Simvastatin, 10 mg 30 pcs

Pharmacotherapeutic group: hypolipidemic drug, HMG-CoA reductase inhibitor.

ATX code: C10AA01

Pharmacological properties

Simvastatin is a hypolipidemic drug synthetically produced from Aspergillus terreus fermentation product.

Pharmacodynamics:

. After oral administration simvastatin, which is an inactive lactone, undergoes hydrolysis in the liver to form the appropriate form of β-hydroxy acid simvastatin, which is the main metabolite and has high inhibitory activity against HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, the enzyme catalyzing the initial and most important stage of cholesterol biosynthesis.

. Clinical studies have shown the effectiveness of simvastatin in reducing plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C), as well as increasing the concentration of high density lipoprotein cholesterol (HDL-C) in patients with heterozygous familial and non-familial hypercholesterolemia or mixed hyperlipidemia in cases where elevated cholesterol concentration is a risk factor and diet alone is not sufficient. Noticeable therapeutic effect is observed within 2 weeks of taking the drug, the 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 that catalyzes the reaction of mevalonate formation from HMG-CoA. Despite this, simvastatin administration in therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows to maintain the production of biologically necessary amount of mevalonate. Since the early stage of cholesterol biosynthesis is conversion of HMG-CoA to mevalonate, it is believed that simvastatin administration 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 biosynthesis processes in the body.

While cholesterol is a precursor of all steroid hormones, no clinical effect of simvastatin on steroidogenesis has 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 the high-affinity LDL receptor. The mechanism of reduction of LDL cholesterol concentration after simvastatin administration may be due to both a decrease in the concentration of LDL cholesterol and activation of LDL receptor, which leads to a decrease in formation and increased catabolism of LDL cholesterol. Simvastatin therapy also significantly decreases the concentration of apolipoprotein B (apo B). Since each LDL 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 a multicenter, randomized, double-blind, placebo-controlled trial, simvastatin reduced the risk of overall mortality by 30%, CHD mortality by 42%, and the incidence of nonfatal confirmed myocardial infarctions by 37%. Simvastatin also reduced the risk of the need for surgical interventions to restore coronary blood flow (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes mellitus, the risk of major coronary complications was reduced by 55%. Moreover, simvastatin significantly (by 28%) reduced the risk of fatal and non-fatal cerebrovascular events (strokes and transient cerebrovascular events).

In a multicenter, randomized, double-blind, placebo-controlled Heart Protection Study (HPS), the effectiveness of simvastatin therapy was demonstrated in patients with or without hyperlipidemia who were at high risk for CHD due to concomitant diabetes mellitus, a history of stroke, and other vascular disease. Before starting 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 by 18%, and 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), as well as 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 mellitus, peripheral vascular disease or cerebrovascular disease. In patients with diabetes mellitus, simvastatin reduced by 21% the risk of serious vascular complications, including the need for surgery to restore peripheral blood flow, amputation of the lower extremities, and the occurrence of trophic ulcers.

In another multicenter, placebo-controlled study using coronary blood flow quantification, simvastatin (as measured by coronary angiography) slowed the progression of coronary atherosclerosis and the appearance of both new areas of atherosclerosis and new total occlusions, whereas patients treated with standard therapy had a steady progression of atherosclerotic coronary artery damage.

Subgroup analysis of two studies that included patients with hypertriglyceridemia (hyperlipidemia type IV according to Fredrickson classification) showed that simvastatin in dose from 20 to 80 mg per day reduced TG concentration by 21 – 39% (in placebo group by 11-13%), LDL cholesterol – by 23-35% (in the placebo group by 1-3%), non-high-density lipoprotein cholesterol (non-HDL cholesterol, calculated as the difference between the concentration of CHC 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 at a dose of 80 mg daily reduced LDL-C concentration, including intermediate density lipoproteins (IDL) by 51% (in the placebo group by 8%>;), and the concentration of LDL cholesterol including intermediate-density lipoprotein (IDL) and LDL-LPP by 60% (4% in the placebo group).

Pharmacokinetics:

Metabolism

Simvastatin is an inactive lactone that is rapidly hydrolyzed. converting to simvastatin β-hydroxy acid (L-654,969), a strong HMG-CoA reductase inhibitor. The main metabolites of simvastatin in blood plasma are simvastatin β-hydroxy acid (L-654,969) and its b’-hydroxy, b’-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) as well as active and latent inhibitors (all inhibitors) resulting from hydrolysis. Both types of metabolites are detected in plasma during oral administration of simvastatin.

Hydrolysis of simvastatin mainly occurs by “primary passage” through the liver, so the concentration of unchanged simvastatin in human plasma is low (less than 5% of the dose taken). Maximum concentration (Cmax) in blood plasma of simvastatin metabolites is reached in 1.3-2.4 hours after a single oral dose. In the study with using 14C-labeled simvastatin plasma concentration of total radioactivity (14C-labeled simvastatin + 14C-labeled simvastatin metabolites) 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, linear character of AUC profile (area under the curve “concentration – time”) of active metabolites in general blood stream is maintained when increasing dose up to 120 mg.

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-654.969 in the systemic bloodstream is less than 5% of the oral dose; 95% of this amount is in the protein-bound state.

The result of active metabolism of simvastatin in the liver (more than 60% in men) is its low concentration in the total blood flow.
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 in the bile. In the study, when taking 100 mg of the drug (5 capsules of 20 mg), 14C-labeled simvastatin 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 by both metabolic products of simvastatin excreted with bile and unabsorbed labeled simvastatin. Less than 0.5% 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 the bulk of simvastatin metabolic products are inactive or weak HMG-CoA reductase inhibitors. In a study examining the proportionality of simvastatin doses of 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 an oral single dose of the appropriate HMG-CoA reductase inhibitor (statin) was approximately 2 times higher than in healthy volunteers. In a study with healthy volunteers, the use of simvastatin at a maximum dose of 80 mg had no effect on the metabolism of midazolam and erythromycin, which are substrates of CYP3A4 isoenzyme. This means that simvastatin is not an inhibitor of CYP3A4 isoenzyme and suggests that oral administration of simvastatin has no effect on plasma concentrations of drugs metabolized by CYP3A4 isoenzyme.

It is known that cyclosporine increases AUC of HM-CoA reductase inhibitors, although the mechanism of drug interaction is not fully understood. The increase in AUC of simvastatin is presumably associated, in particular, with inhibition of CYP3A4 isoenzyme and/or OATP1B1 transport protein (see CONTRAINDICATIONS). In a pharmacokinetic study with diltiazem there was a 2.7-fold increase in AUC of simvastatin β-hydroxy acid, presumably due to inhibition of CYP3A4 isoenzyme (see DISCUSSION, Myopathy/Rhabdomyolysis).

In a pharmacokinetic study with amlodipine there was a 1.6-fold increase in AUC of β-hydroxy acid of simvastatin (see SPECIAL MEASURES, Myopathy/Rhabdomyolysis).

In a pharmacokinetic study with 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 of β-hydroxy acid of simvastatin in blood plasma (see DISCUSSION NOTES, Myopathy/Rabdomyolysis).

The specific pathways of fusidic acid metabolism in the liver are unknown, but interactions between fusidic acid and statins that are metabolized by the CYP3A4 isoenzyme can be assumed (see DISCUSSIONS, Myopathy/Rhabdomyolysis).

The risk of myopathy is increased when plasma concentrations of HMG-CoA reductase inhibitors are elevated. Strong CYP3A4 isoenzyme inhibitors may increase the concentration of HMG-CoA reductase inhibitors and lead to an increased risk of myopathy (see INTERACTION WITH OTHER MEDICINES; SPECIAL NOTES. Myopathy/Rhabdomyolysis).

Active ingredient

Simvastatin

Composition

One film-coated tablet contains:

active ingredient:

simvastatin – 10 mg;

excipients:

microcrystalline cellulose – 70.00 mg,

lactose monohydrate (milk sugar) – 21.00 mg,

pregelatinized starch (starch 1500) – 33.73 mg,

Colloidal silica (aerosil) – 0,75 mg,

ascorbic acid – 2,50 mg,

Butylhydroxyanisole – 0,02 mg,

Stearic acid – 1,25 mg,

Magnesium stearate – 0.75 mg,

Polyvinyl alcohol – 2,33 mg,

Macrogol (polyethylene glycol) – 1,18 mg,

Iron oxide dye – 0,02 mg,

Talc – 0.86 mg,

iron oxide yellow dye – 0,28 mg,

iron oxide red dye – 0,19 mg,

titanium dioxide – 0,97 mg.

How to take, the dosage

Before treatment with Simvastatin, the patient should be prescribed a standard hypocholesterolemic diet, which should be followed during the entire course of treatment. Recommended doses of simvastatin are from 5 to 80 mg per day. The drug should be taken once a day in the evening. If necessary, the dose is increased at intervals of at least 4 weeks to a maximum of 80 mg once daily in the evening. The dose of 80 mg daily is recommended only for patients at high risk of cardiovascular complications if treatment with the drug at lower doses has failed to achieve target lipid levels. and the expected benefits of therapy exceed the possible risks (see DISCUSSION. Myopathy/Rhabdomyolysis).

Patients with coronary heart disease or high risk of CHD

. Standard initial dose of Simvastatin for patients with high risk of CHD in combination with or without hyperlipidemia (in presence of diabetes mellitus, history of stroke or other cerebrovascular diseases, peripheral vascular diseases) as well as for patients with CHD is 40 mg once daily in the evening. Drug therapy should be prescribed simultaneously with diet and physical therapy.

Patients with hyperlipidemia without the above mentioned risk factors

The standard starting dose of Simvastatin is 20 mg once daily in the evening.
For patients who need significant (more than 45%) decrease of LDL-C concentration, the starting dose may be 40 mg once daily in the evening. In patients with mild or moderate hypercholesterolemia simvastatin therapy can be administered in a starting dose of 10 mg once daily. If necessary, the doses should be adjusted according to the above scheme (see DOSAGE AND DOSES).

Patients with homozygous familial hypercholesterolemia

Simvastatin 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, the drug 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 simvastatin, the daily dose of simvastatin should not exceed 40 mg

Companion therapy

The drug simvastatin may be administered both in monotherapy and in combination with bile acid sequestrants.

In patients taking Simvastatin concomitantly with fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate, the maximum recommended dose of Simvastatin is 10 mg daily. For patients taking amiodarone, verapamil, diltiazem or amlodipine simultaneously with simvastatin, the daily dose of Simvastatin should not exceed 20 mg.

In renal impairment

As simvastatin 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 at doses greater than 10 mg per day should be carefully weighed. If such doses are considered necessary, they should be prescribed with caution.

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

The recommended starting dose is 10 mg daily in the evening. The recommended dosing regimen is 10-40 mg daily, the maximum recommended dose of Simvastatin is 40 mg daily. The doses are adjusted 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 concentrations 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, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, gelaprevir, nefazodone, drugs containing cobicistat) and simvastatin is contraindicated (see Table 1. CONTRAINDICATIONS; DISCUSSIONS, Myopathy/Rhabdomyolysis).

Hemfibrozil, cyclosporine, or danazole. See CONTRAINDICATIONS; SPECIAL NOTES. Myopathy/Rhabdomyolysis.

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 (see CONTRAINDICATIONS; SPECIAL NOTES, Myopathy/Rhabdomyolysis).

Amiodarone. The risk of myopathy/rhabdomyolysis is increased with concomitant use of amiodarone with simvastatin. In a clinical study, the incidence of myopathy in patients who concomitantly took simvastatin at a dose of 80 mg and amiodarone was 6% (see DOSAGE AND DOSE; DISCUSSIONS, Myopathy/Rhabdomyolysis).

Slow calcium channel blockers. The risk of myopathy/rhabdomyolysis increases with the simultaneous use of verapamil, diltiazem or amlodipine with simvastatin (see CONTINUATION AND DOSAGE; SPECIFIC DATA, Myopathy/Rhabdomyolysis).

Lomitapide. The risk of myopathy/rhabdomyolysis may be increased with concomitant use of lomitapide with simvastatin (see DOSAGE AND DOSES; SPECIAL DIRECTIONS, Myopathy/Rhabdomyolysis).

Moderate CYP3A4 isoenzyme inhibitors (e.g. dronedarone). When concomitant use of drugs with moderate inhibitory activity against CYP3A4 and simvastatin, especially in higher doses, the risk of myopathy may increase (see DISCUSSION: Myopathy/Rhabdomyolysis). If Simvastatin and moderate CYP3A4 isoenzyme inhibitors are used concomitantly, Simvastatin dose reduction may be required.

Ranolazine (moderate CYP3A4 isoenzyme inhibitor). Concomitant use of ranolazine and simvastatin may increase the risk of myopathy (see DISCUSSION, Myopathy/Rhabdomyolysis). If Simvastatin and ranolazine are used concomitantly, the dose of Simvastatin may need to be reduced.

OATP1B1 transport protein inhibitors. 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 increased risk of myopathy (see CONTRAINDICATIONS; SPECIAL NOTES: Myopathy/Rhabdomyolysis).

Fusidic acid. Concomitant use of fusidic acid and simvastatin may increase the risk of myopathy (see SPECIAL NOTES: Myopathy/Rhabdomyolysis).

Nicotinic acid (at least 1 g/day). When concomitant use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g/day) there have been described cases of myopathy/rhabdomyolysis (see GENERAL DESCRIPTION: Myopathy/Rhabdomyolysis).

Colchicine. When concomitant use of colchicine and simvastatin in patients with
renal insufficiency there have been described cases of myopathy and rhabdomyolysis. In case of combined therapy with these drugs these patients should be under close supervision.

Indirect anticoagulants (coumarin derivatives). Simvastatin at a dose of 20-40 mg daily potentiates the effect of coumarin anticoagulants: prothrombin time, defined as the international normalized ratio (MHO), increases from baseline of 1.7 to 1.8 in healthy volunteers and from 2.6 to 3.4 in patients with hypercholesterolemia. In patients taking coumarin anticoagulants, prothrombin time should be determined before the start of simvastatin therapy, and often enough during the initial period of treatment to exclude significant changes in this index. As soon as a stable MHO value is achieved, its further determination should be performed 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.

Other interactions

Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme and may increase plasma concentrations of drugs metabolized by the CYP3A4 isoenzyme. When using the juice in the usual amount (1 cup 250 ml per day), this effect is minimal (there is a 13% increase in HMG-CoA reductase inhibitors activity when assessed by the AUC value) and has no clinical significance. However, consumption of grapefruit juice in large volumes significantly increases plasma HMG-CoA reductase inhibitor activity. In this regard, consumption of grapefruit juice during therapy with simvastatin should be avoided (see SPECIAL NOTES: Myopathy/Rhabdomyolysis).

Special Instructions

Myopathy/Rhabdomyolysis

Simvastatin, like other statins, may cause myopathy, which is manifested by muscle pain, soreness or weakness and is accompanied by an increase in CPK activity (more than 10 times the GFR). Myopathy may manifest as rhabdomyolysis, sometimes accompanied by secondary acute renal failure due to myoglobinuria. In rare cases, a lethal outcome has been observed. Risk of myopathy development is increased with increase of plasma concentration of substances with inhibitory effect against HMG-CoA reductase. Risk factors for myopathy include older age (65 years and older), female gender, uncontrolled hypothyroidism, and impaired renal function.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose-dependent. In clinical studies, the incidence of myopathy was 0.03%, 0.08%, and 0.61% in doses of 20, 40, and 80 mg daily, respectively. In these studies, patients were closely monitored and a number of drugs that may interact with simvastatin were not used.

In a clinical trial in which patients with a history of myocardial infarction were taking Simvastatin at a dose of 80 mg daily, the incidence of myopathy was approximately 1.0%, and in patients taking the drug at a dose of 20 mg daily it was 0.02%. Approximately half of the cases of myopathy were reported during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.

In patients taking simvastatin at a dose of 80 mg per day, the risk of myopathy is higher than with other statins causing a comparable decrease in LDL cholesterol concentrations. Therefore, this drug at a dose of 80 mg per day should be administered only to patients at high risk of cardiovascular complications, in whom therapy with the drug at lower doses has not achieved the desired therapeutic effect, and the expected benefit of treatment exceeds the possible risk. If a patient taking Simvastatin at a dose of 80 mg requires treatment with another drug that may interact with Simvastatin, the dose of Simvastatin should be reduced or another statin with less potential for possible drug interaction should be prescribed (see CONTRAINDICATIONS: DOSAGE AND DOSE).

All patients starting therapy with Simvastatin, as well as patients who need to increase the dose, should be warned about the possibility of myopathy and informed to seek immediate medical attention if any unexplained muscle pain, muscle soreness or muscle weakness occurs. Therapy with the drug should be discontinued immediately if myopathy is suspected or diagnosed. The presence of the above symptoms and/or more than a 10-fold increase in CPK activity compared to IGN indicates the presence of myopathy. In most cases, after immediate discontinuation of Simvastatin, myopathy symptoms resolve and CPK activity decreases. In patients starting Simvastatin or switching to higher doses of the drug, periodic determination of CPK activity is advisable, but there is no guarantee that such monitoring can prevent the development of myopathy.

Many patients who underwent rhabdomyolysis during therapy with Simvastatin have a complicated history, including impaired renal function, usually due to diabetes mellitus. Such patients require more careful monitoring. Therapy with Simvastatin should be temporarily discontinued several days before major surgical interventions, as well as during the postoperative period.

In a clinical trial in which patients at high risk for cardiovascular disease were taking simvastatin at a dose of 40 mg once daily, the incidence of myopathy was approximately 0.24% among patients of Chinese ethnicity and 0.05% among patients of other ethnicity. Although the only Chinese patients in this clinical trial were of the Mongoloid race, caution should be exercised when prescribing simvastatin to patients of the Mongoloid race, particularly when prescribing it at low doses.

The risk of myonathy/rhabdomyolysis increases with concomitant use of Simvastatin with the following drugs.

Controlled combinations of drugs

• Severe inhibitors of CYP3A4 isoenzyme. Concomitant therapy with strong CYP3A4 isoenzyme inhibitors at therapeutic doses (e.g., itraconazole, ketoconazole, nosaconazole, voriconazole, erythromycin, clarithromycin, telitrominin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone or drugs containing cobicistat) is contraindicated. If short-term treatment with strong CYP3A4 isoenzyme inhibitors cannot be avoided, therapy with Simvastatin should be interrupted during their use (see CONTRAINDICATIONS; INVOLVEMENT WITH OTHER MEDICINES).
• Hemfibrozil, cyclosporine or danazole. Simultaneous use of these drugs with Simvastatin is contraindicated (see CONTRAINDICATIONS; CONTRAINDICATIONS WITH OTHER MEDICINATIONS).

Other Drugs

• Other Fibrates. In patients taking fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate, the dose of simvastatin should not exceed 10 mg per day. If simvastatin and fenofibrate are used concomitantly, the risk of myopathy does not exceed the sum of the risks of treatment with each drug separately. Fenofibrate in combination with simvastatin should be administered with caution, since both drugs may cause the development of myopathy. Adding fibrate therapy to simvastatin therapy usually leads to a small additional decrease in LDL cholesterol concentrations, but a more pronounced decrease in TG concentrations and increase in HDL cholesterol concentrations can be achieved. In small short clinical trials in which both drugs were used under close supervision, combination therapy of fibrates with simvastatin was not accompanied by the development of myopathy (see INTRODUCTION WITH OTHER MEDICINES). In patients taking amiodarone the dose of simvastatin should not exceed 20 mg per day (see CONTRAINDICATIONS WITH OTHER MEDICINATIONS). In patients taking veraquiamil, diltnazem or amlodipine the dose of simvastatin should not exceed 20 mg per day (see CONTRAINDICATIONS WITH OTHER MEDICINATIONS). In patients with homozygous familial hypercholesterolemia who are taking lomitapide, the dose of simvastatin should not exceed 40 mg per day (see CONTRAINDICATIONS WITH OTHER MEDICINES). Concomitant use of drugs with moderate inhibitory activity against CYP3A4 isoenzyme and simvastatin, especially in higher doses, may increase the risk of myopathy. Simultaneous use of simvastatin with moderate CYP3A4 isoenzyme inhibitors may require correction of simvastatin dose.
• Fusidic acid. Concomitant use of fusidic acid and simvastatin may increase the risk of myopathy (see INTERACTING WITH OTHER MEDICINES). Simultaneous use of simvastatin and fusidic acid is not recommended. If the use of systemic agents of fusidic acid is considered necessary, Simvastatin should be withdrawn for the period of this therapy. In exceptional cases where prolonged therapy with systemic fusidic acid is necessary, such as for the treatment of severe infections, the simultaneous use of Simvastatin and fusidic acid should be considered on a case by case basis and the combined therapy should be conducted under close medical supervision.
• Nicotinic acid (in lipid-lowering doses of at least 1 g/day). If Simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g/day) are used concomitantly, cases of myopathy/rhabdomyolysis have been described. In a clinical study involving patients at high risk of cardiovascular disease and well-controlled LDL-C concentration with simvastatin at a dose of 40 mg/day with or without ezetimibe 10 mg/day it was shown that there is no additional positive effect on cardiovascular outcomes when concomitant use of nicotinic acid in lipid-lowering doses (at least 1 g/day). Thus, the benefit of concomitant use of simvastatin with nicotinic acid at lipid-lowering doses (at least 1 g/day) should be carefully weighed against the potential risks of combined therapy. In addition, the incidence of myopathy in this study was approximately 0.24% among Chinese patients when taking simvastatin at 40 mg or simvastatin/ezetimibe at 40/10 mg compared to 1.24%) among Chinese patients when taking simvastatin at 40 mg or simvastatin/ezetimibe at 40/10 mg simultaneously with a 40 mg/2 g slow-release laropiprant/nicotinic acid dose. Despite the fact that in this clinical trial the only representatives of Mongoloid race were patients of Chinese nationality, concomitant use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g/day) in patients of Mongoloid race is not recommended, since the incidence of myopathy is higher in patients of Chinese nationality than in patients of other nationalities (see “Interrelationships between Chinese and other nationalities”).

Impacts on the liver

In some adult patients taking Simvastatin, a sustained increase in “hepatic” enzyme activity (more than 3 times the GFR) has been observed.) When therapy was discontinued or interrupted, hepatic transaminase activity usually gradually returned to baseline levels.

Elevated hepatic transaminase activity was not associated with jaundice or other clinical symptoms. No hypersensitivity reactions were detected. Some of the above patients had abnormal results of functional liver tests before treatment with Simvastatin and/or abused alcohol.

Liver function tests are recommended for all patients before initiation of treatment and then according to clinical indications. Patients who are planned to increase the dose of simvastatin up to 80 mg per day should have additional liver function tests before starting the indicated dosage, then 3 months after the start of its use and then regularly repeated (e.g., once every six months) during the first year of treatment.

Particular attention should be paid to patients with elevated “hepatic” transaminase activity. These patients should have liver function tests repeated as soon as possible and thereafter regularly until normalization of the activity of “hepatic” transaminases. In cases where the activity of hepatic transaminases increases, especially with a steady 3-fold excess of HGH, the drug should be discontinued. Increased alanine aminotransferase (AJ1T) activity may be caused by muscle damage, so increased AL G and CPK activity may indicate the development of myopathy.

Rare post-registration reports of fatal and non-fatal cases of hepatic failure have been reported in patients taking statins, including simvastatin. If during simvastatin treatment severe liver damage with clinical symptoms and/or hyperbilirubinemia or jaundice develops, therapy should be immediately discontinued. If no other cause of this pathology has been identified, re-prescription of the drug is contraindicated. In patients who abuse alcohol and/or patients with liver dysfunction, the drug should be used with extreme caution. Active liver disease or unexplained increase in the activity of “hepatic” transaminases are contraindications to the prescription of Simvastatin.

In treatment with Simvastatin, as in the treatment with other hypolipidemic drugs, a moderate (less than 3-fold higher) increase in “hepatic” transaminases was observed. These changes appeared soon after the start of treatment, were often transient, were not accompanied by any symptoms, and did not require interruption of treatment.

Ophthalmologic examination

The data of current long-term clinical studies contain no information regarding adverse effects of Simvastatin on the human eye lens.

The use in children aged 10-17 years

The safety and efficacy of Simvastatin in children aged 10-17 years with heterozygous familial hypercholesterolemia have been evaluated in controlled clinical trials with young men 10-17 years and girls 10-17 years at least 1 year after menarche. In pediatric patients taking Simvastatin, the adverse event profile was comparable to that of patients taking placebo. The use of Simvastatin at a dose greater than 40 mg per day has not been studied in pediatric patients. In this study, there was no observable effect of simvastatin administration on growth and puberty in boys and girls or any effect on the duration of menstrual cycle in girls. Girls should be advised of appropriate contraceptive methods during treatment with Simvastatin. The use of simvastatin has not been studied in children younger than 10 years and in girls 10-17 years before menarche.

The use in elderly patients

In patients aged over 65 years, the efficacy of Simvastatin, as assessed by the level of reduction in the concentration of CHB and LDL cholesterol, was similar to that observed in the general population. No significant increase in the incidence of adverse events or changes in laboratory parameters were observed. However, in a clinical trial of Simvastatin at a dose of 80 mg per day, an increased risk of myopathy was observed in patients older than 65 years compared to patients younger than 65 years.

Impact on the ability to drive vehicles and operate machinery

Simvastatin has no or negligible effect on the ability to drive vehicles and operate machinery. Nevertheless, when driving vehicles or operating machinery, it should be taken into account that rare cases of dizziness have been reported in the post-registration period.

Contraindications

• High sensitivity to any component of the drug.
• Hepatic disease in the active phase or persistent increase in plasma “liver” transaminases of unknown etiology.
• Pregnancy or breast-feeding.
• Age under 18 years of age (except children 10-17 years of age with heterozygous familial hypercholesterolemia) (see INDICATIONS FOR USE).
• Lactose intolerance, lacgase deficiency or glucose-galactose malabsorption.
• Co-treatment with strong CYP3A4 isoenzyme inhibitors (itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and preparations containing cobicistat) (see “CYP3A4 inhibitors”).
• Companion treatment with gemfibrozil, cyclosporine or danazole (see ALIGNMENT WITH OTHER MEDICINARY MEDICINATIONS; SPECIAL DIRECTIONS, Myopathy/Rhabdomyolysis). Myopathy/Rhabdomyolysis).

WARNING

. Patients who have undergone rhabdomyolysis during simvastatin therapy with a complicated history (impaired renal function, usually due to diabetes mellitus) require closer monitoring and simvastatin therapy should be temporarily stopped in these patients several days before major surgical interventions and also in the postoperative period.

In patients with persistently elevated serum transaminase activity (exceeding 3 times the upper limit of normal), the drug should be discontinued; in severe renal failure (CK < 30 ml/min), the appropriateness of prescribing the drug at doses > 10 mg daily should be carefully weighed and, if necessary, should be administered with caution;

If alcohol is abused prior to treatment.

Side effects

The drug Simvastatin 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 Simvastatin.

In pre-registration clinical trials, adverse events occurring with a frequency of at least 1%, which were evaluated by investigators as possibly, probably or definitely related to taking the drug, were abdominal pain, constipation and flatulence. Other adverse events that occurred in 0.5-0.9% of patients were asthenia and headache.

There have been rare reports of the development of myopathy (see DISCUSSION. Myopathy/Rhabdomyolysis).

In a clinical trial (HPS) in which patients took simvastatin at a dose of 40 mg daily or placebo for an average of 5 years, the pattern of adverse events was similar in the simvastatin and placebo groups. The frequency of discontinuation of therapy due to adverse events was also comparable in the two groups (4.8% in the simvastatin group and 5.1% in the placebo group). The incidence of myopathy in patients taking simvastatin was less than 0.1%. Elevation of “hepatic” transaminases activity (more than 3 times the upper limit of normal (ULN), confirmed by repeated study) was observed in 0.21% of patients of simvastatin group and 0.09% of placebo group patients.

There are reports of the possibility of developing the following adverse events (rare: >0.01%) and <0.1%, very rare: <0.01%), frequency not established: the frequency cannot be estimated 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. Frequent Not Established: depression.

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

Respiratory system disorders: Frequency not determined: interstitial lung disease.

Reproductive system disorders: Frequency not established: erectile dysfunction.

Allergic and immunopathological reactions: Rarely developed hypersensitivity syndrome. which was manifested by angioneurotic edema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, blood “flushes” to the skin, 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 creatinephosphokinase (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 (see SPECIAL NOTES: Myopathy/Rhabdomyolysis).

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 findings

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 have been reported cases of increased CPK activity (see SPECIAL NOTES). Increases in glycosylated hemoglobin (HbAlc) and fasting serum glucose concentrations have been reported with statins, including simvastatin.

Children (10-17 years)

In a clinical trial involving patients aged 10-17 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of treatment in the group taking simvastatin was comparable to the safety and tolerability profile of treatment in the group taking placebo (see Table 1. SPECIFIC NOTES, Use in children aged 10-17 years).

Overdose

Several cases of overdose have been reported, the maximum dose taken being 3.6 g. No overdose consequences have been identified in any patient. Overdose is treated with general measures, including supportive and symptomatic therapy.

Similarities

Vasilip, Simvastatin