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 high risk of CHD

Patients at high risk of CHD (with or without hyperlipidemia). In patients at high risk of CHD (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 CHD or predisposition to CHD, simvastatin is indicated for:

– reducing the risk of overall mortality by reducing mortality due to CHD;

– reducing the risk of serious vascular and coronary complications: nonfatal myocardial infarction, coronary death, stroke, and revascularization procedures;

– reducing the risk of having to perform coronary blood flow restoration surgery (such as aortocoronary artery bypass grafting and percutaneous transluminal coronary angioplasty);

– reducing the risk of the need for peripheral blood flow repair surgery and other noncoronary revascularization;

– reducing the risk of hospitalization for angina attacks.

Hyperlipidemia

– As an adjunct to diet when the use of diet alone and other non-drug therapies in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson Classification Type IIa hyperlipidemia) or mixed hypercholesterolemia (Fredrickson Classification Type IIb hyperlipidemia) is not sufficient to

∙ reduced elevated concentrations of COX, LDL cholesterol, TG, and apolipoprotein B (apo B);

∙ increased concentrations of HDL cholesterol;

p> ∙ decreased ratio of HDL/CHDL and LDL/CHDL;

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

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

– primary dysbetalipoproteinemia (Fredrickson classification type III hyperlipidemia).

Application in children and adolescents with heterozygous familial hypercholesterolemia

. Use of simvastatin concomitantly with diet is indicated to reduce elevated concentrations of CHC, LDL cholesterol, TG, and apo B in young males 10-17 years old and in girls 10-17 years old, at least one year after menarche (first menstrual bleeding), with heterozygous familial hypercholesterolemia.

Active ingredient

Composition

One film-coated tablet contains:

Dosage 10 mg

the 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 (hydroxypropyl cellulose) – 2.00 mg;

croscarmellose sodium – 2.00 mg;

citric acid monohydrate – 1.25 mg;

p> butyl hydroxyanisole – 0.02 mg;

calcium stearate – 1.00 mg;

film coating:

hypromellose – 2.0000 mg,

hyprolose (hydroxypropyl cellulose) – 0.7760 mg,

talcum powder – 0.7704 mg, titanium dioxide – 0.0440 mg,

iron oxide black dye – 0.1616 mg,

iron oxide red dye – 0.1560 mg,

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

Hypromellose (50%),

Hyprolose (hydroxypropyl cellulose) (19.4%),

Hyprolose (hydroxypropyl cellulose)/p>

talk (19.26%),

titanium dioxide (1.1%),

ferric oxide black dye (4.04%),

ferric oxide red dye (3.9%),

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

Dosage 20 mg

The active ingredient: simvastatin – 20.00 mg;

Auxiliary substances:

Lactose monohydrate, 138.46 mg;

Corn starch, 14.00 mg;

Microcrystalline cellulose 101, 10.00 mg;

ascorbic acid – 5.00 mg;

hyprolose (hydroxypropyl cellulose) – 4.00 mg;

croscarmellose sodium – 4.00 mg;

citric acid monohydrate – 2.50 mg;

p> butyl hydroxyanisole – 0.04 mg;

calcium stearate – 2.00 mg;

film coating:

hypromellose – 4.0000 mg,

hyprolose (hydroxypropyl cellulose) – 1.5520 mg,

talc – 1.5408 mg,

titanium dioxide – 0.0880 mg,

ferric oxide black dye – 0.3232 mg,

ferric oxide red dye – 0.3120 mg,

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

hypromellose (50%),

hyprolose (hydroxypropylcellulose) (19.4%),

talk (19.26%),

titanium dioxide (1.1%),

iron oxide black dye (4.04%),

iron oxide red dye (3.9%),

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

How to take, the dosage

Before starting simvastatin treatment, the patient should be prescribed a standard hypocholesterolemic diet, which should be followed during the entire course of treatment.

The 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 of the drug is increased at intervals of at least 4 weeks to a maximum of 80 mg once daily in the evening. It is recommended to use 80 mg daily only in patients with high risk of cardiovascular complications if the drug treatment in lower doses failed to reach the target lipid concentrations and the expected benefit of therapy exceeds the possible risk (see section “Special remarks”Myopathy/Rhabdomyolysis).

Patients with coronary heart disease or at high risk of developing CHD

The standard starting dose of simvastatin for patients at high risk of CHD in combination with or without hyperlipidemia (in the presence of diabetes mellitus, history of stroke or other cerebrovascular disease, peripheral vascular disease) as well as for patients with CHD is 40 mg
once daily in the evening. Drug therapy should be started simultaneously with diet and physical therapy.

Patients with hyperlipidemia without the above risk factors

The standard starting dose of the drug is 20 mg once daily in the evening. For patients who need a significant (more than 45%) decrease in LDL cholesterol concentration, the initial dose may be 40 mg once daily in the evening. In patients with mild or moderate hypercholesterolemia, the drug therapy can be administered in a starting dose of 10 mg once daily. If necessary, the doses should be adjusted according to the above-mentioned scheme (see section “Dosage and administration”).

Patients with homozygous familial hypercholesterolemia

The drug 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 is greater than the possible risk (see Myopathy/Rhabdomyolysis). In these patients, the drug is used in combination with other methods of hypolipidemic treatment (e.g., LDL plasmapheresis) or without other treatment if it is not available.

For patients taking lomitapide concomitantly with simvastatin, the daily dose of the drug should not exceed 40 mg (see sections “Interaction with other medicinal products”, “Special Precautions”Myopathy/Rhabdomyolysis).

Companion therapy

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

In patients taking the drug concomitantly with fibrates other than gemfibrozil (see section “Contraindications”) or fenofibrate, the maximum recommended dose of simvastatin is 10 mg daily.

In patients concomitantly taking amiodarone, verapamil, diltiazem, drugs containing elbasvir or trazoprevir, or amlodipine concomitantly with simvastatin, the daily dose of simvastatin should not exceed 20 mg. Myopathy/Rhabdomyolysis).

In renal impairment

Because simvastatin is excreted by the kidneys in small amounts, there is no need to change doses 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/day should be carefully weighed. If such doses are considered necessary, they should be prescribed with caution (see section “Caution”).

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

The recommended starting dose is 10 mg once daily in the evening. The recommended dosing regimen is 10-40 mg per day, the maximum recommended dose of the drug is 40 mg per day. Selection of the dosage is carried out individually in accordance with the purpose of therapy.

Interaction

Controlled combinations of drugs

Companion therapy with the following drugs is contraindicated:

Severe isoenzyme inhibitorsCYP3A4

Simvastatin is metabolized by the CYP3A4 isoenzyme, but does not inhibit the activity of this isoenzyme. This suggests that simvastatin administration has no effect on the blood concentrations of drugs metabolized by CYP3A4 isoenzyme.

The 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, telaprevir, nefazodone, drugs containing cobicistat) and simvastatin is contraindicated (see Myopathy/Rhabdomyolysis).

Hemfibrozil, cyclosporine, or danazol (see Contraindications, Special Precautions Myopathy/Rabdomyolysis).

Other drugs

Other fibrates

The risk of myopathy is increased when 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 and fenofibrate, the risk of myopathy did not exceed the sum of the risks of monotherapy with each drug (see sections “Contraindications”, “Special Precautions” Myopathy/Rhabdomyolysis).

Amiodarone

The risk of myopathy/rhabdomyolysis increases 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 sections “Dosage and administration” and “Precautions”Myopathy/Rhabdomyolysis).

Slow calcium channel blockers

The risk of myopathy/rhabdomyolysis is increased with the simultaneous use of verapamil, diltiazem or amlodipine with simvastatin (see “Dosage and administration” sections). See sections “Dosage and administration” and “Cautionary statements”Myopathy/Rhabdomyolysis).

Lomitapide

The risk of myopathy/rhabdomyolysis may be increased with concomitant use of lomitapide with simvastatin (see “Dosage and administration” sections. Myopathy/Rhabdomyolysis may increase the risk of myopathy/rhabdomyolysis with lomitapide (see “Dosage and administration” and “Cautionary statements”).

Moderate isoenzyme inhibitorsCYP3A4 (e.g., dronedarone)

Concomitant use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially at higher doses, may increase the risk of myopathy (see Myopathy/Rhabdomyolysis). Concomitant use of simvastatin and moderate CYP3A4 inhibitors may require reducing the dose of simvastatin.

Ranolazine (moderate CYP3A4 isoenzyme inhibitor)

Concomitant use of ranolazine and simvastatin may increase the risk of myopathy (see Ranolazine and simvastatin. Myopathy/Rhabdomyolysis). Simultaneous use of simvastatin and ranolazine may require reducing the dose of simvastatin.

Transport protein inhibitorsOATP1B1

The hydroxy acid of simvastatin is a substrate of the OATP1B1 transport protein. Concomitant use of OATP1B1 transport protein inhibitors and simvastatin may increase plasma concentrations of simvastatin hydroxy acid and increase the risk of myopathy (see Sections “Contraindications”, “Special Precautions” Myopathy/Rhabdomyolysis).

Fusidic acid

The simultaneous use of fusidic acid and simvastatin may increase the risk of myopathy (see “Special Precautions”Myopathy/Rhabdomyolysis).

Breast cancer resistance protein inhibitors (BCRP)

Simvastatin is a substrate of the BCRP efflux transporter. Concomitant use of simvastatin and BCRP inhibitors (e.g., elbasvir and grazoprevir) may increase the plasma concentration of simvastatin and increase the risk of myopathy. Concomitant use of simvastatin and BCRP inhibitors may require adjustment of the drug dose (see sections “Dosage and administration”, “Special Precautions” Myopathy/Rhabdomyolysis).

Nicotinic acid (at least 1 g per day)

When Simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g/day) are used concomitantly, there have been cases of myopathy/rhabdomyolysis (see sect. Myopathy/Rhabdomyolysis).

Colchicine

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

Direct 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 (INR), increases from a 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 treatment period to exclude significant changes in this index. Once a stable INR has been 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 withdrawn. In patients not taking 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 activity. In this regard, consumption of grapefruit juice during simvastatin therapy should be avoided (see section “Special Precautions” Myopathy/Rhabdomyolysis).

Special Instructions

Myopathy/rhabdomyolysis

Simvastatin, like other statins, may cause myopathy, which is manifested by muscle pain, soreness or general weakness and is accompanied by increased CPK activity (more than 10 times the upper limit of normal).

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 trials (median follow-up of 4 years), the incidence of myopathy at doses of 20, 40, and 80 mg daily 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 trial in which patients with a history of myocardial infarction were taking simvastatin at a dose of 80 mg daily (mean follow-up 6.7 years), the incidence of myopathy was approximately 1%, and in patients taking simvastatin 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%. Patients taking simvastatin at a dose of 80 mg daily have a higher risk of myopathy than other statins causing a comparable decrease in LDL cholesterol concentrations.

Therefore, simvastatin 80 mg daily should only be prescribed in patients at high risk of cardiovascular complications in whom therapy with the drug in lower doses failed to achieve 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 Sections “Contraindications”, “Administration and Doses”).

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 simvastatin should be discontinued immediately if myopathy is suspected or diagnosed. The presence of the above symptoms and/or 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, myopathy symptoms resolve and CPK activity decreases.

In patients starting simvastatin or transitioning to a higher dose 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 on simvastatin therapy have a complicated history, including impaired renal function, usually due to diabetes mellitus. Such patients require closer monitoring.

Therapy with simvastatin should be temporarily discontinued several days before major surgical interventions, as well as in the postoperative period.

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

While 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, in particular by prescribing it at low doses.

The risk of myopathy/rhabdomyolysis increases with concomitant use of simvastatin with the following drugs:

Contraindicated drug combinations

Strong CYP3A4 isoenzyme inhibitors

Concomitant therapy with strong CYP3A4 isoenzyme inhibitors at therapeutic doses (e.g., 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 medicinal products”).

Hemfibrozil, cyclosporine or danazole

The concomitant use of these drugs with simvastatin is contraindicated (see Sections “Contraindications” and “Interaction with other drugs”).

Other drugs

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. When concomitant use of simvastatin and fenofibrate, the risk of myopathy does not exceed the sum of the risks of treatment with each drug separately.

Phenofibrate in combination with simvastatin should be used with caution because both drugs may cause myopathy. Adding fibrate therapy to simvastatin therapy usually leads to a small additional decrease in LDL cholesterol concentrations, but allows to achieve a more pronounced decrease in HDL cholesterol concentrations.

In small short clinical trials in which both drugs were used under close supervision, combined therapy with fibrates and simvastatin was not accompanied by the development of myopathy (see section “Interaction with other medicinal products”).

Amiodarone

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

Slow calcium channel blockers

In patients taking verapamil, diltiazem or amlodipine the dose of simvastatin should not exceed 20 mg daily (see section “Interaction with other medicinal products”).

Lomitapide

In patients with homozygous familial hypercholesterolemia taking lomitapide, the dose of simvastatin should not exceed 40 mg daily (see section “Interaction with other medicinal products”).

Moderate CYP3A4 isoenzyme inhibitors

The risk of myopathy may increase with concomitant use of drugs with moderate inhibitory activity against CYP3A4 and simvastatin, especially in high doses. Simultaneous use of simvastatin with moderate CYP3A4 isoenzyme inhibitors may require dose adjustment of simvastatin.

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

The concomitant 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 possibility of concomitant use of simvastatin and fusidic acid should be considered on a case-by-case basis, and the combination therapy should be conducted under close medical supervision.

Breast cancer resistance protein (BCRP) inhibitors

The concomitant use of simvastatin and BCRP inhibitors (e.g., elbasvir and trazoprevir) may result in increased plasma concentrations of simvastatin and increased risk of myopathy, so dose adjustments of simvastatin may be required.

While 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 daily (see section “Interaction with other medicinal products”).

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

In concomitant use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g per day) there are cases of myopathy/rhabdomyolysis.

In a clinical study (median follow-up of 3.9 years) involving patients at high cardiovascular risk with well-controlled LDL-C concentrations, with simvastatin at a dose of 40 mg daily with or without ezetimibe, no additional beneficial effect on cardiovascular outcomes was shown with concomitant use of nicotinic acid in lipid-lowering doses (at least 1 g daily).

Thus, the benefit of concomitant use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g per day) must be carefully weighed against the potential risks of combination 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 concurrently with a 40 mg/2 g slow-release laropiprant/nicotinic acid dose.

Despite the fact that in this clinical trial the only representatives of the Mongoloid race were patients of Chinese ethnicity, concomitant use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g/day) in patients of Mongoloid race is not recommended because the incidence of myopathy is higher than in patients of other ethnicities (see section “Interaction with other medicinal products”).

The effect on the liver

In some adult patients taking simvastatin, a sustained increase in the activity of “hepatic” enzymes (more than 3 times the upper limit of normal) was observed. At discontinuation or interruption of simvastatin therapy, activity of “hepatic” transaminases gradually returned to the initial level.

Elevated liver 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 prior to 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 in whom it is planned to increase simvastatin dose up to 80 mg per day should undergo additional liver function tests before proceeding to the indicated dose, 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 regularly thereafter until normalization of “hepatic” transaminase activity. In those cases where the activity of “hepatic” transaminases increases, especially with a steady 3-fold excess of the upper limit of normal, the drug should be discontinued.

Alanine aminotransferase (ALT) activity increase may be caused by muscle damage; therefore, increase of ALT and CPK activity may indicate development of myopathy (see section “Special indications” Myopathy/Rhabdomyolysis).

Rare post-registration reports of fatal and non-fatal cases of hepatic failure have been received in patients taking statins, including simvastatin.

If during treatment with simvastatin severe liver damage with clinical symptoms and/or hyperbilirubinemia or jaundice develops, therapy should be stopped immediately. If no other cause of this pathology has been identified, reapplication of simvastatin is contraindicated.

The drug should be used with extreme caution in patients who abuse alcohol and/or in patients with liver dysfunction. Active liver disease or unexplained increase in the activity of “hepatic” transaminases are contraindications for prescribing simvastatin.

In treatment with simvastatin, as well as in treatment with other hypolipidemic drugs, a moderate (exceeding the upper limit of normal not more than 3-fold) increase in “hepatic” transaminases activity 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 and adolescents aged 10-17 years

The safety and efficacy of simvastatin in children and adolescents aged 10-17 years with heterozygous familial hypercholesterolemia have been evaluated in controlled clinical trials involving young men 10-17 years and girls 10-17 years at least one 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 and adolescent 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 about appropriate contraceptive methods during treatment with simvastatin (see section “Contraindications”).

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, assessed by the degree of reduction of CHB and LDL cholesterol, was similar to that observed in the general population.

There was no significant increase in the incidence of adverse events or changes in laboratory parameters. However, in a clinical study of simvastatin at a dose of 80 mg daily, an increased risk of myopathy was observed in patients older than 65 years compared to patients younger than 65 years.

Influence on driving and operating machinery

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

Synopsis

Circular biconvex brown film-coated tablets. On cross section the core is white or almost white.

Contraindications

Contraindications

– hypersensitivity to any component of the drug;

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

– pregnancy or breastfeeding;

– age less than 18 years (except for children and adolescents 10-17 years of age with heterozygous familial hypercholesterolemia) (see “Indications for use”).

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

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

Concomitant treatment with gemfibrozil, cyclosporine, or danazol (see Sections “Interaction with other drugs” and “Special Precautions”). Interactions with other drugs, Myopathy/Rhabdomyolysis Special Instructions);

Caution

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 discontinued in such patients several days before major surgical interventions, as well as in the postoperative period; in patients with sustained 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 in doses exceeding 10 mg/day should be carefully considered and, if necessary, they should be used with caution; in alcohol abuse before treatment.

Side effects

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 simvastatin-specific adverse events.

In the pre-registration clinical trials, the adverse events that occurred with a frequency of at least 1%, which were evaluated by investigators as possibly, probably or definitely related to simvastatin administration, 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 section “Myopathy/Rhabdomyolysis Special Indications”).

In a clinical trial (HPS) in which 20536 patients took simvastatin (n=10269) at a dose of 40 mg daily or placebo (n=10267) for an average of 5 years, the pattern of adverse events was similar in the simvastatin and placebo groups. The incidence 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 receiving simvastatin was less than 0.1%. Elevation of “liver” transaminases activity (more than 3 times higher than upper limit of normal (ULN), confirmed by repeated study) was observed in
0.21% of patients of simvastatin group and in 0.09% of patients of placebo group.

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: it is not possible to estimate the frequency based on available data):

Blood and lymphatic system disorders:

rare – anemia.

Disorders of the immune system:

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

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

There have also been rare post-registration reports of cognitive impairment (e.g., various memory disorders – forgetfulness, memory impairment, amnesia, confusion) associated with the use of statins. 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.

Nervous system disorders:

Rare – dizziness, peripheral neuropathy, paresthesia;

very rare – insomnia;

frequency not established – depression.

Disorders of the respiratory system, thoracic and mediastinal organs:

frequency not established – interstitial lung disease.

Gastrointestinal disorders:

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

very rare – fatal and nonfatal 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 determined – tendinopathy, possibly with tendon rupture.

Reproductive system and mammary gland disorders:

frequency not determined – erectile dysfunction.

Laboratory and instrumental data

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

Elevations of 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 adolescents (10-17 years)

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

Overdose

Particular cases of overdose have been reported, with a maximum dose of 3.6 g taken. No overdose has occurred in any patient.

The treatment of overdose involves general measures, including supportive and symptomatic therapy.

Pregnancy use

Pregnancy

Simvastatin is contraindicated in pregnant women. Since the safety for pregnant women is not proven and there are no data that simvastatin treatment during pregnancy has obvious benefits, the drug should be discontinued immediately at the onset of pregnancy. Simvastatin use during pregnancy may reduce the concentration of mevalonate (a precursor in cholesterol biosynthesis) in the fetus. Atherosclerosis is a chronic disease and usually discontinuation of hypolipidemic 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, are trying to become pregnant, or suspect they are pregnant. Treatment with the drug should be suspended for the 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

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

Similarities