levels of creatinine phosphokinase (CPK) mildly. This increase in CPK levels is significant to patients with myalgia or myopathy and patients who are taking simvastatin concurrently with cyclosporine, fibric acid derivatives or nicotinic acid.
Levels of creatinine kinase should be measured before treatment with simvastatin and every 4 months, thereafter. Further, if the patient experiences significant weakness, myalgia or myopathy, creatinine kinase activity must be obtained. If CPK activity exceeds twice its normal value, then Cholestrol should be discontinued. Upon cessation of Cholestrol, myopathy immediately disappears.
Increased risk of rhabdomyolysis with acute renal failure is associated with the use of simvastatin.
As reversible increase in levels of serum aminotransferases may occur, liver function of the patient must be assessed before the start of the treatment with simvastatin.
Other adverse effects associated with the use of simvastatin, which in most cases are improved with discontinuance of Cholestrol are thrombocytopenic purpura, cataract (with concurrent erythromycin use), alopecia, proteinuria, reduction in measures of cognitive functions, neuropathy and impotence.
Drug Interactions
Since myopathy and rhabdomyolysis may develop with the use of simvastatin, drugs that can cause myopathy when given alone eg, fibric acid derivatives (ie, gemfibrozil and clofibrate) and nicotinic acid, may increase the risk of myopathy with simvastatin (see Dosage & Administration).
If simvastatin is administered with CYP3A4 inhibitors, the plasma level of Cholestrol shall be increased, thereby, increasing the risk of side effects. CYP3A4 inhibitors include azole antifungals (ketoconazole, itraconazole), erythromycin, clarithromycin, cyclosporine, HIV protease inhibitors (ritonavir, nelfinavir, saquinavir), amiodarone, verapamil, nefazodone and diltiazem.
Co-administration of simvastatin with diltiazem and amlodipine also increases the plasma concentrations of simvastatin and increased risk of myopathy. With diltiazem, there was a reduction of total cholesterol and LDL-cholesterol levels observed. However, with concurrent treatment of amlodipine, the increase (30% AUC) is not sufficient to alter the pharmacodynamic response of simvastatin.
When simvastatin is prescribed with warfarin or coumarin anticoagulants, the hypoprothrombinemic response of Cholestrol may be increased, thereby, increasing prothrombin time. Cases of bleeding have also been reported. It is advised that rate of prothrombin time be monitored closely if treatment with simvastatin is initiated or discontinued. However, in at least 1 clinical trial, simvastatin did not affect the antiplatelet activity of clopidogrel.
Although, the additive effect of bile acid-binding resins eg, cholestyramine and niacin, are useful in treating disorders involving elevated levels of LDL-cholesterol in the circulation, these bile acid sequestrants may bind or delay absorption of simvastatin. Thus, it is advised that simvastatin be given ≥1 hr before or 2-4 hrs after administering the resin.
A patient under treatment with simvastatin may exhibit a reduced response to the drug when phenytoin was added for epilepsy. Phenytoin induces the CYP3A4 isoform, which is involved in statin metabolism. Increase in cholesterol level ceases when phenytoin is discontinued.
Rifampicin, an inducer of CYP3A4, may also reduce the patient's response to Cholestrol by reducing the plasma concentration of simvastatin in the blood.
Reports of rhabdomyolysis with concurrent use of warfarin and fusidic acid have also been reported.
Concomitant use of simvastatin with grapefruit juice increases the concentration of antihyperlipidemic drugs in the blood thereby, increasing the risk of potential adverse effects. Thus, simvastatin should not be administered along with large quantity of grapefruit juice.
If simvastatin is administered with CYP3A4 inhibitors, the plasma level of Cholestrol shall be increased, thereby, increasing the risk of side effects. CYP3A4 inhibitors include azole antifungals (ketoconazole, itraconazole), erythromycin, clarithromycin, cyclosporine, HIV protease inhibitors (ritonavir, nelfinavir, saquinavir), amiodarone, verapamil, nefazodone and diltiazem.
Co-administration of simvastatin with diltiazem and amlodipine also increases the plasma concentrations of simvastatin and increased risk of myopathy. With diltiazem, there was a reduction of total cholesterol and LDL-cholesterol levels observed. However, with concurrent treatment of amlodipine, the increase (30% AUC) is not sufficient to alter the pharmacodynamic response of simvastatin.
When simvastatin is prescribed with warfarin or coumarin anticoagulants, the hypoprothrombinemic response of Cholestrol may be increased, thereby, increasing prothrombin time. Cases of bleeding have also been reported. It is advised that rate of prothrombin time be monitored closely if treatment with simvastatin is initiated or discontinued. However, in at least 1 clinical trial, simvastatin did not affect the antiplatelet activity of clopidogrel.
Although, the additive effect of bile acid-binding resins eg, cholestyramine and niacin, are useful in treating disorders involving elevated levels of LDL-cholesterol in the circulation, these bile acid sequestrants may bind or delay absorption of simvastatin. Thus, it is advised that simvastatin be given ≥1 hr before or 2-4 hrs after administering the resin.
A patient under treatment with simvastatin may exhibit a reduced response to the drug when phenytoin was added for epilepsy. Phenytoin induces the CYP3A4 isoform, which is involved in statin metabolism. Increase in cholesterol level ceases when phenytoin is discontinued.
Rifampicin, an inducer of CYP3A4, may also reduce the patient's response to Cholestrol by reducing the plasma concentration of simvastatin in the blood.
Reports of rhabdomyolysis with concurrent use of warfarin and fusidic acid have also been reported.
Concomitant use of simvastatin with grapefruit juice increases the concentration of antihyperlipidemic drugs in the blood thereby, increasing the risk of potential adverse effects. Thus, simvastatin should not be administered along with large quantity of grapefruit juice.
Storage
Store at temperatures not exceeding 30°C.
Action
Simvastatin, an antihyperlipidemic drug, is a synthetic structural analogue of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) and belongs to the HMG-CoA reductase inhibitor group known as statins.
Pharmacology: Simvastatin, when hydrolyzed to its active form, acts by competing with the reduced intermediate of HMG-CoA to inhibit HMG-CoA reductase from synthesizing mevalonic acid, which is a precursor of cholesterol. HMG-CoA reductase is the rate-limiting enzyme involved in sterol biosynthesis.
Free HMG-CoA is then metabolized back to acetyl-CoA and is available for many other processes in the body.
The inhibition of HMG-CoA reductase induces the increase of high-affinity low-density lipoproteins (LDL) receptors. This leads to the increased catabolic rate of LDL-cholesterol and the extraction of LDL precursors, very-low density (VDRL) remnants, by the liver; thus, reducing the pool of LDL-cholesterol in the blood.
Simvastatin causes a beneficial increase in concentrations of HDL-cholesterol in the blood and is associated with a decrease in plasma triglycerides.
Pharmacokinetics: Simvastatin is an active lactone prodrug which, upon ingestion, is hydrolyzed in the gastrointestinal tract (GIT) to its β-hydroxyacid form, simvastalic acid. It undergoes extensive first-pass metabolism in the liver and produces several oxidation products by cytochrome P-450 isoenzyme CYP3A4. Only a small proportion of the dose, <5% reaches the systemic circulation as active metabolites.
Both simvastatin and its active metabolite are 95% protein bound. Although mainly are excreted in the bile, about 10-15% of the metabolites are recovered in the urine as inactive forms. The t½ is 1.9 hrs for its active metabolite.
Pharmacology: Simvastatin, when hydrolyzed to its active form, acts by competing with the reduced intermediate of HMG-CoA to inhibit HMG-CoA reductase from synthesizing mevalonic acid, which is a precursor of cholesterol. HMG-CoA reductase is the rate-limiting enzyme involved in sterol biosynthesis.
Free HMG-CoA is then metabolized back to acetyl-CoA and is available for many other processes in the body.
The inhibition of HMG-CoA reductase induces the increase of high-affinity low-density lipoproteins (LDL) receptors. This leads to the increased catabolic rate of LDL-cholesterol and the extraction of LDL precursors, very-low density (VDRL) remnants, by the liver; thus, reducing the pool of LDL-cholesterol in the blood.
Simvastatin causes a beneficial increase in concentrations of HDL-cholesterol in the blood and is associated with a decrease in plasma triglycerides.
Pharmacokinetics: Simvastatin is an active lactone prodrug which, upon ingestion, is hydrolyzed in the gastrointestinal tract (GIT) to its β-hydroxyacid form, simvastalic acid. It undergoes extensive first-pass metabolism in the liver and produces several oxidation products by cytochrome P-450 isoenzyme CYP3A4. Only a small proportion of the dose, <5% reaches the systemic circulation as active metabolites.
Both simvastatin and its active metabolite are 95% protein bound. Although mainly are excreted in the bile, about 10-15% of the metabolites are recovered in the urine as inactive forms. The t½ is 1.9 hrs for its active metabolite.
MedsGo Class
Dyslipidaemic Agents
Features
Brand
Cholestrol
Full Details
Dosage Strength
20mg
Drug Ingredients
- Simvastatin
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Simvastatin
Dosage Form
Film-Coated Tablet
Registration Number
DRP-1375
Drug Classification
Prescription Drug (RX)