Azterol

Azterol

simvastatin

Manufacturer:

S Kant Healthcare

Distributor:

International Apex
Full Prescribing Info
Contents
Simvastatin.
Description
20 mg: Each film-coated tablet contains 20 mg Simvastatin.
40 mg: Each film-coated tablet contains 40 mg Simvastatin.
Action
Pharmacology: Pharmacodynamics: Simvastatin, a cholesterol lowering agent, is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductases, 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 high density lipoprotein (HDL) cholesterol.
Pharmacokinetics: Simvastatin is absorbed from the gastrointestinal tract and must be hydrolyzed to its active β-hydroxyacid form. Other active metabolites have been detected and a number of inactive metabolites are also formed. Simvastatin is a substrate for the cytochrome P450 isoenzyme CYP3A4 and undergoes extensive first-pass metabolism in the liver, its primary site of action. Less than 5% of the oral dose has been reported to reach the circulation as active metabolites. Both simvastatin and its β-hydroxyacid metabolite are about 95% bound to plasma proteins. Simvastatin is mainly excreted in the faeces via the bile as metabolites. About 10 to 15% is recovered in the urine, mainly in inactive forms. The half-life of the active β-hydroxyacid metabolite is 1.9 hours.
Indications/Uses
Simvastatin is indicated in patients with coronary heart disease and hypercholesterolemia, to reduce the risk of total mortality by reducing coronarydeath, to reduce the risk of non-fatal myocardial infarction and to reduce the risk for undergoing myocardial revascularization procedures.
Reduction of elevated total and LDL cholesterol in patients with primary hypercholesterolemia (type IIa and IIb hyperlipoproteinemia.)
Reduction of elevated LDL cholesterol levels in patients with combined hypercholesterolemia and hypertriglyceridaemia where hypercholesterolemia is the major abnormality (type IIb hyperlipoproteinemia).
Dosage/Direction for Use
Adult: For the treatment of hyperlipidaemias, the usual initial dose is 10 to 20 mg in the evening; an initial dose of 40 mg may be used in patients who require a large reduction in cholesterol or who are at high cardiovascular risk. The dose may be adjusted at intervals of not less than 4 weeks up to a maximum of 80 mg once daily in the evening. Patients with homozygous familial hypercholesterolemia may be treated with 40 mg once daily in the evening or 80 mg daily in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg.
For cardiovascular risk reduction in high-risk patients, disease or diabetes mellitus, the usual dose is 20 to 40 mg once daily. Patients who are at moderate risk may be given a dose of 10 mg once daily. The dose of simvastatin should be reduced in patients at risk of myopathy, including patients with severe renal impairment.
For patients taking drugs that interact with simvastatin, dose reduction is also advised, as follows: ciclosporin or danazol, initial dose 5 mg once daily and maximum dose 10 mg once daily; gemfibrozil or other fibrates, or nicotinic acid, maximum dose 10 mg once daily; amiodarone or verapamil, maximum dose 20 mg once daily; diltiazem, maximum dose 40 mg once daily.
Children: The management of hyperlipidaemias in children and adolescents is controversial and is usually reserved for those with familial hyperlipidaemias who have a high risk of premature cardiovascular disease.
The BNFC recommends the following doses for children with hyperlipidaemia: age 5 to 10 years: initial dose 5 mg at night, increased if necessary at intervals of at least 4 weeks to a maximum dose of 20 mg at night; age 10 to 18 years: initial dose 10 mg at night, increased if necessary at intervals of at least 4 weeks to a maximum dose of 40 mg at night.
Administration in renal impairment: Simvastatin appears to be safe and effective in patients with dyslipidaemia and renal impairment, and there is some evidence that they may have beneficial effects on renal function. Patients with severe renal impairment may be at increased risk of developing myopathy or rhabdomyolysis and lower doses may be appropriate in such patients. Dose reduction may also be needed for statins that are excreted by the kidneys. Simvastatin does not undergo significant renal excretion and no dose modification is required in patients with mild or moderate renal impairment. However, in patients with severe renal impairment the recommended initial dose is 5 mg once daily and doses above 10 mg once daily should be used with caution.
In the Elderly: Maximum reduction 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 immunosuppresive drugs concomitantly with Simvastatin, therapy should begin with 5 mg of Simvastatin and should not exceed 10 mg/day.
Contraindications
Contraindicated in patients with hypersensitivity to the drug or any of its components.
Special Precautions
Liver disease: Simvastatin should not be given to patients with active liver disease. Liver function should be assessed before starting treatment and subsequently when clinically indicated; additional assessment after 3 months and before and after dosage increases has been advised for some statins, particularly when high doses are given. Statins should not be used in patients who already have unexplained persistently raised serum-aminotransferase concentrations and should be stopped if marked or persistent increases in serum-aminotransferase concentrations occur.
Myopathy: Simvastatin may cause myopathy and rhabdomyolysis, especially at higher doses. Should be stopped if creatine phosphokinase increases significantly or if myopathy is diagnosed. Should be used with caution in patients with renal impairment as the risk of myopathy is increased.
Use in 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 fetus.
Use In Pregnancy & Lactation
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 fetus.
Adverse Reactions
The most common adverse effects of therapy with simvastatin and other statins are gastrointestinal disturbances. Other adverse effects reported include headache, skin rashes, dizziness, blurred vision, insomnia, and dysgeusia. Reversible increases in serum-aminotransferase concentrations may occur and liver function should be monitored. Hepatitis and pancreatitis have been reported. Hypersensitivity reactions including anaphylaxis and angioedema have also occurred. Myopathy, characterized by myalgia and muscle weakness and associated with increased creatine phosphokinase concentrations, has been reported, especially in patients also taking ciclosporin, fibric acid derivatives, or nicotinic acid. Rarely, rhabdomyolysis with acute renal failure may develop.
Effects on the blood pressure: Transient symptomatic hypotension was reported in 3 patients on simvastatin. Two of the patients were also taking antihypertensive medication.
Effects on the kidneys: Proteinuria was reported in 10 patients taking Simvastatin 40 mg daily. The protein loss was of a pattern typical for increased glomerular permeability. In 2 patients proteinuria disappeared when simvastatin was withdrawn and recurred on its subsequent reintroduction.
Effects on the liver: Statins cause dose-related increases in liver enzymes but the incidence appears to be low with low to moderate doses and serious hepatic effects appear to be rare. Monitoring of liver function tests is advised, the value of routine assessment has been questioned. There is some evidence that the incidence of hepatic reactions may be higher with fluvastatin than with other statins, but this is not yet established.
Effects on sleep patterns: For reports on the effects of HMG-CoA reductase inhibitors, including Simvastatin, on sleep patterns, a reduction in the length of continuous sleep was observed.
Effects on mental function: There have been conflicting reports of the effects of statins on mental function and a number of adverse psychiatric reactions have been reported with statins and with other lipid regulating drugs, although the exact association is unclear. There have been a few case reports of depressive symptoms developing in patients treated with pravastatin or simvastatin. Epidemiological studies have suggested that use of statins may be associated with improved psychological status and a reduction in the risk of depression and suicide.
Porphyria: Simvastatin was considered to be unsafe in patients with acute porphyria because it has been shown to be porphyrinogenic in animals or in vitro systems.
Drug Interactions
Immunosuppresive 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 immunosuppresive 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. The most serious consequence of drug interactions with simvastatin and other statins is the development of myopathy or rhabdomyolysis. Drugs that can cause myopathy when given alone increase the risk of myopathy with all statins; these drugs include fibric acid derivatives (fibrates or gemfibrozil), and nicotinic acid. The risk of myopathy is also increased by drugs that increase the plasma concentrations of statins, by inhibiting their metabolism or by inhibiting their uptake into the liver. Since the statins have different metabolic pathways, these interactions depend on the individual drug concerned. Simvastatin is metabolized by the cytochrome P450 isoenzyme CYP3A4, as are atorvastatin and lovastatin, and interactions may occur with drugs that inhibit this enzyme, including ciclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV-protease inhibitors, nefazodone, danazol, amiodarone, and verapamil; there may also be a similar interaction with grapefruit juice. Such combinations should be used with caution, if at all, and dose reduction may be advised. Contraindicates the use of simvastatin in patients receiving potent CYP3A4 inhibitor (see as follows under Fruit Juices).
Antidepressants: Myositis and rhabdomyolysis, with raised liver enzyme values, have been reported in patients given simvastatin with nefazodone; in one case the reaction appeared to be precipitated by the addition of azithromycin. Increased creatine kinase concentrations also occurred in a patient given pravastatin with nefazodone.
Antibacterial: Erythromycin and other macrolides are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma concentrations and the risk of myopathy with some statins. Increased plasma concentrations of simvastatin have been reported with erythromycin. There have been reports of myopathy or rhabdomyolysis in patients receiving simvastatin with clarithromycin, and in patients receiving lovastatin with azithromycin, clarithromycin, or erythromycin. Rifampicin, an inducer of CYP2C9 and CYP3A4, may reduce the bioavailability of fluvastatin, and has also been reported to reduce the plasma concentration of simvastatin and atorvastatin.
Antifungals: Itraconazole and ketoconazole are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma concentrations and the risk of myopathy with some statins. Raised plasma concentrations of simvastatin have been reported. Myopathy and rhabdomyolysis have been reported with simvastatin and itraconazole or ketoconazole and with lovastatin and itraconazole. Fluconazole inhibits CYP2C9 and has been reported to increase the plasma concentration of fluvastatin. There has also been a report of rhabdomyolysis in a patient taking fluconazole and simvastatin.
Antivirals: HIV-protease inhibitors are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may affect the metabolism of simvastatin and other statins. Studies have shown increased plasma concentrations of both simvastatin and atorvastatin with nelfinavir, and with ritonavir-boosted saquinavir, whereas the plasma concentration of pravastatin was reduced with ritonavir-boosted saquinavir. Rhabdomyolysis has been reported in a patient taking simvastatin when ritonavir was added to her therapy. Efavirenz is an inducer of CYP3A4 and a study in healthy subjects found that it could reduce plasma concentrations of atorvastatin and simvastatin; plasma concentrations of pravastatin were also reduced, although it is not metabolized by CYP3A4.
Antiarrhythmics: Amiodarone is an inhibitor of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma concentrations of statins metabolized by this enzyme, increasing the risk of toxicity. There have been reports of myopathy and rhabdomyolysis in patients taking amiodarone and simvastatin (in some cases with other CYP3A4 inhibitors), and a pharmacokinetic study found that amiodarone increased plasma-simvastatin concentrations in healthy subjects. High doses of simvastatin are not recommended in patients taking amiodarone.
Calcium-channel blockers: Calcium-channel blockers may increase plasma concentrations of some statins, probably by inhibition of the cytochrome P450 isoenzyme CYP3A4. Pharmacokinetic studies have reported increased plasma concentrations of simvastatin with verapamil, and with diltiazem, and of lovastatin with diltiazem; the small increase with simvastatin and lacidipine was not considered clinically relevant. The interaction between statins and diltiazem has also been reported in patients. A retrospective study found that the cholesterol-lowering effect of simvastatin was greater in patients who were also receiving diltiazem, and there have also been reports of rhabdomyolysis, associated with hepatitis in 1 case, 3 in patients receiving simvastatin and diltiazem together. Rhabdomyolysis and hepatitis have also been reported in patients receiving atorvastatin with diltiazem.
Immunosuppressants: Myopathy and rhabdomyolysis have been reported in patients receiving atorvastatin, lovastatin, or simvastatin with immunosuppressant regimens including ciclosporin. The mechanism of the interaction may be additive toxicity, since both statins and ciclosporin are known to cause myopathy, but effects on plasma concentrations may also be involved. Pharmacokinetic studies have shown that ciclosporin increases the plasma concentrations of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin.
Lipid regulating drugs: Myopathy and myositis are recognized adverse effects of both statins and fibric acid derivatives, including fibrates and gemfibrozil, and the risk is increased if they are given together. There has also been a report of both hepatotoxicity and rhabdomyolysis in a patient given a statin and gemfibrozil together. The interaction between gemfibrozil and statins may also have a pharmacokinetic basis; studies have shown increased plasma concentrations of atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin when given with gemfibrozil. Myopathy has also been reported, in patients given statins with nicotinic acid.
Thyroxine: Increased thyroid stimulating hormone concentrations, requiring increased doses of levothyroxine, have been reported when simvastatin.
Colchicine: Acute myopathy has been reported in patients with chronic renal impairment given colchicine with simvastatin.
Danazol: Rhabdomyolysis has been reported in a patient receiving lovastatin with a number of other drugs; it was considered that an interaction with danazol was the most likely cause. A similar reaction has been reported with simvastatin.
Fruit Juices: Grapefruit juice inhibits the cytochrome P450 isoenzyme CYP3A4 and studies using concentrated grapefruit juice have reported increased plasma concentrations of simvastatin, lovastatin, and atorvastatin. Studies using normal strength grapefruit juice have found considerable increases in plasma concentrations of atorvastatin and simvastatin. There is also a case report of a woman receiving simvastatin who developed symptoms of rhabdomyolysis 4 days after she started eating one grapefruit each day.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
C10AA01 - simvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab 20 mg x 30's. 40 mg x 30's.
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