Zocor, 10 mg tablets, 28 pcs.

The drug Zocor® (simvastatin) is a hypolipidemic drug synthetically derived from the fermentation product of Aspergillus terreus.

Pharmacodynamics

. After oral administration simvastatin being inactive lactone is hydrolyzed in liver to form its corresponding form β-hydroxy acid simvastatin which is main metabolite and has high inhibitory activity against HMG-CoA (Z-hydroxy-3-methylglutaryl-Coenzyme A) reductase of enzyme catalyzing initial and most important stage of cholesterol biosynthesis.

. Clinical studies showed effectiveness of Zocor® preparation with regard to reduction of plasma total cholesterol (TC) concentration of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and very-low-density lipoprotein cholesterol (VLDL-C) and increase of VLDL-C concentration in blood. concentration of high density lipoprotein cholesterol (HDL-C) in patients with heterozygous familial and nonfamilial hypercholesterolemia or mixed hyperlipidemia, when an increased concentration of cholesterol is a risk factor and diet alone is not enough. Noticeable therapeutic effect is observed within 2 weeks of taking the drug maximum therapeutic effect – within 4-6 weeks after the start of treatment. The effect persists with the continuation of therapy. When discontinuation of simvastatin treatment cholesterol concentration returns to the initial value observed before the start of treatment.

The active metabolite of simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme catalyzing the reaction of mevalonate formation from HMG-CoA. Despite this, taking Zocor® in therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows preserving the production of biologically necessary amount of mevalopate. Since the early stage of cholesterol biosynthesis is conversion of HMG-CoA to mevalonate, it is considered that the use of Zocor® should not cause accumulation of potentially toxic sterols in the body. In addition, HMG-CoA is rapidly metabolized back to acetyl-CoA, which is involved in many biosynthetic processes in the body. Although cholesterol is a precursor of all steroid hormones, no clinical effects of simvastatin on steroidogenesis have been observed. Because simvastatin did not cause an increase in bile lithogenicity, its effect on increasing the incidence of cholelithiasis is unlikely.

Simvastatin reduces both elevated and normal LDL cholesterol concentrations. LDL is formed from very low density lipoproteins (VLDL). LDL catabolism is predominantly performed by high-affinity LDL receptor. The mechanism of LDL-C concentration decrease after simvastatin administration may be due to both decrease of LDL-C concentration and activation of LDL-receptor that leads to decrease of formation and increase of LDL-C catabolism.

In simvastatin therapy apolipoprotein B (apo B) concentration is also significantly reduced. Since each JIpNP particle contains one molecule of apo B and small amounts of apo B are found in other lipoproteins it can be assumed that simvastatin not only causes loss of cholesterol in LDL particles but also reduces the concentration of circulating LDL particles.

In addition, simvastatin increases HDL cholesterol concentration and decreases plasma TG concentration. As a result of these changes, the ratios of CHC/HDL and LDL/HDL decrease.

In the Scandinavian study of the effect of simvastatin on survival (4S), the effect of Zocor® therapy on overall mortality (median time of patient participation 54 years) was evaluated in 4444 patients with coronary heart disease (CHD) and a baseline COX concentration of 212-309 mg/dL (55-80 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled trial, Zocor® reduced the risk of overall mortality by 30% of CHD mortality by 42% of the incidence of nonfatal confirmed myocardial infarctions by 37%.

The drug Zocor® also reduced the risk of the necessity of surgical interventions to restore coronary blood flow (aortocoronary bypass or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes the risk of major coronary complications was reduced by 55%. Moreover, Zocor® significantly (by 28%) reduced the risk of fatal and non-fatal cerebrovascular events (strokes and transient cerebrovascular events).

In a 5-year, multicenter, randomized, double-blind, placebo-controlled heart protection study (HPS), the effectiveness of Zocor® therapy was demonstrated in 20536 patients with or without hyperlipidemia who were at high risk for CHD due to a history of concomitant diabetes mellitus stroke and other vascular disease. Before therapy, 33% of patients had LDL concentrations less than 116 mg/dL, 25% of patients had LDL concentrations between 116 mg/dL and 135 mg/dL, and 42% of patients had LDL concentrations greater than 135 mg/dL.

. In this study, simvastatin at a dose of 40 mg daily compared with placebo reduced overall mortality by 13% risk of CHD-related death – 18% risk of major coronary complications (including nonfatal myocardial infarction or CHD-related death) – by 27% the need for surgical interventions to restore coronary blood flow (including aortocoronary bypass and percutaneous transluminal angioplasty) and peripheral blood flow and other types of noncoronary revascularization – by 30% and 16%, respectively the risk of stroke – by 25%. The frequency of hospitalization for heart failure (HF) was reduced by 17%.

The risk of major coronary and vascular complications was reduced by 25% in patients with or without CHD, including patients with diabetes with peripheral vascular disease or cerebrovascular disease. In patients with diabetes simvastatin reduced by 21% the risk of serious vascular complications, including the need for surgery to restore the peripheral blood flow amputation of the lower extremities and the occurrence of trophic ulcers.

In another multicenter placebo-controlled study with 404 patients using quantitative assessment of coronary blood flow, simvastatin (by coronary angiography) slowed progression of coronary atherosclerosis and the appearance of both new areas of atherosclerosis and new total occlusions, whereas steady progression of coronary atherosclerotic lesions was observed in patients receiving standard therapy.

The subgroup analysis of two studies with 147 patients with hypertriglyceridemia (hyperlipidemia type IV according to Fredrickson classification) showed that simvastatin in dose from 20 to 80 mg daily reduced GH concentration by 21-39% (in placebo group by 11-13%)./p>

LDL cholesterol – by 23-35% (in the placebo group by 1-3%) non-high-density lipoprotein cholesterol (non-HDL cholesterol is calculated as the difference between the concentration of OSH and HDL cholesterol concentration) – by 26-43% (in the placebo group by 1-3%) and increased HDL cholesterol by 9-14% (in the placebo group by 3%).

In 7 patients with dysbetalipoproteinemia (hyperlipidemia type III according to Fredrickson classification) simvastatin in dose of 80 mg daily reduced LDL-C concentration including intermediate density lipoproteins (IDL) by 51% (in placebo group by 8%) and LDL-C and IDL-C concentration by 60% (in placebo group by 4%).

Pharmacokinetics:

Metabolism

Simvastatin is an inactive lactone that is rapidly hydrolyzed into simvastatin β-hydroxy acid (L-654969) a strong HMG-CoA reductase inhibitor. The main metabolites of simvastatin in blood plasma are simvastatin β-hydroxy acid (L-654969) and its 6′-hydroxy 6′-hydroxymethyl and 6′-exomethylene derivatives. HMG-CoA reductase inhibition is a criterion for quantification of all pharmacokinetic studies of β-hydroxy acid metabolites (active inhibitors) and active and latent inhibitors (all inhibitors) produced by hydrolysis. Both types of metabolites are detected in blood plasma when taking oral simvastatin.

Hydrolysis of simvastatin mainly occurs during “primary passage” through the liver so the concentration of unchanged simvastatin in human plasma is low (less than 5% of the dose taken). Maximal concentration (Cmax) in blood plasma of simvastatin metabolites is reached in 13-24 hours after a single dose intake. In study with using 14C-labeled simvastatin plasma concentration of total radioactivity (14C-labeled simvastatin + 14C-labeled metabolites of simvastatin) reached maximum in 4 hours and rapidly decreased to approximately 10% of maximum value within 12 hours after a single oral dose.

Despite the fact that range of recommended therapeutic doses of simvastatin is from 5 to 80 mg per day the linear character of AUC profile (area under curve “concentration – time”) of active metabolites in total blood flow is maintained in increasing dose up to 120 mg.

Absorption

About 85% of the oral dose of simvastatin is absorbed. Food intake (within standard hypocholesterol diet) immediately after taking simvastatin does not influence pharmacokinetic profile of the drug.

Distribution

After oral administration higher concentrations of simvastatin are detected in the liver than in other tissues. The concentration of the active metabolite simvastatin L-654969 in systemic bloodstream is less than 5% of the oral dose; 95% of this amount is in protein-bound state. Active metabolism of simvastatin in the liver (more than 60% in men) results in its low concentration in the total bloodstream. The possibility of penetration of simvastatin through the blood-brain barrier and the blood-placental barrier has not been studied.

In “primary passage” through the liver simvastatin is metabolized with subsequent excretion of simvastatin and its metabolites with bile.
In the study, when taking 100 mg of the drug (5 capsules of 20 mg) 14C-labeled simvastatin was accumulated in blood urine and feces. About 60% of the ingested dose of labeled simvastatin was detected in stools and about 13% in urine. Labeled simvastatin in feces was represented as products of metabolism of simvastatin excreted with bile and unabsorbed labeled simvastatin. Less than 05% of the ingested dose of labeled simvastatin was detected in urine as active metabolites of simvastatin.

In plasma, 14% of the AUC was due to active inhibitors and 28% to all HMG-CoA reductase inhibitors. The latter indicates that mainly the metabolic products of simvastatin are inactive or weak HMG-CoA reductase inhibitors.

In a dose-proportionality study of simvastatin 5 10 20 60 90 and 120 mg, there was no significant deviation from the linearity of AUC in the total bloodstream with increasing dose. Pharmacokinetic parameters with single and multiple oral doses of simvastatin showed that simvastatin does not accumulate in tissues with multiple oral doses.

In a study in patients with severe renal impairment (creatinine clearance (CK) less than 30 ml/min) the total plasma concentration of HMG-CoA reductase inhibitors after oral single dose of appropriate HMG-CoA reductase inhibitor (statin) was approximately 2 times higher than in healthy volunteers.

In study with participation of healthy volunteers simvastatin at maximum dose of 80 mg had no effect on metabolism of midazolam and erythromycin which are substrates of CYP3A4 isoenzyme. This means that simvastatin is not CYP3A4 inhibitor and suggests that oral administration of simvastatin has no effect on the plasma concentration of drugs metabolized by CYP3A4 isoenzyme.

It is known that cyclosporine increases AUC of HMG-CoA reductase inhibitors although the mechanism of drug interaction is not fully understood. Increase of AUC of simvastatin is presumably connected in particular with inhibition of CYP3A4 isoenzyme and/or OATP1B1 transport protein (see CONTRAINDICATIONS).

In a pharmacokinetic study with diltiazem there was a 27-fold increase in AUC of β-hydroxy acid simvastatin, presumably due to inhibition of CYP3A4 isoenzyme (see DISCUSSIONS Myopathy/Rhabdomyolysis).

In a pharmacokinetic study a 16-fold increase in AUC of β-hydroxy acid simvastatin was observed when used concomitantly with amlodipine.

In a pharmacokinetic study in a concomitant use of a single dose of 2 g slow-release nicotinic acid and simvastatin 20 mg there was a slight increase in AUC of simvastatin and β-hydroxy acid of simvastatin and Cmax β-hydroxy acid of simvastatin in blood plasma (see SPECIAL NOTES Myopathy/Rhabdomyolysis). The specific pathways of metabolism of fusidic acid in the liver are unknown; however, it can be assumed that there is an interaction between fusidic acid and statins that are metabolized by CYP3A4 isoenzyme.

The risk of myopathy increases with increased plasma concentrations of HMG-CoA reductase inhibitors. Strong CYP3A4 isoenzyme inhibitors may increase the concentration of HMG-CoA reductase inhibitors and lead to an increased risk of myopathy

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Indications

Active ingredient

Composition

How to take, the dosage

Before treatment with Zocor® the patient should be prescribed a standard hypocholesterolemic diet, which should be followed during the whole course of treatment.
Recommended doses of Zocor® are from 5 to 80 mg per day. The drug should be taken once a day in the evening. If necessary, the dose of the preparation is increased with intervals of not less than 4 weeks up to 80 mg once a day in the evening. The dose of 80 mg daily is recommended only for patients with high risk of cardiovascular complications if treatment with the drug in lower doses did not allow to reach the target lipid levels and the expected benefit of therapy exceeds the possible risk.

Patients with coronary heart disease or high risk of CHD The standard initial dose of Zocor® for patients at high risk of CHD in combination with or without hyperlipidemia (in case of diabetes or other cerebrovascular disease in past history of peripheral vascular disease) and for patients with CHD is 40 mg 1 time per day in evening. Drug therapy should be prescribed simultaneously with diet and physical therapy.

Patients with hyperlipidemia without above mentioned risk factors

The standard starting dose of Zocor® is 20 mg once daily in the evening. For patients who need significant (more than 45%) decrease of LDL cholesterol concentration the initial dose may be 40 mg once daily in the evening. For patients with mild or moderate hypercholesterolemia, Zocor® therapy can be administered in initial dose of 10 mg once per day. If necessary the doses should be adjusted according to the above mentioned scheme.

Patients with homozygous familial hypercholesterolemia

The drug Zocor® is recommended in a dose of 40 mg daily taken once in the evening. The dose of 80 mg is recommended only if the expected benefit of therapy outweighs the possible risk (see SPECIAL NOTES Myopathy/Rhabdomyolysis). In these patients, Zocor® is used in combination with other methods of hypolipidemic treatment (e.g. LDL-apheresis) or without such treatment if it is not available.

For patients taking lomitapide concomitantly with Zocor® the daily dose of Zocor® should not exceed 40 mg.

Companion therapy

The drug Zocor® may be administered either in monotherapy or in combination with bile acid sequestrants.

In patients taking Zocor® concomitantly with fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate the maximum recommended dose of Zocor® is 10 mg daily.

In patients taking amiodarone verapamil diltiazem or amlodipine concomitantly with Zocor® the daily dose of Zocor8 should not exceed 20 mg.

In renal failure

As Zocor® is excreted by the kidneys in small amounts there is no need to change the dose in patients with moderate renal impairment. In patients with severe renal impairment (CKD < 30 ml/min) the appropriateness of prescribing the drug in doses exceeding 10 mg per day should be carefully weighed. If such doses are deemed necessary, they should be prescribed with caution.

The use in children and adolescents 10-17 years of age with heterozygous familial hypercholesterolemia

The recommended starting dose is 10 mg daily in the evening. Recommended dosage regimen is 10-40 mg per day; maximum recommended dosage of Zocor® is 40 mg per day. Selection of doses is carried out individually according to the goals of therapy.

Interaction

Contraindicated drug combinations

Companion therapy with the following drugs is contraindicated.

Powerful inhibitors of CYP3A4 isoenzyme. Simvastatin is metabolized by CYP3A4 isoenzyme but does not inhibit the activity of this isoenzyme. This suggests that simvastatin administration has no effect on the plasma concentration of drugs metabolized by CYP3A4 isoenzyme. Strong CYP3A4 isoenzyme inhibitors increase the risk of myopathy by reducing the excretion rate of simvastatin. Simultaneous use of strong CYP3A4 isoenzyme inhibitors (e.g. itraconazole quetracopazole pozaconazole voriconazole erythromycin clarithromycin telithromycin HIV protease inhibitors boceprevir telaprevir nefazodone cobicistat containing drugs) and simvastatin is contraindicated (see Table 1. contraindications; myopathy/rhabdomyolysis).

Hemfibrozil cyclosporine or danazol.

Interaction with other drugs

Other fibrates. The risk of myopathy increases with concomitant use of simvastatin with gemfibrozil (see CONTRAINDICATIONS) and other fibrates (except fenofibrate). These hypolipidemic agents may cause myopathy in monotherapy. When concomitant use of simvastatin with fenofibrate, the risk of myopathy did not exceed the sum of the risks with monotherapy with each drug.

Amiodarone. The risk of myopathy/rhabdomyolysis is increased with concomitant use of amiodarone with simvastatin. In clinical study incidence of myopathy in patients concomitantly taking simvastatin in dose of 80 mg and amiodarone was 6%. Risk of myopathy/rhabdomyolysis increases with concomitant use of verapamil diltiazem or amlodipine with simvastatin.

Lomitapide. The risk of myopathy/rhabdomyolysis may increase with concomitant use of lomitapide with simvastatin

Moderate CYP3A4 isoenzyme inhibitors (e.g. dronedarone). In concomitant use of drugs with moderate inhibitory activity against CYP3A4 isoenzyme and simvastatin especially in higher doses the risk of myopathy may increase. If Zocor® and moderate CYP3A4 isoenzyme inhibitors are used concomitantly, the dose of Zocor® may need to be reduced.

Ranolazine (moderate CYP3A4 isoenzyme inhibitor). Concomitant use of ranolazine and simvastatin may increase the risk of myopathy (see DISCUSSION Myopathy/Rhabdomyolysis). In concomitant use of Zocor® and ranolazine it may be necessary to reduce the dose of Zocor®.
Inhibitors of OATP1B1 transport protein. Hydroxy acid of simvastatin is a substrate of OATP1B1 transport protein. Concomitant use of OATP1B1 transport protein inhibitors and simvastatin may lead to increased plasma concentrations of simvastatin hydroxy acid and an increased risk of myopathy.

Fusidic acid. Concomitant use of fusidic acid and simvastatin may increase the risk of myopathy.

Nicotinic acid (at least 1 g/day). When concomitant use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g/day), cases of myopathy/rhabdomyolysis have been described.

Colchicine. When concomitant use of colchicine and simvastatin in patients with renal insufficiency, cases of myopathy and rhabdomyolysis have been described.

When combined therapy with these drugs these patients should be closely monitored.

Indirect anticoagulants (coumarin derivatives). Simvastatin in dose 20-40 mg per day potentiates effect of coumarin anticoagulants: prothrombin time determined as the international normalized ratio (INR) increases from baseline level of 17 to 18 in healthy volunteers and from 26 to 34 in patients with hypercholesterolemia. In patients taking coumarin anticoagulants prothrombin time should be determined before starting therapy with simvastatin and often enough during the initial period of treatment to exclude significant changes in this indicator. As soon as a stable INR value is achieved, its further determination should be carried out at intervals recommended for monitoring patients receiving anticoagulant therapy. Regular measurement of prothrombin time is also recommended if the dose of simvastatin is changed or after its withdrawal. In patients who have not taken anticoagulants simvastatin therapy has not been associated with the occurrence of bleeding or changes in prothrombin time.

Special Instructions

It is recommended that liver function tests be performed (and repeated periodically thereafter) before starting treatment.

When transaminase levels begin to exceed 3 times the upper normal limit, the drug should be discontinued.

Patients who abuse alcohol and/or have a history of liver disease are prescribed with caution.

Contraindications

Side effects

The drug Zocor® is generally well tolerated and most side effects are mild and transient. Less than 2% of patients who participated in clinical trials discontinued treatment due to the development of adverse events inherent to Zocor®.

In the pre-registration clinical trials the adverse events with a frequency of at least 1%, which were evaluated by the investigators as probably or definitely related to the drug administration, were constipation and flatulence. Other adverse events that occurred in 05-09% of patients were asthenia and headache.

There have been rare reports of the development of myopathy.

In a clinical trial (HPS) in which 20536 patients took Zocor® (n = 10269 patients) at a dose of 40 mg daily or placebo (n = 10267 patients) for an average of 5 years, the pattern of adverse events was similar in the Zocor® and placebo groups. The incidence of discontinuation of therapy due to adverse events was also comparable in the two groups (48% in the Zocor® group and 51% in the placebo group). The incidence of myopathy in patients treated with Zocor® was less than 01%. Elevation of “liver” transaminases activity (more than 3 times of upper limit of normal (ULN), confirmed by repeated study) was observed in 021% of Zocor® group and 009% of placebo group patients.

There are reports of the possibility of the following adverse events (rare: ≥ 001% and <01% very rare: <001% incidence not established: it is not possible to estimate the incidence based on available data):

Hematopoietic organs: Rare: Anemia.

Skin disorders: Rare: skin rash itching alopecia.

Digestive system disorders: Rare: dyspepsia nausea vomiting diarrhea pancreatitis hepatitis/jaundice. Very rare: fatal and non-fatal liver failure.

Central nervous system and sensory organs: Rare: dizziness peripheral neuropathy paresthesias. Very rare: insomnia. Infrequent: depression.

Musculoskeletal system disorders: Rare: myalgia muscle cramps rhabdomyolysis. Frequency not established: tendinopathy possibly with tendon rupture.

Respiratory system: Frequency not determined: interstitial lung disease.

Reproductive system disorders: Frequency not established: erectile dysfunction.

Allergic and immunopathological reactions: Rarely developed hypersensitivity syndrome manifested by angioneurotic edema lupus-like syndrome rheumatic polymyalgia dermatomyositis vasculitis thrombocytopenia eosinophilia increased erythrocyte sedimentation rate (ESR) arthritis arthralgia urticaria photosensitivity fever “flushes” blood to the skin face shortness of breath and general weakness.

There have been very rare reports of immune-mediated necrotizing myopathy (autoimmune myopathy) caused by statins. Immune-mediated myopathy is characterized by proximal muscle weakness and elevated serum creatine phosphokinase (CPK) activity that persists despite statin treatment withdrawal. A muscle biopsy shows necrotizing myopathy without significant inflammation. Improvement is seen with therapy with immunosuppressive drugs.

There have also been rare post-registration reports of cognitive impairment (e.g., various memory impairments – forgetfulness memory loss amnesia confusion) associated with statin use. These cognitive impairments have been reported with all statins. The reports were generally classified as non-serious, with varying duration to symptom onset (from 1 day to several years) and time to resolution (median 3 weeks). Symptoms were reversible and resolved after withdrawal of statin therapy.

The following adverse events have been reported with some statins:

– sleep disturbances including nightmares;
– sexual dysfunction gynecomastia.

Laboratory indices

There have been rare reports of the development of a marked and persistent increase in the activity of “hepatic” transaminases. Increased activity of alkaline phosphatase and gamma-glutamyl transpeptidase has also been reported. Deviations in liver function tests are usually mild and transient. There are reports of cases of increased CPK activity.

Elevations in glycosylated hemoglobin (HbAlc) and fasting serum glucose concentrations have been reported with statins including Zocor®.

Children and adolescents (10-17 years)

In a clinical study involving patients aged 10-17 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of treatment in the group taking Zocor® was comparable to the safety and tolerability profile of the group taking placebo.

Overdose

A few cases of overdose have been reported with a maximum dose of 36 g. No overdose effects have been observed in any patient.

The treatment of overdose is generalized, including supportive and symptomatic therapy.

Similarities