Indications
- Treatment of hypercholesterolemia, as an adjunct to diet to lower total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations in patients with primary hypercholesterolemia (type IIa and IIb) and little reductionin triglyceride levels.
- Primary prevention (level 1) of coronary artery events: In hypercholesterolemic patients without obvious clinical manifestations of coronary artery disease, simvastatin is indicated to reduce the risk of myocardial infarction and death from cardiovascular diseases; reduce the risk of undergoing coronary revascularization procedures.
- Atherosclerosis: In hypercholesterolemic patients with clinical manifestations of coronary artery disease, including prior myocardial infarction. Simvastatin is indicated to slow the progression of coronary atherosclerosis and reduce the risk of acute coronary artery events.
Dosage and administration
Administration: Simvastatin tablets should be taken in the evening, either with or without food.
- The starting dose is 5 – 10 mg once daily. Adjustmentsin dosage should be made every 4 weeks.
- The maintenance dose is 5 – 40 mg once daily.
Note:
- Patients should be placed on a standard cholesterol lowering diet before receiving HMG – CoA reductase inhibitors and thisdiet should be maintained during simvastatin treatment.
- Concomitant use of large quantities of grapefruit juice (> 1 liter/day) and simvastatin should be avoided.
- The simvastatin dose should not exceed 10 mg daily when administered along with verapamil, diltiazem, dronedarone.
- The simvastatin dose should not exceed 10 mg daily when coadministration with amiodarone, amlodipine, ranolazine.
Contraindications
- Patients with hypersensitivity to simvastatin or any component of the medicine.
- Active liver disease or unexplained persistent elevations of serum transaminases.
- Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, posaconazole, gemfibrozil, cyclosporine, danazol).
- Pregnant women or nursing mothers.
Precautions
- Before starting the treatment, the causes of hypercholesterolemia should be excluded, including poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, blood protein disorders, cholestatic liver disease caused by some other drugs, alcoholism.
- The levels of total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides should be measured. The levels of lipid should be measured periodically at intervals of not less than 4 weeks and dosage is adjusted according to the patient’s response to medicine. The target of treatment is to reduce LDL cholesterol. Therefore, the levels of LDL- C is used to begin the treatment and to evaluate the response of treatment. Only if LDL-C levels are not determined, the total cholesterol should be used to monitor the treatment.
- Simvastatin may increase serum transaminases. Liver enzyme tests are recommended to be performed before starting simvastatin therapy and as clinically indicated thereafter.
- Monitoring creatine kinase (CK) levels should be considered in the following cases:
+ Before treatment, CK tests should be performed in cases as follows: Patients with renal impairment, hypothyroidism, personal history or family history of hereditary muscular disorders, a history of the muscular disease due to previous use of statins or fibrates, history of liver disease and/ or excessive alcohol consumption; elderly patients (> 70 years old) at risk of rhabdomyolysis; potential drug interactions and some particular patients. In these cases, benefit – risk analysis should be considered and the patients should be clinically monitored when treated with simvastatin. If the result of creatine kinase test is more than 5 times the upper limit of normal, simvastatin should not be used.
+ During simvastatin therapy, patients should inform about the symptoms of muscle such as muscle pain, muscle stiffness, muscle weakness etc. When these symptoms occur, CK test should be carried out to give patients appropriate intervention.
- Simvastatin therapy should be temporarily or immediately discontinued if patients exhibit symptoms of severe acute muscle disease or are at risk of acute renal failure due to rhabdomyolysis (e.g. severe acute infection; hypotension; surgery and major trauma; metabolic, endocrine, electrolyte abnormalities or uncontrolled seizures).
- Simvastatin should only be administered to women of child-bearing age when these patients are not really pregnant and the treatment with other drugs fail to control
- Adverse reactions must be monitored closely during the course of
Interactions
- Risk of muscle injury increases when simvastatin is concurrently used with the following drugs: Gemfibrozil, other cholesterol–lowering medications belonging to fibrate group, high-dose niacin (> 1 g/ day), colchicine.
- Concomitant use of lipid-lowering medications belonging to simvastatin group for the treatment of HIV and hepatitis C virus (HCV) may increase the risk of muscle damage, the most serious is rhabdomyolysis, impaired renal function which lead to kidney failure and can be fatal.
- Bile acid resins can decrease markedly the bioavailability of simvastatin when they are co-administered with simvastatin. Therefore, bile acid resins should be spaced several hours apart from simvastatin.
- Simvastatin may enhance the effect of
- No clinically significant adverse interactions have been reported when simvastatin is co-administered with ACE inhibitors, beta-blockers, calcium-channel blockers, diuretics and non-steroidal anti-inflammatory drugs.
- In order to avoid drug interactions, inform your doctor or pharmacist about the drugs you are using.
Pregnancy and lactation
Pregnancy: Because statins decrease cholesterol synthesis and, possibly, the synthesis of other biologically active substances derived from cholesterol. Simvastatin may be harmful to the fetus if used during pregnancy. Therefore, simvastatin is contraindicated during pregnancy.
Lactation: It is not known whether simvastatin is excreted in human milk. 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, simvastatin should not be used during breastfeeding.
Effects on ability to drive and use machines
Simvastatin may cause headache, dizziness, blurred vision, cognitive impairment. Caution should be exercised when driving vehicles and operating machinery.
Undesirable effects
Simvastatin is well-tolerated. However, some people may experience the following side effects:
- Common, ADR > 1/100
- Diarrhea, constipation, flatulence, abdominal pain, nausea; headache, dizziness, blurred vision, insomnia, asthenia, myalgia, joint pain, transient elevations in liver enzymes which are recovered after discontinuation of the drug.
- Cognitive impairment (memory loss, confusion ).
- Increased HbA1c levels.
- Uncommon, 1/1000 < ADR < 1/100: Myopathy (muscle weakness in conjunction with increases in plasma creatine phosphokinase levels); rash; rhinitis, sinusitis, pharyngitis, cough.
- Rare, ADR < 1/1000: Myositis, rhabdomyolysis leading to acute renal failure secondary due to myoglobinuria.
Inform your doctor about any undesirable effect occurring during treatment with this product.
Pharmacodynamic properties
- Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG – CoA) reductase, suppresses the conversion of HMG – CoA to mevalonate, a precursor of cholesterol.
- Simvastatin inhibits the biosynthesis of cholesterol, reduces the amount ofcholesterol in the liver cells, stimulates the synthesis of LDL receptors (low density lipoprotein), thereby increases the transport of LDL from the blood and eventually reduces plasma cholesterol concentrations. At normal doses, HMG – CoA reductase is not entirely inhibited, so there is enough mevalonic acid for many metabolic process.
- All statins reduce LDL levels effectively. This class of drugs lowers LDL cholesterol by 25% to 45%, depending on the doses. Simvastatin seems effective 2 fold higher than lovastatin and the effect of simvastatin at daily dose of 40 mg may be a little stronger than that of 80 mg of lovastatin.
- Statins increase HDL cholesterol (high density lipoprotein) by 5 – 15 % and therefore lower LDL/ HDL and total cholesterol/ HDL ratios. Statins also lower plasma triglyceride levels (10 – 30 %) by increasing the clearance of VLDL (very low density lipoprotein) residues via upregulation of the LDL receptors. Response to treatment with statins can be seen within 1-2 weeks after starting the drug. Maximal response is generally achievedwithin 4-6 weeks and maintained during long-term treatment. In clinical studies, there are evidences showing that statins significantly reduced coronary events, all available cardiovascular events and reduced the total mortality in patients with coronary artery disease (a history of angina pectoris or acute myocardial infarction) and in patients with plasma cholesterol greater than or equal to 5 mmol/l.
- In the 4S study (Scandinavian Simvastatin Survival Study), simvastatin used at doses of 20 – 40 mg/day for 4444 patients with increased cholesterol and angina pectoris or prior myocardial infarction, reduced the risk of mortality (30%), the risk of coronary heart disease (42%) and the risk of having a hospital-verified non-fatal MI (37%). This was a placebo-controlled study and performed for a median duration of 5.4 years.
- Statins also have a role in primary prevention (level 1) of coronary artery disease in hypercholesterolemic patients with high risk of coronary events.
Pharmacokinetic properties
- The drug is rapidly absorbed after oral administration, simvastatin is a prodrug which undergoesextensive first-pass metabolism to produce active metabolite.
- The absorption of simvastatin is not affected by food. The bioavailability of simvastatin is low because of extensive first-passmetabolism in the liver (> 60%). Peak serum concentrations of active metabolites were attained within 1.3 to 2.4 hours. Simvastatin was 95% bound to protein. Simvastatin is lipophilic, thus it crosses the blood-brain barrier. Simvastatin was metabolized primarily in the liver (> 70%) to active metabolites, then most excreted in the feces. Renal excretion of simvastatin is 13%.
Overdose and management
- A few cases of overdosage have been reported. No patients had any specific symptoms and all patients recovered without sequelae.
- In the event of an overdose, treatmentis symptomatic and supportive. Simvastatin is not removed significantly from the circulation by hemodialysis because it is highly bound to plasma proteins.
KEEP OUT OF REACH OF CHILDREN
READ CAREFULLY THE INSTRUCTIONS BEFORE USE
FOR FURTHER INFORMATIONS, CONSULT YOUR PHYSICIAN
USE ONLY UNDER A PHYSICIAN’S PRESCRIPTION
Storage: Protect from humidity and light, below 300C.
Shelf – life: 36 months from the manufacturing date.
Do not use after the expiry date printed on the box.
A1202001402
