Apo-Simvastatin

Apo-Simvastatin

simvastatin

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Simvastatin.
Description
Each tablet contains simvastatin 10 mg.
Action
Pharmacology: Apo-Simvastatin is a lipid-lowering agent derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, Apo-Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes an early and rate-limiting step in the biosynthesis of cholesterol. Clinical studies show Apo-Simvastatin to be highly effective in reducing total plasma cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) concentrations, and increasing high-density lipoprotein cholesterol (HDL-C) in heterozygous familial and non-familial forms of hypercholesterolemia, and in mixed hyperlipidemia when elevated cholesterol was cause for concern and diet alone has been insufficient. Marked responses are seen within 2 weeks and maximum therapeutic responses occur within 4-6 weeks. The response is maintained during continuation of therapy. When therapy with Apo-Simvastatin is stopped, cholesterol and lipids return to pre-treatment levels.
The active form of simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with Apo-Simvastatin would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is also metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.
In animal studies, after oral dosing, simvastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, the primary site of action, with subsequent excretion of drug in the bile. Systemic exposure of the active form of simvastatin in man has been found to be <5% of the oral dose. Of this, 95% is bound to human plasma proteins.
In the Scandinavian Simvastatin Survival Study (4S), the effect on total mortality of therapy with Apo-Simvastatin for a median of 5.4 years was assessed in 4444 patients with coronary heart disease (CHD) and baseline total-C 212-309 mg/dL (5.5-8 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, Apo-Simvastatin reduced the risk of death by 30%, of CHD death by 42% and of having a hospital-verified non-fatal myocardial infarction by 37%. Apo-Simvastatin reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes mellitus, the risk of a major coronary event was reduced by 55%. Furthermore, Apo-Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (stroke and transient ischemic attacks) by 28%.
In the Heart Protection Study (HPS), the effects of therapy with Apo-Simvastatin for a mean duration of 5 years were assessed in 20,536 patients, with or without hyperlipidemia, who were at high risk of coronary heart disease (CHD) events because of diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease or CHD. At baseline, 33% had LDL levels <116 mg/dL; 25% had levels between 116 mg/dL and 135 mg/dL; and 42% had levels >135 mg/dL.
In this multicenter, randomised, double-blind, placebo-controlled study, Apo-Simvastatin 40 mg/day compared with placebo reduced the risk of total mortality by 13%, due to a reduction in CHD deaths (18%). Apo-Simvastatin also decreased the risk of major coronary events (a composite endpoint comprising non-fatal MI or CHD deaths) by 27%. Apo-Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30% and 16%, respectively. Apo-Simvastatin reduced the risk of hospitalization for angina pectoris by 17%. The risks of major coronary events and major vascular events (a composite endpoint comprising major events, stroke or revascularization procedures) were reduced by about 25% in patients with or without CHD, including diabetics and patients with peripheral or cerebrovascular disease. In addition, within the subgroup of patients with diabetes, Apo-Simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations or leg ulcers by 21%. The risk reductions produced by Apo-Simvastatin in both major vascular events and major coronary events were evident and consistent regardless of patient age, gender, baseline LDL-C, TG, apolipoprotein A-I or apolipoprotein B level, presence or absence of hypertension, creatinine levels up to the entry limit of 2.3 mg/dL, presence or absence of baseline cardiovascular medications [ie, aspirin, β-blockers, angiotensin converting enzyme (ACE) inhibitors or calcium channel blockers], smoking status, alcohol intake or obesity. By 5 years, 32% of patients in the placebo group were taking a statin (outside of the study protocol), so that the observed risk reductions underestimate the real effect of simvastatin.
In a multicenter, placebo-controlled clinical trial in 404 patients using quantitative coronary angiography, Apo-Simvastatin slowed the progression of coronary atherosclerosis and reduced the development of both new lesions and new total occlusions, whereas coronary atherosclerotic lesions steadily worsened over 4 years in patients receiving standard care.
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. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other non-pharmacological measures alone has been inadequate.
Patients at High Risk of Coronary Heart Disease (CHD) or With Existing CHD: In patients at high risk of coronary heart events because of existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, Apo-Simvastatin is indicated to reduce the risk of total mortality by reducing CHD deaths; reduce the risk of non-fatal myocardial infarction and stroke; and reduce the need for coronary and non-coronary revascularization procedures. In hypercholesterolemic patients with CHD, Apo-Simvastatin slows the progression of coronary atherosclerosis, including reducing the development of new lesions and new total occlusions.
Patients with Hyperlipidemia: An adjunct to diet to reduce elevated total-C, LDL-C, TG and apolipoprotein B (apo B) and to increase HDL-C in patients with primary hypercholesterolemia including, heterozygous familial hypercholesterolemia (Fredrickson type IIa) or combined (mixed) hyperlipidemia (Fredrickson type IIb), when response to diet and other nonpharmacological measures is inadequate. Apo-Simvastatin, therefore, lowers the LDL-C/HDL-C and total-C/HDL ratios.
Apo-Simvastatin is also indicated as an adjunct to diet and other non-dietary measures for the treatment of patients with homozygous familial hypercholesterolemia to reduce elevated total-C, LDL-C and apo B.
Dosage/Direction for Use
The dosage range for Apo-Simvastatin is 5-80 mg/day, given as a single dose in the evening. Adjustments of dosage, if required, should be made at interval of not less than 4 weeks, to a maximum 80 mg/day given as a single dose in the evening.
Patients at High Risk of Coronary Heart Disease (CHD) or with Existing CHD: Patients with coronary heart disease can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Patients at high risk for a CHD event due to existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease have been shown to benefit from 40 mg/day and can be started at this dose.
Patients with Hyperlipidemia (Not In The Previous Risk Categories): The patient should be placed on a standard cholesterol-lowering diet before receiving Apo-Simvastatin and should continue on this diet during treatment with Apo-Simvastatin.
The usual starting dose is 10 mg/day given as a single dose in the evening. Patients who require a reduction in LDL-C (>45%) may be started at 40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified previously.
Patients with Homozygous Familial Hypercholesterolemia: Based on the results of a controlled clinical study, the recommended dosage for patients with homozygous familial hypercholesterolemia is Apo-Simvastatin 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg and an evening dose of 40 mg. Apo-Simvastatin should be used as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable. Concomitant Therapy: Apo-Simvastatin is effective alone or in combination with bile acid sequestrants.
In patients taking cyclosporine, danazol, gemfibrozil, other fibrates (except fenofibrate) or lipid-lowering doses (≥1 g/day) of niacin concomitantly with Apo-Simvastatin, the dosage of Apo-Simvastatin should not exceed 10 mg/day. In patients taking amiodarone or verapamil concomitantly with Apo-Simvastatin, the dose of Apo-Simvastatin should not exceed 20 mg/day (see Myopathy/Rhabdomyolysis under Precautions and Interactions).
Renal Insufficiency: Because Apo-Simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency.
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosages >10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.
Apo-Simvastatin may be taken with or without food (Avoid excessive consumption (>1 L/day) of grapefruit juice).
Overdosage
A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. General measures should be adopted.
Contraindications
Hypersensitivity to any component of Apo-Simvastatin.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and nursing (see Precautions).
Special Precautions
Myopathy/Rhabdomyolysis: Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy, manifested as muscle pain, tenderness or weakness with creatine kinase (CK) >10 times 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.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin with the following: Potent inhibitors of CYP3A4 eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors of nefazodone, particularly with higher doses of simvastatin (see Interactions).
Other Drugs: Gemfibrozil and other fibrates or lipid-lowering doses (≥1 g/day) of niacin, particularly with higher doses of simvastatin (see Interactions). However, 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.
Cyclosporine or danazol particularly with higher doses of simvastatin (see Interactions).
Amiodarone or verapamil with higher doses of simvastatin (see Interactions). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.
Diltiazem: Patients on diltiazem treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy is approximately 1% in these patients. In clinical studies, the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltiazem (see Interactions).
The risk of myopathy/rhabdomyolysis is dose-related. The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.03% at 20 mg, 0.08% at 40 mg and 0.4% at 80 mg.
Consequently: Use of simvastatin concomitantly with potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin, HIV protease inhibitors or nefazodone) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, danazol, gemfibrozil, other fibrates (except fenofibrate) or lipid lowering doses (≥1 g/day) of niacin. The combined use of simvastatin with gemfibrozil should be avoided unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the use of simvastatin in patients receiving other fibrates (except fenofibrate), niacin, cyclosporine or danazol should be carefully weighed against the risks of these drug combinations. Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone. Addition of fibrates or niacin to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. Combinations of fibrates or niacin with low doses of simvastatin have been used without myopathy in small, short-term clinical studies with careful monitoring.
The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of simvastatin at doses >20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
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/or 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, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Hepatic Effects: In clinical trials, persistent increases (to >3x the ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. Some of these patients had abnormal liver function tests prior to therapy with simvastatin and/or consumed substantial quantities of alcohol.
In 4S, the number of patients with more than 1 transaminase elevation to >3x the ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs 12 [0.6%]). The frequency of single elevations of SGPT (ALT) to 3x the ULN was significantly higher in the simvastatin group in the 1st year of the study (20 vs 8, p=0.023) but not thereafter. Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2221) and 5 in the placebo group (n=2223). Of the 1986 simvastatin-treated patients in 4S with normal liver function tests (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to >3x the ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. All of the patients in this study received a starting dose of simvastatin 20 mg; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1105 patients, the 6-month incidence of persistent hepatic transaminase elevations considered drug-related was 0.7% and 1.8% at the 40- and 80-mg dose, respectively.
In HPS, in which 20,536 patients were randomized to receive Apo-Simvastatin 40 mg/day or placebo, the incidences of elevated transaminases (>3x ULN confirmed by repeat test) were 0.21% (n=21) for patients treated with Apo-Simvastatin and 0.09% (n=9) for patients treated with placebo.
It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (eg, semiannually) for the 1st year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transminase levels show evidence of progression, particularly if they rise to 3x the ULN and are persistent, the drug should be discontinued.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.
As with other lipid-lowering agents, moderate (<3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
Ophthalmic Evaluations: In the absence of any drug therapy, an increase in the prevalence of lens opacities with time is expected as a result of aging. Current long-term data from clinical studies do not indicate an adverse effect of simvastatin on the human lens.
Use in pregnancy: Apo-Simvastatin is contraindicated during pregnancy.
Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the 1st trimester to Apo-Simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Apo-Simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Apo-Simvastatin may reduce the fetal levels observed of mevalonate which is a precursor of cholesterol biosynthesis.
Atherosclerosis is a chronic process and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, Apo-Simvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Apo-Simvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See Contraindications.)
Use in lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking Apo-Simvastatin should not breastfeed their infants (see Contraindications).
Use in children: Safety and effectiveness in children have not been established. Apo-Simvastatin is not recommended for pediatric use at this time.
Use in the elderly: For patients >65 years who received simvastatin in controlled clinical studies, efficacy, as assessed by reduction in total-C and LDL-C, appeared similar to that seen in the population as a whole and there was no apparent increase in the frequency of clinical or laboratory adverse findings.
Use In Pregnancy & Lactation
Use in pregnancy: Apo-Simvastatin is contraindicated during pregnancy.
Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the 1st trimester to Apo-Simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Apo-Simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Apo-Simvastatin may reduce the fetal levels observed of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, Apo-Simvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Apo-Simvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See Contraindications.)
Use in lactation: Apo-Simvastatin is contraindicated during nursing. It is not known whether simvastatin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking Apo-Simvastatin should not breastfeed their infants (see Contraindications).
Adverse Reactions
Apo-Simvastatin is generally well tolerated; for the most part, side effects have been mild and transient in nature. Less than 2% of patients were discontinued from controlled clinical studies due to side effects attributable to Apo-Simvastatin.
In the premarketing controlled clinical studies, adverse effects occurring with a frequency of ≥1% and considered by the investigator as possibly, probably or definitely drug-related were: Abdominal pain, constipation and flatulence. Other side effects occurring in 0.5-0.9% of patients were asthenia and headache.
Myopathy has been reported rarely.
In HPS involving 20,536 patients treated with 40 mg/day of Apo-Simvastatin (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with Apo-Simvastatin and patients treated with placebo over the mean 5 years of the study. In this mega-trial, only serious adverse effects and discontinuations due to any adverse effects were recorded. Discontinuation rates due to side effects were comparable (4.8% in patients treated with Apo-Simvastatin compared with 5.1% in patients treated with placebo). The incidence of myopathy was <0.1% in patients treated with Apo-Simvastatin. Elevated transaminases (>3x ULN confirmed by repeat test) occurred in 0.21% (n=21) of patients treated with Apo-Simvastatin compared with 0.09% (n=9) of patients treated with placebo.
In 4S involving 4444 patients treated with 20-40 mg/day of Apo-Simvastatin (n=2221) or placebo (n=2223), the safety and tolerability profiles were comparable between treatment groups over the median 5.4 years of the study.
The following additional side effects were reported either in uncontrolled clinical trials or in marketed use: Nausea, diarrhea, rash, dyspepsia, pruritus, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting and anemia. Rarely, rhabdomyolysis and hepatitis/jaundice occurred. An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: Angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea and malaise.
Laboratory Test Findings: Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. Liver function test abnormalities generally have been mild and transient. Increases in CK levels, derived from skeletal muscle, have been reported (see Precautions).
Drug Interactions
Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore, it is not expected to affect concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (as follows) increase the risk of myopathy by reducing the elimination of simvastatin. (See Precautions.)
Myopathy/Rhabdomyolysis: Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone.
Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone: The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent inhibitors of CYP3A4, but which can cause myopathy when given alone (see Precautions): Gemfibrozil, niacin (nicotinic acid) ≥1 g/day and other fibrates. However, 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.
Other Drug Interactions: Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin (see Precautions).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin (see Precautions).
Diltiazem: Patients on diltiazem treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy (see Myopathy/Rhabdomyolysis under Precautions).
Other Interactions: Grapefruit juice contains ≥1 components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250-mL 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, very large quantities (>1 L daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided (see Precautions).
Coumarin Derivatives: In 2 clinical studies, 1 in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: The prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7-1.8 and from 2.6-3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Storage
APO-SIMVASTATIN should be stored below 25°C.
ATC Classification
C10AA01 - simvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
Tab 10 mg (light pink, are imprinted with "APO10" x 30's.
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