Simvastatin-Vertex, 20 mg 30 pcs

Pharmacotherapeutic group

Hypolipidemic drug – HMG-CoA reductase inhibitor.

ATC code

C10AA01

Pharmacological properties

Simvastatin is a hypolipidemic agent obtained synthetically from the fermentation product of Aspergillus terreus.

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-methyl-glutaryl 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 total plasma cholesterol (TG), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C), and elevated high-density lipoprotein cholesterol (HDL-C) in patients with heterozygous familial and nonfamilial hypercholesterolemia, or mixed hyperlipidemia, when elevated cholesterol is a risk factor and diet alone is not sufficient.

Significant 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, taking simvastatin at therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows to maintain the production of biologically necessary amount of mevalonate.

Because an early step in cholesterol biosynthesis is the conversion of HMG-CoA to mevalonate, it is believed that simvastatin use 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 carried out by the high-affinity LDL receptor.

The mechanism of reduction of LDL cholesterol concentration after simvastatin administration may be due to both reduction of LDL cholesterol concentration and activation of LDL receptor, which leads to decreased formation and increased catabolism of LDL cholesterol. With simvastatin therapy the concentration of apolipoprotein B (apo B) is also significantly reduced.

Since each LDL particle contains one apo B molecule, 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 LDL-C and LDL-C/HDL-C decrease.

In the Scandinavian study of the effect of simvastatin on survival (4S), the effect of simvastatin therapy on overall mortality (median time to patient participation 5.4 years) was evaluated in 4,444 patients with coronary heart disease (CHD). Simvastatin reduced the risk of overall mortality, CHD mortality, and the incidence of nonfatal confirmed myocardial infarctions.

Simvastatin also reduced the risk of the need for surgical interventions to restore coronary blood flow (aortocoronary bypass or percutaneous transluminal coronary angioplasty). In patients with diabetes mellitus, the risk of major coronary complications was reduced. Moreover, simvastatin significantly reduced the risk of fatal and non-fatal cerebrovascular events (strokes and transient cerebrovascular events).

In the 5-year Heart Protection Study (HPS), the efficacy of simvastatin therapy was demonstrated in 20536 patients with or without hyperlipidemia who were at high risk for CHD due to concomitant diabetes, a history of stroke and other vascular disease.

. In this multicenter, randomized, double-blind, placebo-controlled trial, simvastatin at a dose of 40 mg/day compared with placebo reduced overall mortality, risk of CHD-related death, risk of major coronary complications (including nonfatal myocardial infarction or death coronary intervention (including coronary artery bypass grafting and percutaneous transluminal angioplasty), as well as peripheral blood flow and other noncoronary revascularization.

Simvastatin reduced the risk of stroke as well as the risk of hospitalization for angina. The risk of major coronary and vascular complications was reduced in patients with or without CHD, including patients with diabetes mellitus, peripheral vascular disease or cerebrovascular disease. In patients with diabetes mellitus simvastatin reduced the risk of serious vascular complications, including the need for surgical interventions to restore peripheral blood flow, amputation of the lower extremities, as well as the occurrence of trophic ulcers.

In another multicenter placebo-controlled study involving 404 patients 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 receiving standard therapy had a steady progression of atherosclerotic coronary artery damage.

. A subgroup analysis of 2 studies that included 147 patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia) showed that simvastatin at a dose of 20 to 80 mg/day reduced TG concentration, LDL cholesterol, non-high-density lipoprotein cholesterol (non-HDL cholesterol, calculated as the difference between the COX concentration and HDL concentration) and increased HDL cholesterol.

Analysis of another subgroup of 7 patients with dysbetalipoproteinemia (Fredrickson type III hyperlipidemia), simvastatin at a dose of 80 mg daily reduced LDL-C concentration, including intermediate-density lipoprotein (IDL), as well as LDL-C and LDL-C concentrations.

Pharmacokinetics

Eabsorption

About 85% of the oral dose of simvastatin is absorbed.

Eating food (within standard hypocholesterol diet) immediately after taking the drug does not affect pharmacokinetic profile of simvastatin.

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 bound to plasma proteins.

The result of active metabolism of simvastatin in the liver (more than 60% in men) is 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.

Metabolism

Simvastatin is an inactive lactone that is rapidly hydrolyzed 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 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) 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 (C_max) of simvastatin in blood plasma is reached 1.3-2.4 hours after a single oral dose. In a study using ¹⁴C-labeled simvastatin, the plasma concentration of total radioactivity (¹⁴C-labeled simvastatin + ¹⁴C-labeled simvastatin metabolites) peaked after 4 hours and rapidly decreased to approximately 10% of the maximum within 12 hours of a single oral dose. Despite the range of recommended therapeutic doses of simvastatin from 5 to 80 mg per day, the linear nature of AUC profile (area under the “concentration-time” curve) of active metabolites is maintained when increasing the dose up to 120 mg.

In “primary passage” through the liver simvastatin is metabolized with subsequent excretion of simvastatin and its metabolites in the bile.

In a study of 100 mg of simvastatin (5 20 mg capsules), 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% 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, no significant deviation from the linearity of AUC in the total bloodstream with increasing dose was observed. Pharmacokinetic parameters with single and multiple oral administration of simvastatin showed that simvastatin does not accumulate in tissues with multiple oral administration.

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 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 transport protein OATP1B1 (see section “Contraindications”).

In pharmacokinetic study in concomitant use with diltiazem there was a 2.7-fold increase in AUC of β-hydroxy acid simvastatin, presumably due to inhibition of CYP3A4 isoenzyme (see section “Special indications” Myopathy/Rhabdomyolysis).

In a pharmacokinetic study, concomitant administration of a single dose (2 g) of slow-release nicotinic acid and simvastatin 20 mg showed a slight increase in AUC of simvastatin and β-hydroxy acid and C_max of β-hydroxy acid simvastatin in plasma (see “Special Indications. Myopathy/Rhabdomyolysis).

The specific pathways of fusidic acid metabolism in the liver are unknown, but it can be assumed that there are interactions between fusidic acid and simvastatin, which are metabolized by CYP3A4 isoenzyme (see section “Special indications” 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 sections “Interaction with other medicinal products” and “Myopathy/Rhabdomyolysis special notes”).

Particular patient groups

The SLCO1B1 gene polymorphism

Carriers of the c.521T˃C allele of the SLCO1B1 gene have lower OATP1B1 transport protein activity. The AUC of the main active metabolite, simvastatin hydroxy acid, is 120% in heterozygous carriers (CT) of the C allele and 221% in homozygous carriers (CC), relative to patients with the most expressed genotype (TT). The frequency of the C allele in the European population is 18%. Patients with SLCO1B1 gene polymorphism have the risk of increased exposure to simvastatin hydroxy acid, which may lead to an increased risk of rhabdomyolysis (see Cautionary Note).

Indications

Patients with coronary heart disease or at high risk of coronary artery disease

In patients at high risk for developing CAD (with or without hyperlipidemia), such as patients with diabetes mellitus, patients with a history of stroke or other cerebrovascular disease, patients with peripheral vascular disease, or patients with CAD or a predisposition to CAD, simvastatin is indicated for:

– reducing the risk of overall mortality by reducing mortality as a result of coronary artery disease;

– reducing the risk of serious vascular and coronary complications: non-fatal myocardial infarction, coronary death, stroke, revascularization procedure;

– reducing the risk of the need for surgical interventions to restore coronary blood flow (such as coronary artery bypass grafting and percutaneous transluminal coronary angioplasty);

– reducing the risk of the need for surgery to restore peripheral blood flow and other types of non-coronary revascularization;

– reducing the risk of hospitalization due to angina attacks.

Hyperlipidemia

– as an adjunct to diet, when the use of diet alone and other non-drug treatments in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (hyperlipidemia type IIa according to the Fredrickson classification) or mixed hypercholesterolemia (hyperlipidemia type IIb according to the Fredrickson classification) is insufficient for:

∙ reducing the increased concentration of total cholesterol, LDL cholesterol, TG, apolipoprotein B (apo B);

∙ increasing the concentration of HDL cholesterol;

∙ reducing the ratio of LDL cholesterol/HDL cholesterol and TC/HDL cholesterol;

– hypertriglyceridemia (hyperlipidemia type IV according to the Fredrickson classification);

– addition to diet and other treatments for patients with homozygous familial hypercholesterolemia to reduce elevated concentrations of total cholesterol, LDL cholesterol and apo B;

– primary dysbetalipoproteinemia (hyperlipidemia type III according to the Fredrickson classification).

Use in children and adolescents with heterozygous familial hypercholesterolemia

The use of simvastatin along with a diet is indicated to reduce elevated concentrations of total cholesterol, LDL cholesterol, TG, apo B in boys 10-17 years old and girls 10-17 years old, at least one year after menarche (first menstrual bleeding), with heterozygous familial hypercholesterolemia.

Pharmacological effect

Pharmacotherapeutic group

Lipid-lowering agent – ​​HMG-CoA reductase inhibitor.

ATX code

S10AA01

Pharmacological properties

Simvastatin is a lipid-lowering agent obtained synthetically from a fermentation product of Aspergillus terreus.

Pharmacodynamics

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

Clinical studies have shown the effectiveness of simvastatin in reducing plasma 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 those cases where elevated cholesterol levels are a risk factor and diet alone is not enough.

A noticeable therapeutic effect is observed within 2 weeks of taking the drug, the maximum therapeutic effect is observed within 4-6 weeks after the start of treatment. The effect persists with continued therapy. When you stop taking simvastatin, cholesterol concentrations return to the original value observed before treatment.

The active metabolite of simvastatin is a specific inhibitor of HMG-CoA reductase, an enzyme that catalyzes the formation of mevalonate from HMG-CoA. Despite this, taking simvastatin in therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows maintaining the production of a biologically necessary amount of mevalonate.

Since the conversion of HMG-CoA to mevalonate is an early step in cholesterol biosynthesis, it is believed that the use of simvastatin should not cause the 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 to all steroid hormones, no clinical effect of simvastatin on steroidogenesis has been observed. Since simvastatin did not increase the lithogenicity of bile, it is unlikely to influence the increase in the incidence of cholelithiasis.

Simvastatin reduces both elevated and normal concentrations of LDL cholesterol. LDL is formed from very low-density lipoproteins (VLDL). LDL catabolism is predominantly mediated by the high-affinity LDL receptor.

The mechanism for reducing the concentration of LDL cholesterol after taking simvastatin may be due to both a decrease in the concentration of VLDL cholesterol and activation of LDL receptors, which leads to a decrease in the formation and increased catabolism of LDL cholesterol. Simvastatin therapy also significantly reduces 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 the concentration of HDL cholesterol and reduces the concentration of TG in the blood plasma. As a result of these changes, the ratios of total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol decrease.

In the Scandinavian Simvastatin Survival Study (4S), the effect of simvastatin therapy on all-cause mortality (median patient participation time 5.4 years) was assessed in 4444 patients with coronary artery disease (CAD). Simvastatin reduced the risk of total mortality, mortality from coronary artery disease, and the incidence of nonfatal confirmed myocardial infarction.

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). In patients with diabetes mellitus, the risk of major coronary complications was reduced. Moreover, simvastatin significantly reduced the risk of fatal and non-fatal cerebrovascular accidents (stroke and transient cerebrovascular accident).

In the 5-year Heart Protection Study (HPS), the effectiveness of simvastatin therapy was demonstrated in 20,536 patients with or without hyperlipidemia who were at high risk for developing coronary artery disease due to concomitant diabetes mellitus, a history of stroke, and other vascular diseases.

In this multicenter, randomized, double-blind, placebo-controlled study, simvastatin 40 mg/day compared with placebo reduced overall mortality, the risk of death attributable to coronary artery disease, the risk of major coronary events (including nonfatal myocardial infarction or death attributable to coronary artery disease), and the need for surgical interventions to restore coronary blood flow (including coronary artery bypass grafting and percutaneous transluminal angioplasty), as well as peripheral blood flow and other types of non-coronary revascularization.

Simvastatin reduced the risk of stroke, as well as the risk of hospitalization for angina pectoris. The risk of major coronary and vascular complications was reduced in patients with or without coronary artery disease, including patients with diabetes mellitus, peripheral vascular disease, or cerebrovascular disease. In patients with diabetes mellitus, simvastatin reduced the risk of developing serious vascular complications, incl. the need for surgical interventions to restore peripheral blood flow, amputation of the lower extremities, as well as the occurrence of trophic ulcers.

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

Subgroup analysis from 2 studies, which included 147 patients with hypertriglyceridemia (hyperlipidemia type IV according to the Fredrickson classification), showed that simvastatin at a dose of 20 to 80 mg/day reduced the concentration of TG, LDL cholesterol, non-high density lipoprotein cholesterol (non-HDL cholesterol, calculated as the difference between the concentration of total cholesterol and the concentration of HDL cholesterol) and increased HDL cholesterol.

In an analysis of another subgroup of 7 patients with dysbetalipoproteinemia (Fredrickson type III hyperlipidemia), simvastatin at a dose of 80 mg per day reduced LDL-C concentrations, including intermediate-density lipoproteins (IDL), as well as VLDL-C and VLDL-C concentrations.

Pharmacokinetics

Suction

About 85% of the ingested dose of simvastatin is absorbed.

Eating (as part of a standard cholesterol-lowering diet) immediately after taking the drug does not affect the pharmacokinetic profile of simvastatin.

Distribution

After oral administration, higher concentrations of simvastatin are detected in the liver than in other tissues.

The concentration of the active metabolite of simvastatin L-654,969 in the systemic circulation is less than 5% of the oral dose; 95% of this amount is bound to plasma proteins.

The result of active metabolism of simvastatin in the liver (more than 60% in men) is its low concentration in the general bloodstream. The possibility of simvastatin penetrating the blood-brain barrier and the blood-placental barrier has not been studied.

Metabolism

Simvastatin is an inactive lactone that is rapidly hydrolyzed to simvastatin β-hydroxy acid (L-654.969), a potent inhibitor of HMG-CoA reductase. The main metabolites of simvastatin in blood plasma are β-hydroxy acid of simvastatin (L-654.969) and its 6′-hydroxy, 6′-hydroxymethyl and 6′-exomethylene derivatives. HMG-CoA reductase inhibition is the quantification criterion for all pharmacokinetic studies of β-hydroxy acid metabolites (active inhibitors) and active and latent inhibitors (all inhibitors) resulting from hydrolysis. Both types of metabolites are detected in blood plasma when simvastatin is taken orally.

Hydrolysis of simvastatin mainly occurs during the “first pass” through the liver, therefore the concentration of unchanged simvastatin in human plasma is low (less than 5% of the dose taken). The maximum concentration (Cmax) of simvastatin in blood plasma is achieved 1.3-2.4 hours after oral administration of a single dose. In a study with 14C-labeled simvastatin, plasma concentrations of total radioactivity (14C-labeled simvastatin + 14C-labeled simvastatin metabolites) peaked at 4 hours and decreased rapidly to approximately 10% of the maximum within 12 hours of a single oral dose. Although the range of recommended therapeutic doses of simvastatin is from 5 to 80 mg per day, the linear nature of the AUC (area under the concentration-time curve) profile of active metabolites is maintained when the dose is increased to 120 mg.

Removal

During the “primary passage” through the liver, simvastatin is metabolized with subsequent excretion of simvastatin and its metabolites in the bile.

In a study, when taking 100 mg of simvastatin (5 capsules of 20 mg), 14C-labeled simvastatin accumulated in the blood, urine and feces. About 60% of the administered dose of labeled simvastatin was detected in feces and about 13% in urine. Labeled simvastatin in feces was represented by both simvastatin metabolic products excreted in bile and unabsorbed labeled simvastatin. Less than 0.5% of the administered dose of labeled simvastatin was detected in the urine as active simvastatin metabolites. In plasma, 14% of AUC was due to active inhibitors and 28% to all HMG-CoA reductase inhibitors.

The latter indicates that the metabolic products of simvastatin are mainly inactive or weak inhibitors of HMG-CoA reductase. In a dose proportionality study of simvastatin, 5, 10, 20, 60, 90 and
120 mg, no significant deviation from linearity in total circulation AUC was observed with increasing dose. Pharmacokinetic parameters for single and repeated oral administration of simvastatin showed that simvastatin does not accumulate in tissues after repeated oral administration.

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

In a study involving healthy volunteers, the use of simvastatin at a maximum dose of 80 mg did not affect the metabolism of midazolam and erythromycin, which are substrates of the CYP3A4 isoenzyme. This means that simvastatin is not an inhibitor of the CYP3A4 isoenzyme and suggests that oral administration of simvastatin does not affect the plasma concentrations of drugs metabolized by the CYP3A4 isoenzyme.

Cyclosporine is known to increase the AUC of HMG-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 the CYP3A4 isoenzyme and/or the transport protein OATP1B1 (see section “Contraindications”).

In a pharmacokinetic study, when used simultaneously with diltiazem, an increase in the AUC of the β-hydroxy acid simvastatin by 2.7 times was observed, presumably due to inhibition of the CYP3A4 isoenzyme (see section “Special Instructions” Myopathy/Rhabdomyolysis).

In a pharmacokinetic study, with the simultaneous use of a single dose (2 g) of nicotinic acid sustained release and simvastatin 20 mg, a slight increase in the AUC of simvastatin and β-hydroxy acid and Cmax of simvastatin β-hydroxy acid in blood plasma was observed (see section “Special Instructions” Myopathy/Rhabdomyolysis).

The specific pathways of metabolism of fusidic acid in the liver are unknown, but it can be assumed that there is an interaction between fusidic acid and simvastatin, which are metabolized by the CYP3A4 isoenzyme (see section “Special Instructions” Myopathy/Rhabdomyolysis).

The risk of developing myopathy increases with increasing concentrations of HMG-CoA reductase inhibitors in the blood plasma. Strong inhibitors of the CYP3A4 isoenzyme may increase the concentration of HMG-CoA reductase inhibitors and lead to an increased risk of developing myopathy (see sections “Interaction with other drugs”, “Special instructions” Myopathy/Rhabdomyolysis).

Special patient groups

Polymorphism of the SLCO1B1 gene

Carriers of the c.521T˃C allele of the SLCO1B1 gene have lower activity of the OATP1B1 transport protein. The AUC of the main active metabolite, the hydroxy acid simvastatin, is 120% in heterozygous carriers (CT) of the C allele and 221% in homozygous carriers (CC), relative to patients with the most severe genotype (TT). The frequency of occurrence of the C allele in the European population is 18%. Patients with SLCO1B1 gene polymorphisms are at risk of increased exposure to the hydroxyacid simvastatin, which may lead to an increased risk of rhabdomyolysis (see Precautions).

Special instructions

Myopathy/rhabdomyolysis

Simvastatin, like other statins, can cause myopathy, which manifests itself as muscle pain, soreness or general weakness and is accompanied by an increase in CPK activity (more than 10 times the upper limit of normal).

Myopathy may manifest itself in the form of rhabdomyolysis, sometimes accompanied by secondary acute renal failure due to myoglobinuria. In rare cases, death has occurred. The risk of developing myopathy increases with increasing plasma concentrations of substances that have an inhibitory effect on HMG-CoA reductase. Risk factors for developing myopathy include older age (65 years or older), female gender, uncontrolled hypothyroidism, and impaired renal function.

As with treatment with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis is dose dependent. In clinical studies (median follow-up of 4 years), the incidence of myopathy at doses of 20, 40 and 80 mg per day was 0.03%, 0.08% and 0.61%, respectively. In these studies, patients were closely monitored and a number of drugs that may interact with simvastatin were not used.

In a clinical study in which patients with a history of myocardial infarction were treated with simvastatin 80 mg daily (mean follow-up 6.7 years), the incidence of myopathy was approximately 1%, compared with 0.02% in patients treated with simvastatin 20 mg daily. 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 developing myopathy is higher than when using other statins that cause a comparable decrease in LDL cholesterol concentrations.

Therefore, simvastatin at a dose of 80 mg per day should be prescribed only to patients with a high risk of cardiovascular complications, in whom therapy with the drug at lower doses did not achieve the desired therapeutic effect, and the expected benefit of treatment outweighs the possible risk.

If a patient taking simvastatin 80 mg requires treatment with another drug that may interact with simvastatin, the dose of simvastatin should be reduced or another statin that has less potential for possible drug interaction should be prescribed (see sections “Contraindications”, “Dosage and Administration”).

All patients starting therapy with simvastatin, as well as patients who need to increase their dose, should be warned about the possibility of myopathy and informed about the need to immediately contact a doctor if any unexplained muscle pain, muscle soreness or muscle weakness occurs.

Simvastatin therapy should be discontinued immediately if myopathy is suspected or diagnosed. The presence of the above symptoms and/or a more than tenfold increase in CPK activity compared to the upper limit of normal indicates the presence of myopathy. In most cases, after immediate discontinuation of simvastatin, the symptoms of myopathy resolve and CPK activity decreases.

In patients starting to take simvastatin or increasing the dose of the drug, periodic monitoring of CPK activity is advisable, but there is no guarantee that such monitoring can prevent the development of myopathy.

Many patients who experienced rhabdomyolysis during simvastatin therapy had a complicated medical history, including impaired renal function, usually due to diabetes mellitus. Such patients require more careful monitoring.

Simvastatin therapy should be temporarily discontinued several days before major surgery and in the postoperative period.

In a clinical study in which patients at high risk for cardiovascular disease received simvastatin 40 mg once daily (median follow-up 3.9 years), the incidence of myopathy was approximately 0.24% among Chinese patients (n=5468) and 0.05% among other ethnicities (n=7367).

Although the only Mongoloid patients in this clinical study were Chinese, caution should be exercised when prescribing simvastatin to Mongoloid patients, particularly when administering it at low doses.

The risk of developing myopathy/rhabdomyolysis increases when simvastatin is used concomitantly with the following drugs:

Contraindicated drug combinations

Strong CYP3A4 inhibitors

Concomitant therapy with strong inhibitors of the CYP3A4 isoenzyme at therapeutic doses (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) is contraindicated. If short-term treatment with strong CYP3A4 inhibitors cannot be avoided, simvastatin therapy should be interrupted for the period of their use (see sections “Contraindications”, “Interaction with other drugs”).

Gemfibrozil, cyclosporine or danazol

The simultaneous use of these drugs with simvastatin is contraindicated (see sections “Contraindications”, “Interaction with other drugs”).

Other medicines

Other fibrates

In patients taking fibrates other than gemfibrozil (see section “Contraindications”) or fenofibrate, the dose of simvastatin should not exceed 10 mg per day. With simultaneous use of simvastatin and fenofibrate, the risk of developing myopathy does not exceed the sum of the risks when treating each drug separately.

Fenofibrate should be used with caution in combination with simvastatin, as both drugs can cause the development of myopathy. Adding fibrate therapy to simvastatin therapy usually results in a small additional reduction in LDL cholesterol concentrations, but allows for a more pronounced reduction in HDL cholesterol concentrations.

In small, short clinical studies in which both drugs were used under close supervision, combination therapy with fibrates and simvastatin was not associated with the development of myopathy (see section “Interactions with other drugs”).

Amiodarone

In patients taking amiodarone, the dose of simvastatin should not exceed 20 mg per day (see section “Interaction with other drugs”).

Blockers of “slow” calcium channels

In patients taking verapamil, diltiazem or amlodipine, the dose of simvastatin should not exceed 20 mg per day (see section “Interactions with other drugs”).

Lomitapide

In patients with homozygous familial hypercholesterolemia taking lomitapide, the dose of simvastatin should not exceed 40 mg per day (see section “Interactions with other drugs”).

Moderate CYP3A4 inhibitors

With simultaneous use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially in high doses, the risk of developing myopathy may increase. When simvastatin is used concomitantly with moderate inhibitors of the CYP3A4 isoenzyme, a dose adjustment of simvastatin may be required.

Fusidic acid

Concomitant use of fusidic acid and simvastatin may increase the risk of developing myopathy (see section “Interaction with other drugs”).

The simultaneous use of simvastatin and fusidic acid is not recommended. If the use of systemic fusidic acid preparations is considered necessary, simvastatin should be discontinued during this therapy.

In exceptional cases where long-term therapy with systemic fusidic acid is necessary, for example for the treatment of severe infections, the possibility of concomitant use of simvastatin and fusidic acid should be considered on a case-by-case basis and combination therapy should be carried out under close medical supervision.

Breast cancer resistance protein (BCRP) inhibitors

Concomitant use of simvastatin and BCRP inhibitors (for example, elbasvir and trazoprevir) may increase plasma concentrations of simvastatin and increase the risk of developing myopathy, so dose adjustment of simvastatin may be required.

Although the concomitant use of simvastatin with elbasvir and trazoprevir has not been studied, for patients taking simvastatin concomitantly with drugs containing elbasvir or trazoprevir, the dose of simvastatin should not exceed 20 mg per day (see section “Interactions with other drugs”).

Nicotinic acid (in lipid-lowering doses of at least 1 g per day)

With the simultaneous use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g per day), cases of myopathy/rhabdomyolysis have been described.

In a clinical trial (median follow-up of 3.9 years) in patients at high risk of cardiovascular disease and well-controlled LDL-C concentrations, using simvastatin at a dose of 40 mg per day with or without ezetimibe, it was shown that there was no additional positive effect on cardiovascular outcomes with concomitant use of niacin at lipid-lowering doses (at least 1 g per day).

Thus, the benefit of simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g per day) should be carefully weighed against the potential risks of combination therapy. Additionally, in this study, the incidence of myopathy was approximately 0.24% among Chinese patients receiving simvastatin 40 mg or simvastatin/ezetimibe 40/10 mg, compared with 1.24% among Chinese patients receiving simvastatin 40 mg or simvastatin/ezetimibe 40/10. mg simultaneously with laropiprant/nicotinic acid sustained release at a dose of 40 mg/2 g.

Despite the fact that in this clinical study the only representatives of the Mongoloid race were patients of Chinese nationality, the simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g / day) in patients of the Mongoloid race is not recommended, since the incidence of myopathy is higher than in patients of other nationalities (see section “Interaction with other drugs”).

Effect on the liver

Some adult patients taking simvastatin experienced sustained elevations in liver enzymes (more than 3 times the upper limit of normal). When simvastatin therapy was discontinued or interrupted, the activity of liver transaminases gradually returned to the initial level.

Increased activity of liver transaminases was not associated with jaundice or other clinical symptoms. No hypersensitivity reactions were identified. Some of the above patients had abnormal liver function tests before starting treatment with simvastatin and/or abused alcohol.

Before starting treatment, and then in accordance with clinical indications, liver function tests are recommended in all patients. For patients in whom the dose of simvastatin is planned to be increased to 80 mg per day, additional liver function tests should be performed before starting the indicated dose, then after 3 months after starting its use, and then regularly repeated (for example, once every six months) during the first year of treatment.

Particular attention should be paid to patients with increased activity of “liver” transaminases. These patients need to repeat liver function tests in the near future and then regularly until the activity of “liver” transaminases normalizes. In cases where the activity of “liver” transaminases increases, especially when the upper limit of normal is persistently exceeded by 3 times, the drug should be discontinued.

The cause of increased alanine aminotransferase (ALT) activity may be muscle damage, so increased ALT and CPK activity may indicate the development of myopathy (see section “Special Instructions” Myopathy/Rhabdomyolysis).

There have been rare post-marketing reports of fatal and non-fatal cases of liver failure in patients taking statins, including simvastatin.

If severe liver damage with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with simvastatin, therapy should be discontinued immediately. If no other cause for the development of this pathology has been identified, re-prescribing simvastatin is contraindicated.

In patients who abuse alcohol and/or in patients with impaired liver function, the drug should be used with extreme caution. Active liver disease or unexplained increases in liver transaminases are contraindications for the use of simvastatin.

During treatment with simvastatin, as with treatment with other lipid-lowering drugs, a moderate (exceeding the upper limit of normal by no more than 3 times) increase in the activity of “liver” 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.

Ophthalmological examination

Data from modern long-term clinical studies do not contain information regarding the adverse effects of simvastatin on the human lens.

Use in children and adolescents aged 10-17 years

The safety and effectiveness of simvastatin in children and adolescents aged 10-17 years with heterozygous familial hypercholesterolemia were assessed in controlled clinical studies in boys aged 10-17 years and girls aged 10-17 years at least one year after menarche. In pediatric patients receiving simvastatin, the adverse event profile was comparable to that of patients receiving placebo.

The use of simvastatin at a dose of more than 40 mg per day has not been studied in pediatric and adolescent patients. In this study, there was no significant effect of simvastatin on the growth and puberty of boys and girls or any effect on the length of the menstrual cycle in girls. Girls should be advised about proper methods of contraception during treatment with simvastatin (see section “Contraindications”).

The use of simvastatin has not been studied in children under 10 years of age or in girls 10–17 years of age before menarche.

Use in elderly patients

In patients over the age of 65 years, the effectiveness of simvastatin, assessed by the degree of reduction in total cholesterol and LDL cholesterol, was similar to the effectiveness observed in the general population.

There was no significant increase in the frequency of adverse events or changes in laboratory parameters. However, in a clinical study of simvastatin 80 mg daily, patients over 65 years of age had an increased risk of developing myopathy compared with patients under 65 years of age.

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Simvastatin

Composition

One film-coated tablet contains:

Dosage 10 mg

active ingredient:

simvastatin – 10.00 mg;

excipients:

lactose monohydrate – 69.23 mg;

corn starch – 7.00 mg;

microcrystalline cellulose 101 − 5.00 mg;

ascorbic acid – 2.50 mg;

hyprolose (hydroxypropylcellulose) – 2.00 mg;

croscarmellose sodium – 2.00 mg;

citric acid monohydrate – 1.25 mg;

butylated hydroxyanisole – 0.02 mg;

calcium stearate – 1.00 mg;

film shell:

hypromellose – 2.0000 mg,

hyprolose (hydroxypropylcellulose) – 0.7760 mg,

talc – 0.7704 mg, titanium dioxide – 0.0440 mg,

iron dye black oxide – 0.1616 mg,

red iron oxide dye – 0.1560 mg,

iron oxide yellow dye – 0.0920 mg or dry mixture for film coating containing

hypromellose (50%),

hyprolose (hydroxypropylcellulose) (19.4%),

talc (19.26%),

titanium dioxide (1.1%),

iron dye black oxide (4.04%),

iron oxide red dye (3.9%),

iron oxide yellow dye (2.3%) – 4.0000 mg.

Dosage 20 mg

active ingredient: simvastatin – 20.00 mg;

excipients:

lactose monohydrate – 138.46 mg;

corn starch – 14.00 mg;

microcrystalline cellulose 101 − 10.00 mg;

ascorbic acid – 5.00 mg;

hyprolose (hydroxypropylcellulose) – 4.00 mg;

croscarmellose sodium – 4.00 mg;

citric acid monohydrate – 2.50 mg;

butylated hydroxyanisole – 0.04 mg;

calcium stearate – 2.00 mg;

film shell:

hypromellose – 4.0000 mg,

hyprolose (hydroxypropylcellulose) – 1.5520 mg,

talc – 1.5408 mg,

titanium dioxide – 0.0880 mg,

iron dye black oxide – 0.3232 mg,

red iron oxide dye – 0.3120 mg,

iron oxide yellow dye – 0.1840 mg or dry mixture for film coating containing

hypromellose (50%),

hyprolose (hydroxypropylcellulose) (19.4%),

talc (19.26%),

titanium dioxide (1.1%),

iron dye black oxide (4.04%),

iron oxide red dye (3.9%),

iron oxide yellow dye (2.3%) – 8.0000 mg.

Pregnancy

Pregnancy

Simvastatin is contraindicated in pregnant women. Since safety in pregnant women has not been proven and there is no evidence that treatment with simvastatin during pregnancy provides obvious benefit, the drug should be discontinued immediately if pregnancy occurs. The use of simvastatin during pregnancy may reduce the concentration of mevalonate (a precursor in cholesterol biosynthesis) in the fetus. Atherosclerosis is a chronic disease and usually stopping lipid-lowering drugs during pregnancy has little effect on the long-term risks associated with primary hypercholesterolemia. Therefore, the drug should not be used in women who are pregnant, trying to become pregnant, or suspect that they are pregnant. Treatment with the drug should be suspended for the entire duration of pregnancy or until pregnancy is diagnosed, and the woman herself is warned about the possible danger to the fetus (see section “Contraindications”).

Breastfeeding period

There are no data on the excretion of simvastatin and its metabolites in milk. If it is necessary to prescribe the drug to a woman during breastfeeding, it should be taken into account that many drugs pass into breast milk, and there is a risk of developing serious adverse reactions. As a result, the drug should be discontinued during breastfeeding.

Contraindications

Contraindications

– hypersensitivity to any component of the drug;

– liver disease in the active phase or persistent increase in the activity of “liver” transaminases in the blood plasma of unknown etiology;

– pregnancy or breastfeeding period;

– age up to 18 years (except for children and adolescents 10-17 years old with heterozygous familial hypercholesterolemia) (see section “Indications for use”);

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

– concomitant treatment with strong inhibitors of the CYP3A4 isoenzyme (itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and drugs containing cobicistat) (see sections “Interaction with other drugs”, “Special instructions” Myopathy/Rhabdomyolysis);

– concomitant treatment with gemfibrozil, cyclosporine or danazol (see sections “Interaction with other drugs”, “Special instructions” Myopathy/Rhabdomyolysis);

With caution

Patients who have experienced rhabdomyolysis during simvastatin therapy with a complicated history (impaired renal function, usually due to diabetes mellitus) require more careful monitoring, and simvastatin therapy should be temporarily discontinued in such patients several days before major surgery, as well as 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 case of severe renal failure (creatinine clearance <30 ml/min), the advisability of prescribing the drug in doses exceeding 10 mg/day should be carefully considered and, if necessary, they should be used with caution; with alcohol abuse before treatment.

Side Effects

Simvastatin is generally well tolerated and most side effects are mild and transient. Less than 2% of patients participating in clinical trials discontinued treatment due to the development of adverse events characteristic of simvastatin.

In pre-registration clinical studies, adverse events occurring with an incidence of at least 1% and assessed by investigators as possibly, probably or definitely related to simvastatin were abdominal pain, constipation and flatulence. Other adverse events that occurred in
0.5-0.9% of patients had asthenia and headache.

There have been rare reports of the development of myopathy (see section “Special Instructions” Myopathy/Rhabdomyolysis).

In a clinical trial (HPS) in which 20,536 patients received simvastatin (n=10,269) 40 mg daily or placebo (n=10,267) for an average of 5 years, the pattern of adverse events was similar between the simvastatin and placebo groups. The rate of treatment discontinuation 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 receiving simvastatin was less than 0.1%. An increase in the activity of “liver” transaminases (more than 3 times higher than the upper limit of normal (ULN), confirmed by repeated testing) was observed in
0.21% of patients in the simvastatin group and 0.09% of patients in the placebo group.

The following adverse events have been reported (rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%; frequency not established: frequency cannot be estimated based on available data):

Blood and lymphatic system disorders:

rare – anemia.

Immune system disorders:

Rarely, hypersensitivity syndrome developed, which was manifested by anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, flushing of the facial skin, shortness of breath and general weakness.

There have been very rare reports of immune-mediated necrotizing myopathy (autoimmune myopathy) associated with statin use. Immune-mediated myopathy is characterized by proximal muscle weakness and increased serum creatine phosphokinase (CPK) activity that persist despite discontinuation of statin treatment. Muscle biopsy shows necrotizing myopathy without significant inflammation. Improvement is observed with therapy with immunosuppressive drugs (see section “Special Instructions” Myopathy/Rhabdomyolysis).

There have also been rare post-marketing reports of cognitive impairment (eg, various memory impairments – forgetfulness, memory loss, amnesia, confusion) associated with statin use. These cognitive impairments have been reported with all statins. 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). The symptoms were reversible and resolved after discontinuation of statin therapy.

Nervous system disorders:

rare – dizziness, peripheral neuropathy, paresthesia;

very rare – insomnia;

frequency not established – depression.

Disorders of the respiratory system, chest and mediastinal organs:

frequency not established – interstitial lung disease.

Gastrointestinal disorders:

rare – dyspepsia, nausea, vomiting, diarrhea, pancreatitis, hepatitis/jaundice;

very rare – fatal and non-fatal liver failure.

Skin and subcutaneous tissue disorders:

rare – skin rash, itching, alopecia.

Muscle, skeletal and connective tissue disorders:

rare – myalgia, muscle cramps, rhabdomyolysis;

frequency not established – tendinopathy, possibly with tendon rupture.

Disorders of the reproductive system and mammary glands:

frequency not established – erectile dysfunction.

Laboratory and instrumental data

There are rare reports of the development of a pronounced and persistent increase in the activity of “liver” transaminases. Increased alkaline phosphatase and gamma-glutamyl transpeptidase activities have also been reported. Deviations in liver function tests are usually mild and transient. There is information about cases of increased CPK activity (see section “Special instructions”).

Increases in glycosylated hemoglobin (HbAlc) and fasting serum glucose concentrations have been reported with statins, including simvastatin.

The following adverse events have been reported with some statins:

¾ sleep disturbances, including nightmares;

¾ sexual dysfunction, gynecomastia.

Children and teenagers (10-17 years old)

In a clinical study of patients aged 10-17 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of treatment in the simvastatin group was comparable to the safety and tolerability profile of treatment in the placebo group (see section “Special Instructions” Use in children and adolescents aged 10-17 years).

Interaction

Contraindicated drug combinations

Concomitant therapy with the following drugs is contraindicated:

Strong CYP3A4 inhibitors

Simvastatin is metabolized by the CYP3A4 isoenzyme, but does not inhibit the activity of this isoenzyme. This suggests that taking simvastatin does not affect the blood concentration of drugs metabolized by the CYP3A4 isoenzyme.

Strong inhibitors of the CYP3A4 isoenzyme increase the risk of developing myopathy by reducing the rate of elimination of simvastatin. Concomitant use of strong CYP3A4 inhibitors (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) and simvastatin is contraindicated (see sections “Contraindications”, “Special instructions” Myopathy/Rhabdomyolysis).

Gemfibrozil, cyclosporine or danazol (see sections “Contraindications”, “Special instructions” Myopathy/Rhabdomyolysis).

Other medicines

Other fibrates

The risk of developing myopathy increases with simultaneous use of simvastatin with gemfibrozil (see section “Contraindications”) and other fibrates (except fenofibrate). These lipid-lowering drugs can cause myopathy in monotherapy. With simultaneous use of simvastatin with fenofibrate, the risk of developing myopathy did not exceed the sum of the risks with monotherapy with each drug (see sections “Contraindications”, “Special instructions” Myopathy/Rhabdomyolysis).

Amiodarone

The risk of developing myopathy/rhabdomyolysis increases when amiodarone is used concomitantly with simvastatin. In a clinical study, the incidence of myopathy in patients taking simvastatin at a dose of 80 mg and amiodarone simultaneously was 6% (see sections “Dosage and Administration”, “Special Instructions” Myopathy/Rhabdomyolysis).

Blockers of “slow” calcium channels

The risk of developing myopathy/rhabdomyolysis increases with simultaneous use of verapamil, diltiazem or amlodipine with simvastatin (see sections “Method of administration and dosage”, “Special instructions” Myopathy/Rhabdomyolysis).

Lomitapide

The risk of developing myopathy/rhabdomyolysis may increase with simultaneous use of lomitapide with simvastatin (see sections “Dosage and Administration”, “Special Instructions” Myopathy/Rhabdomyolysis).

Moderate CYP3A4 inhibitors (eg, dronedarone)

With simultaneous use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially at higher doses, the risk of developing myopathy may increase (see section “Special Instructions” Myopathy/Rhabdomyolysis). When simvastatin is used concomitantly with moderate CYP3A4 inhibitors, a dose reduction of simvastatin may be required.

Ranolazine (moderate CYP3A4 inhibitor)

With simultaneous use of ranolazine and simvastatin, the risk of developing myopathy may increase (see section “Special Instructions” Myopathy/Rhabdomyolysis). When simvastatin and ranolazine are used concomitantly, a dose reduction of simvastatin may be required.

OATP1B1 transport protein inhibitors

Simvastatin hydroxy acid is a substrate of the transport protein OATP1B1. Concomitant use of OATP1B1 transport protein inhibitors and simvastatin may lead to an increase in plasma concentrations of simvastatin hydroxy acid and an increased risk of developing myopathy (see sections “Contraindications”, “Special Instructions” Myopathy/Rhabdomyolysis).

Fusidic acid

With simultaneous use of fusidic acid and simvastatin, the risk of developing myopathy may increase (see section “Special Instructions” Myopathy/Rhabdomyolysis).

Breast cancer resistance protein (BCRP) inhibitors

Simvastatin is a substrate of the BCRP efflux transporter. Concomitant use of simvastatin and BCRP inhibitors (for example, elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of developing myopathy. With simultaneous use of simvastatin and BCRP inhibitors, a dose adjustment of the drug may be required (see sections “Dosage and Administration”, “Special Instructions” Myopathy/Rhabdomyolysis).

Nicotinic acid (at least 1 g per day)

With the simultaneous use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g/day), cases of myopathy/rhabdomyolysis have been described (see section “Special Instructions” Myopathy/Rhabdomyolysis).

Colchicine

With the simultaneous use of colchicine and simvastatin in patients with renal failure, cases of myopathy and rhabdomyolysis have been described. When combined with these drugs, such patients should be under close medical supervision.

Indirect anticoagulants (coumarin derivatives)

Simvastatin at a dose of 20-40 mg per day potentiates the effect of coumarin anticoagulants: prothrombin time, defined as the international normalized ratio (INR), increases from an initial level 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 starting simvastatin therapy, and also often enough during the initial period of treatment to exclude significant changes in this indicator. Once a stable INR is achieved, further determinations should be made at intervals recommended for monitoring patients receiving anticoagulant therapy. When changing the dose of simvastatin or discontinuing it, regular measurement of prothrombin time is also recommended. In patients not taking anticoagulants, simvastatin therapy was not associated with bleeding or changes in prothrombin time.

Other types of interaction

Grapefruit juice contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of drugs metabolized by CYP3A4. When drinking the juice in the usual amount (1 glass 250 ml per day), this effect is minimal (there is an increase in the activity of HMG-CoA reductase inhibitors by 13% when assessed by AUC value) and has no clinical significance. However, drinking grapefruit juice in large volumes significantly increases the activity of HMG-CoA reductase in the blood plasma. In this regard, it is necessary to avoid drinking grapefruit juice during therapy with simvastatin (see section “Special Instructions” Myopathy/Rhabdomyolysis).

Overdose

Several cases of overdose were reported, the maximum dose taken was 3.6 g. No overdose effects were identified in any patient.

To treat overdose, general measures are used, including supportive and symptomatic therapy.

Storage conditions

Store in a place protected from light at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

2 years.

Do not use after expiration date.

Manufacturer

Vertex, Russia