Ifistatin

Ifistatin

simvastatin

Manufacturer:

Unique Pharm

Distributor:

Uni Drug
Full Prescribing Info
Contents
Simvastatin.
Description
Each film coated tablet contains: Simvastatin USP 10mg/20mg.
Action
Simvastatin, is a cholesterol lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, Simvastatin, which is an inactive lactone, is hydrolysed to the corresponding beta-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG Co A) reductase. This enzyme catalyses the conversion of HMG Co A 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 LDL cholesterol concentration. The mechanism of the LDL-lowering effect of Simvastatin may involve both reduction of very low density lipoprotein (VLDL) cholesterol concentration 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 increase of variable magnitude in HDL cholesterol.
Indications/Uses
Therapy with lipid altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
Simvastatin is indicated in patients with coronary heart disease and hypercholesterolemia to reduce the risk of total mortality, reducing coronary death, to reduce the risk of non-fatal myocardial infarction and to reduce the risk for undergoing myocardial revascularisation procedures.
Simvastatin is indicated for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia (Types IIa and IIb). Simvastatin is also indicated to reduce elevated LDL cholesterol levels in patients with combined hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality (Type II b hyperlipoproteinemia).
Dosage/Direction for Use
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of simvastatin should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. Patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C lowering treatment(s) that provides greater LDL-C lowering.
The patient should be placed on a standard cholesterol lowering diet before receiving Simvastatin and should continue on this diet during treatment with Simvastatin. The recommended starting dose is 5-10 mg once a day in the evening. The recommended dosage range is 5-40mg/day as a single dose in the evening, the maximum recommended dose is 40mg/day. 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. Since the goal of treatment is to lower LDL-C, its levels should 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. Patients requiring reduction in LDL cholesterol of 20% or more to achieve their goal should be started on 10 mg/day of Simvastatin. A starting dose of 5 mg/day should be considered for patients requiring smaller reductions and for the elderly. Adjustment 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. In the elderly, maximum reductions in LDL cholesterol may be achieved with daily doses of 20 mg of Simvastatin or less. 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. Simvastatin is effective alone or when used concomitantly with bile-acid sequestrants. Use of Simvastatin with fibrate-type drugs such as Gemfibrozil or Clofibrate should be avoided. Dosage when taken with cyclosporine, gemfibrozil. In patients taking cyclosporine concomitantly, therapy should begin with 5 mg/day and should not exceed 10 mg/day.
In combination with Gemfibrozil or niacin, the dose of Simvastatin should not exceed 10 mg/day. In patients taking amiodarone or verapamil concomitantly, Simvastatin dose should not exceed 20 mg/day.
Overdosage
A few cases of overdosage with Simvastatin have been reported. No patient had any specific symptoms and all patients recovered without sequelae. The maximum dose taken was 450 mg. Until further experience is obtained, no specific treatment of overdosage with Simvastatin can be recommended. The dialyzability of Simvastatin and it's metabolites in man is not known at present.
Contraindications
Hypersensitivity. Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy and nursing mothers.
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconzole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone).
Concomitant administration of gemfibrozil, cyclosporine, or danazol.
Special Precautions
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
As with other statins, the risk of myopthy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopthy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year treatment, use of the 80-mg dose of simvastatin should be restricted to patients who have been taking simvastatin 80mg chronically (e.g. for 12 months or more) without evidence of muscle toxicity. Patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C lowering treatments(s) that provides greater LDL-C lowering. In patients taking simvastatin 80 mg for whom an interacting agent is needed, a lower dose of simvastatin or an alternative statin-based regimen with less potential for drug-drug interactions should be used.
In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing simvastatin to Asian patients and the lowest dose necessary should be employed.
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid modifying doses (>1 g/day) of niacin. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (>1 g/day) of niacin. Therefore, the benefit of the combined use of simvastatin with niacin should be carefully weighed against the potential risks of the combination. In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with extended-release niacin/laropiprant 2 g/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in non-Chinese patients, coadministration of simvastatin with lipid modifying doses (>1 g/day) of niacin is not recommended in Asian patients.
All patients starting therapy with simvastatin or whose dose of simvastatin is being increased should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.
The presence of these symptoms, and a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased. Periodic CK determinations are recommended for patients titrating to the 80 mg dose. There is no assurance that such monitoring will prevent myopathy.
Prescribing recommendations for interacting agents are summarized in the table as follows: (See table.)

Click on icon to see table/diagram/image

Liver dysfunction: Persistent increases in serum transaminases have occurred which fell slowly to pre treatment levels when drug treatment was interrupted or discontinued. It is recommended that liver function tests be performed before the initiation of treatment at 6 or 12 weeks, after initiation of therapy or elevation in dose, and periodically thereafter (i.e. semiannually). Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of therapy is recommended.
Skeletal muscle: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been associated with Simvastatin therapy. Rhabdomyolysis has also been associated with other HMG-Co A reductase inhibitors when they were administered alone or concomitantly with immunosuppressive therapy, fibrates or erythromycin in seriously ill patients. 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 infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte discorders and uncontrolled seizures).
Simvastatin may occasionally cause myopathy, which is manifested as muscle pain or weakness associated with grossly elevated creatine kinase (CK) (more than 10 times the upper limit of normal).
Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred.
Endocrine function: Simvastatin does not reduce plasma cortisol concentration, impair adrenal reserve nor reduce basal plasma testosterone concentration as other HMG-Co A reductase inhibitors.
Caution should be exercised if an HMG-Co A reductase inhibitor or other agent used 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.
Pregnancy and Lactation: Safety in pregnant women has not been established. Simvastatin should be administered to women in childbearing age only when such patients are highly unlikely to conceive. 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, women taking Simvastatin should not nurse their infants.
Paediatric use: Safety and effectiveness in paediatric patients have not been established.
Use In Pregnancy & Lactation
Safety in pregnant women has not been established. Simvastatin should be administered to women in childbearing age only when such patients are highly unlikely to conceive. 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, women taking Simvastatin should not nurse their infants.
Adverse Reactions
Adverse reactions have usually been mild transient. They include abdominal pain, asthenia, constipation, diarrhoea, dyspepsia, flatulence, nausea, headache, upper respiratory infections.
Myopathy has been rarely reported.
There have been rare post-marketing reports of congnitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with stain use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Increases in HbA1c and fasting serum glucose levels have been reported with statins.
Drug Interactions
Immunosuppressive drugs, Itraconazole, Gemfibrozil, Nicotinic acid, Erythromycin: Rhabdomyolysis has been associated when used with HMG-Co A reductase inhibitors.
Digoxin: Slight increase in digoxin concentration is seen in patients receiving digoxin and simvastatin.
Warfarin: Simvastatin modestly potentiated the effect of coumarin anticoagulants resulting in increased prothrombin time. Prothrombin time should be determined before starting treatment and frequently during early therapy to ensure that no significant alteration of prothrombin time occurs.
Simvastatin is metaboliosed by cytochrome P450 isoform 3A4.
Inhibitors of C4P3A4 like Ketoconazole, Erythromycin, Clarithromycin, HIV protease inhibitors, antidepressant nefazodone raise plasma levels of Simvastatin and can increase risk of myopathy.
Use of drugs that may increase risk of myopathy CKP3A4 inhibitors - Itraconazole, Ketoconazole, Erythromycin, Clarithromycin, Protease inhibitor, Nefazodore, Cyclosporin.
Gemfibrozil (fibrates), Niacin, Amiodarone, Verapamil.
Contraindicated drugs: Concomitant use of the following drugs is contraindicated: Potent Inhibitors of CYP3A4: Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity. Therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin.
Concomitant use of drugs labeled as having a potent inhibitory effect on CYP3A4 (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone) is contraindicated.
Other drug interactions: Other Fibrates: The risk of myopathy is increased by gemfibrozil and other fibrates (except fenofibrate); these lipid-lowering drugs can cause myopathy when given alone. When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid.
Amiodarone: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin.
Calcium channel blockers: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine.
Moderate Inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy.
Niacin (nicotinic acid) (≥1g/day): Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1g/day) of niacin.
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.
Other interactions: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250ml glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, because large quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during simvastatin therapy.
Storage
Store below 25°C. Protect from light & moisture.
ATC Classification
C10AA01 - simvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
Tab 10 mg (film-coated) x 3 x 10's. 20 mg (film-coated) x 3 x 10's.
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