Zokor - instructions for use, dose, side effects, contraindications

Composition:1 tablet, film-coated, contains:
Dosage of 10 mg
Active substance: simvastatin 10.00 mg.
Auxiliary substances:
Butyl hydroxy anisole 0.02 mg, ascorbic acid 2.50 mg, lactose monohydrate 70.70 mg, citric acid monohydrate 1.25 mg, pregelatinized starch 10.00 mg, microcrystalline cellulose 5.00 mg, magnesium stearate 0.50 mg; sheath
pills: hypromellose 0.764 mg, giprolose 0.764 mg, titanium dioxide 0.694 mg, talc 0.278 mg, iron oxide dye red 0.0038 mg, iron oxide dye yellow 0.0015 mg
or
Active substance: simvastatin granules 99.50 mg (equivalent to 10.00 mg simvastatin).
Excipients: butyl hydroxy anisole * 0.02 mg, ascorbic acid * 2.50 mg, lactose monohydrate * 70.70 mg, citric acid monohydrate * 1.25 mg, pregelatinized starch * 10.00 mg, microcrystalline cellulose * 5.00 mg, magnesium stearate 0.50 mg; tablet shell: hypromellose 0.764 mg, giprolose 0.764 mg, titanium dioxide 0.694 mg, talc 0.278 mg, iron oxide red oxide 0.0038 mg, iron oxide dye yellow 0.0015 mg.
Dosage of 20 mg
Active substance: simvastatin 20.00 mg.
Excipients: Butyl hydroxy anisole 0.04 mg, ascorbic acid 5.00 mg, lactose monohydrate 141,50 mg, citric acid monohydrate 2.50 mg, pregelatinized starch 20.00 mg, microcrystalline cellulose 10.00 mg, magnesium stearate 1.00 mg; tablet shell: hypromellose 1.65 mg, giprolose 1.65 mg, titanium dioxide 1.50 mg, talc 0.60 mg, iron oxide dye red 0.023 mg, iron oxide dye yellow 0.092 mg
or
Active substance: simvastatin granules 199.00 mg (equivalent to 20.00 mg simvastatin).
Excipients: butyl hydroxy anisole * 0.04 mg, ascorbic acid * 5.00 mg, lactose monohydrate * 141,50 mg,citric acid monohydrate * 2.50 mg, pregelatinized starch * 20.00 mg, microcrystalline cellulose * 10.00 mg, magnesium stearate 1.00 mg; tablet shell: hypromellose 1.65 mg. giprolose 1.65 mg, titanium dioxide 1.50 mg, talc 0.60 mg, iron oxide red oxide 0.023 mg, iron oxide dye yellow 0.092 mg.
* Auxiliary substance is a part of simvastatin granules

Description:Tablets 10 mg
Oval-shaped tablets covered with a film shell, light pink in color, engraved with "MSD 735" on one side and smooth on the other side.
Tablets 20 mg
Oval-shaped tablets covered with a film coating, yellow-brown in color, engraved with "MSD 740" on one side and smooth on the other side.

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.01 Simvastatin

Pharmacodynamics:The drug Zokor® (simvastatin) is a lipid-lowering drug obtained synthetically from the fermentation product of Aspergillus terreus.
Pharmacodynamics
After oral administration simvastatin, which is an inactive lactone, undergoes hydrolysis in the liver with the formation of the corresponding form of the β-hydroxy acid simvastatin, which is the main metabolite and has a high inhibitory activity against HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase,catalyzing the initial and most significant stage of cholesterol biosynthesis. Clinical studies have shown the effectiveness of Zocor® in reducing the concentration of total cholesterol in blood plasma, low density lipoprotein cholesterol (LDL cholesterol), triglycerides (TG), and very low density lipoprotein cholesterol (cholesterol-lowering lipoprotein cholesterol), as well as increasing the concentration of lipoprotein cholesterol high density (LDL-C) in patients with heterozygous familial and non-family hypercholesterolemia or mixed hyperlipidemia in those cases where an elevated cholesterol concentration is a factor risk and the appointment of one diet is not enough. A noticeable therapeutic effect is observed within 2 weeks of taking the drug, the maximum therapeutic effect is within 4-6 weeks after the start of treatment. The effect persists with the continuation of therapy. When discontinuation of simvastatin intake, the 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, an enzyme that catalyzes the formation of mevalonate from HMG-CoA.Despite this, taking Zocor® in therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows to preserve the production of the biologically necessary amount of mevalopat. Since the early stage of cholesterol biosynthesis is the conversion of HMG-CoA to mevalonate, it is believed that the use of Zocor® should not cause the accumulation of potentially toxic sterols in the body. In addition, HMG-CoA is rapidly metabolized back to acetyl-CoA, which participates in many biosynthetic processes in the body. Although cholesterol is the precursor of all steroid hormones, there has been no clinical effect of simvastatin on steroidogenesis. Because the simvastatin did not cause an increase in the lithogenicity of bile, it is unlikely that it will affect the incidence of cholelithiasis.
Simvastatin reduces both increased and normal concentrations of LDL cholesterol. The disease is produced from very low-density lipoproteins (VLDL). The catabolism of LDL is predominantly performed with the help of a high affinity LDL receptor. The mechanism of reducing the concentration of LDL-C after receiving simvastatin may be due to a decrease in the concentration of cholesterol-VLDL, and activation of LDL-retenters,which leads to a decrease in the formation and strengthening of catabolism of LDL cholesterol. With simvastatin therapy, the concentration of apolipoprotein B (apo B) is also significantly reduced. Since each particle of the JINP contains one apo B molecule, and in other lipoproteins small amounts of apo B are found, it can be assumed that simvastatin not only causes loss of cholesterol in LDL particles, but also reduces the concentration of circulating LDL particles.
Besides, simvastatin increases the concentration of HDL cholesterol and reduces the concentration of TG in the blood plasma. As a result of these changes, the ratio of CX / HDL cholesterol and LDL cholesterol / HDL cholesterol is reduced.
In the Scandinavian study of the effects of simvastatin on survival (4S), the effect of Zocor® therapy on overall mortality (median time of participation of patients 5.4 years) was evaluated in 4444 patients with coronary heart disease (CHD) and an initial concentration of OXC of 212-309 mg / dl ( 5.5-8.0 mmol / L). In this multicenter, randomized, double-blind, placebo-controlled study, Zocor® reduced the risk of overall mortality by 30%, mortality from coronary heart disease by 42%, and the incidence of nonfatal, confirmed myocardial infarction by 37%.Zokor® also reduced the risk of requiring surgical procedures to restore coronary blood flow (aortocoronary bypass or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes, the risk of major coronary complications was reduced by 55%. Moreover, the drug Zokor ® significantly (by 28%) reduced the risk of fatal and non-fatal disorders of cerebral circulation (strokes and transient disorders of cerebral circulation).
In a 5-year, multicentre, randomized, double-blind, placebo-controlled heart protection (HPS) study, the efficacy of Zocor® therapy was demonstrated in 20536 patients with or without hyperlipidemia who are at high risk of developing coronary heart disease due to concurrent diabetes mellitus, a history of stroke and other vascular diseases. Before the start of therapy, in 33% of the patients the concentration of LDL was less than 116 mg / dl, in 25% of the patients the concentration of LDL was 116 mg / dL to 135 mg / dl and in 42% of patients the concentration of LDL was more than 135 mg / dL.
In this study simvastatin in a dose of 40 mg per day compared with placebo, reduced total mortality by 13%, the risk of death associated with coronary artery disease by 18%, the risk of major coronary events (including nonfatal myocardial infarction or death associated with coronary artery disease) by 27% , 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 by 30% and 16% respectively, and the risk of stroke by 25%. The frequency of hospitalization for heart failure (JV) decreased by 17%. The risk of developing major coronary and vascular complications was reduced by 25% in patients with or without IHD, including patients with diabetes mellitus, peripheral vascular disease or cerebrovascular disease. In patients with diabetes mellitus simvastatin 21% reduced the risk of serious vascular complications, including the need for surgical interventions to restore peripheral blood flow, amputation of the lower limbs, and the occurrence of trophic ulcers.
In another multicenter, placebo-controlled study involving 404 patients using a quantitative assessment of coronary blood flow simvastatin (according to coronary angiography) slowed the progression of coronary atherosclerosis and the emergence of both new areas of atherosclerosis and new total occlusions, whereas patients receiving standard therapy experienced a steady progression of atherosclerotic lesions of the coronary arteries.
The analysis of subgroups of two studies, in which 147 patients with hypertriglyceridemia (type IV hyperlipidemia according to Fredrickson classification) were included, showed that simvastatin in a dose of 20 to 80 mg per day reduced the concentration of GH by 21-39% (in the placebo group by 11-13%),
LDL cholesterol - by 23-35% (in the placebo group by 1-3%), cholesterol is not high-density lipoprotein (non-HDL cholesterol, calculated as the difference between the concentration of OXC and the concentration of cholesterol-lowering cholesterol) - by 26-43% (in the group placebo by 1-3%) and increases HDL cholesterol by 9-14% (in the placebo group by 3%).
In 7 patients with disbetalipoproteinemia (type III hyperlipidemia according to Fredrickson classification) simvastatin at a dose of 80 mg per day reduced the concentration of LDL cholesterol, including intermediate-density lipoproteins (LDL) by 51% (in the placebo group by 8%),and the concentration of cholesterol and VLDLP cholesterol was increased by 60% (in the placebo group by 4%).

Pharmacokinetics:Metabolism
Simvastatin is an inactive lactone that rapidly hydrolyzes into a β-hydroxy acid of simvastatin (L-654,969), a potent inhibitor of HMG-CoA reductase. The main metabolites of simvastatin in blood plasma are the simvastatin β-hydroxy acid (L-654,969) and its 6'-hydroxy, 6'-hydroxymethyl and 6'-exomethylene derivatives. Inhibition of HMG-CoA reductase is a measure of the quantitative evaluation of all pharmacokinetic studies of β-hydroxydeal metabolites (active inhibitors), as well as active and latent inhibitors (all inhibitors) formed as a result of hydrolysis. Both types of metabolites are determined in the blood plasma when administered simvastatin.
The hydrolysis of simvastatin mainly occurs during "primary passage" through the liver, so the concentration of unchanged simvastatin in human blood plasma is low (less than 5% of the dose taken). The maximum concentration (C_max) in the blood plasma of simvastatin metabolites is achieved through 1,3-2,4 h after ingestion of a single dose. In a study using¹⁴C labeled simvastatin plasma concentration of total radioactivity (¹⁴C labeled simvastatin + ¹⁴C labeled metabolites of simvastatin) peaked at 4 hours and rapidly decreased to about 10% of the maximum value within 12 hours after ingestion of a single dose. Despite the fact that the range of recommended therapeutic doses of simvastatin ranges from 5 to 80 mg per day, the linear profile of the AUC profile (the area under the concentration-time curve) of active metabolites in the total blood flow is maintained with increasing doses up to 120 mg.
Suction
Approximately 85% of the dose of simvastatin taken internally is absorbed.
Eating (within the standard hypocholesterine diet) immediately after taking simvastatin does not affect the pharmacokinetic profile of the drug.
Distribution
After ingestion, higher concentrations of simvastatin are determined 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 ingested dose; 95% of this amount is in protein-related condition.
The result of active metabolism of simvastatin in the liver (more than 60% in men) is its low concentration in the total blood flow.
The possibility of the penetration of simvastatin through the blood-brain barrier and the hematoplacental barrier has not been studied.
Excretion
At the "primary passage" through the liver simvastatin Metabolized with the subsequent removal of simvastatin and its metabolites with bile.
In the study, taking 100 mg of the drug (5 capsules of 20 mg)¹⁴C labeled simvastatin accumulated in the blood, urine and feces. About 60% of the dose of labeled simvastatin was detected in the stool and about 13% in the urine. Labeled simvastatin in fecal masses was represented as the products of the metabolism of simvastatin, secreted with bile, and unabsorbed labeled simvastatin. Less than 0.5% of the dose of labeled simvastatin was detected in the urine as active metabolites of simvastatin.
In blood plasma, 14% of AUC was due to active inhibitors and 28% to all inhibitors of HMG-CoA reductase. The latter indicates that, in the main, the products of simvastatin metabolism are inactive or weak inhibitors of HMG-CoA reductase.
In a study to evaluate the proportionality of the doses of simvastatin 5, 10, 20, 60, 90, and 120 mg, there was no significant deviation from the linearity of AUC in the general blood stream with increasing dose.Pharmacokinetic parameters with single and multiple intake of simvastatin showed that simvastatin Do not accumulate in tissues with repeated ingestion.
In a study in patients with severe renal failure (creatinine clearance less than 30 ml / min), the total concentration of HMG-CoA reductase inhibitors in the blood plasma after ingestion of a single dose of the 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. It means that simvastatin is not an inhibitor of the isoenzyme CYP3A4 and suggests that the intake of simvastatin does not affect the concentration in the blood plasma of drugs metabolized by the isozyme CYP3A4.
It is known that ciclosporin increases AUC inhibitors of HMG-CoA reductase, although the mechanism of drug interaction has not been fully studied. The increase in AUC of simvastatin is presumably associated, in particular, with the inhibition of the isoenzyme CYP3A4 and / or transport protein OATP1B1 (see CONTRAINDICATIONS).
In pharmacokinetic study, while the use of diltiazem observed increase in AUC β-hydroxy simvastatin 2.7 times, presumably due to inhibition of isozyme CYP3A4 (see. SPECIFIC NOTES, Myopathy / Rhabdomyolysis).
In pharmacokinetic study, while the use of amlodipine observed increase AUC β-hydroxy simvastatin 1.6 times (see. SPECIFIC NOTES, Myopathy / Rhabdomyolysis).
In pharmacokinetic study, while the application of a single dose of 2 g of nicotinic acid sustained release 20 mg simvastatin and there was a slight increase in the AUC of simvastatin and β-hydroxy simvastatin and C_max β-hydroxy acids of simvastatin in blood plasma (see SPECIFIC INDICATIONS, Myopathy / Rhabdomyolysis). Specific ways fusidic acid metabolism in the liver is unknown, but one can assume the presence of interaction between fusidic acid and statins, are metabolized isoenzyme CYP3A4 (see. SPECIFIC NOTES, Myopathy / Rhabdomyolysis).
The risk of myopathy increases with an increase in the concentration of HMG-CoA reductase inhibitors in blood plasma.Strong inhibitors of the isoenzyme CYP3A4 can increase the concentration of HMG-CoA reductase inhibitors and lead to an increased risk of myopathy (see INTERACTION WITH OTHER MEDICINES, SPECIFIC INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Indications:Patients with ischemic heart disease or high-risk CHD
In patients with a high risk of developing coronary artery disease (with or without hyperlipidemia), for example, in patients with diabetes mellitus, in patients with a history of stroke or other cerebrovascular diseases, in patients with peripheral vascular disease or in patients with ischemic heart disease or a predisposition to ischemic heart disease Zocor® is indicated for:
- Reduce the risk of overall mortality by reducing mortality due to coronary artery disease.
- Reducing the risk of serious vascular and coronary events:
- non-fatal myocardial infarction,
- coronary death,
- stroke,
revascularization procedures.
- 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 surgical interventions to restore peripheral blood flow and other types of non-coronary revascularization.
- Reducing the risk of hospitalization due to attacks of angina pectoris.
Hyperlipidemia
as a supplement to the diet, when the use of only diets and other non-medicamentous treatments in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson's type II hyperlipidemia), or mixed hypercholesterolemia (Fredrickson's IIb type hyperlipidemia) is not sufficient for:
- decrease in the increased concentration of OXC, LDL cholesterol, TG, apolipoprotein B (apo B);
- increasing the concentration of HDL cholesterol;
- reduction in the ratio of LDL / HDL and HD / HDL cholesterol.
- hypertriglyceridemia (type IV hyperlipidemia according to Fredrickson classification).
- supplement to the diet and other ways of treating patients with homozygous familial hypercholesterolemia to reduce the elevated concentrations of OXC, LDL cholesterol and apo B.
- primary dysbetalapoproteinemia (type III hyperlipidemia according to Fredrickson classification).
Use in children and adolescents with heterozygous familial hypercholesterolemia
The use of Zokor® simultaneously with the diet is indicated to reduce the elevated concentrations of OXC, LDL cholesterol, TG, apo B in young men of 10-17 years and in girls 10-17 years not less than 1 year after menarche (first menstrual bleeding) with heterozygous family hypercholesterolemia.

Contraindications:- Hypersensitivity to any component of the drug.
- Liver disease in the active phase or persistent increase in the activity of "hepatic" transaminases in the blood plasma of an unclear etiology.
- Pregnancy or the period of breastfeeding.
- Age to 18 years (except for children and adolescents 10-17 years with heterozygous familial hypercholesterolemia) (see INDICATIONS FOR APPLICATION).
- Lactose intolerance, lactase deficiency or glucose-galactose malabsorption.
- Concomitant treatment with strong inhibitors of the isoenzyme CYP3A4 (itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevirov, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and preparations containing the co-bicystate).INTERACTION WITH OTHER MEDICINES; SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
- Concomitant treatment with gemfibrozil, cyclosporin or danazol (see INTERACTION WITH OTHER MEDICINES, SPECIFIC INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Carefully:Patients who underwent rhabdomyolysis during therapy with Zokor® with a complicated anamnesis (renal dysfunction, usually due to diabetes mellitus) require more careful observation, and simvastatin therapy should be temporarily discontinued in such patients a few days before major surgical interventions are performed, and also in the postoperative period; in patients with persistent increased activity of serum transaminases (exceeding the upper limit of the norm by 3 times), the drug should be discontinued; In severe renal failure (QC <30 ml / min), the expediency of prescribing the drug at doses> 10 mg per day should be carefully weighed and, if necessary, should be administered with caution; with alcohol abuse prior to treatment.

Pregnancy and lactation:The drug Zokor® is contraindicated in pregnancy.Since safety for pregnant women is not proven and there is no evidence that treatment with the drug during pregnancy brings obvious benefits, taking the drug should be stopped immediately after the onset of pregnancy. Zokor® should be given to women of childbearing age only when the probability of pregnancy is very low. The use of Zocor® during pregnancy can reduce the concentration of mevalonate (a precursor in the biosynthesis of cholesterol) in the fetus. Atherosclerosis is a chronic disease and usually stopping the use of lipid-lowering drugs during pregnancy has a slight effect on the long-term risks associated with primary hypercholesterolemia. In this regard, the drug Zokor® should not be used in women who are pregnant, trying to conceive or suspect that they are pregnant. Treatment with Zocor® should be suspended for the duration of pregnancy or until pregnancy is diagnosed, and the woman herself is warned about possible danger to the fetus (see CONTRAINDICATIONS).
Data on the isolation of simvastatin and its metabolites with breast milk are absent.If it is necessary to administer Zokor® to a woman during lactation, it should be taken into account that many drugs are excreted in breast milk and there is a threat of serious adverse reactions. As a result, during breastfeeding, the drug should be discontinued.

Dosing and Administration:Before starting treatment with Zocor®, the patient should be given a standard hypocholesterol diet, which should be observed throughout the course of treatment.
The recommended dose of Zocor® is 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 maximum to 80 mg once a day in the evening. A dose of 80 mg per day is recommended to be administered only to patients with a high risk of cardiovascular complications if treatment with the drug at lower doses does not allow achieving target lipid levels, and the perceived benefit of therapy exceeds the possible risk (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Patients with coronary heart disease or a high risk of developing coronary artery disease The standard initial dose of Zocor® for patients at high risk for developing coronary artery disease in combination with or without hyperlipidemia (in the presence of diabetes,stroke or other cerebrovascular diseases in history, peripheral vascular disease), as well as for patients with IHD is 40 mg 1 time per day in the evening. Drug therapy should be prescribed simultaneously with diet and exercise therapy.
Patients with hyperlipidemia who do not have the above risk factors
The standard initial dose of Zocor® is 20 mg once a day in the evening. For patients who need a significant (more than 45%) reduction in the concentration of LDL-C, the initial dose may be 40 mg 1 time per day in the evening. Patients with mild or moderate hypercholesterolemia with Zocor® can be given an initial dose of 10 mg once daily. If necessary, the selection of doses should be carried out in accordance with the above scheme (see METHOD OF APPLICATION AND DOSES).
Patients with homozygous familial hypercholesterolemia
The drug Zocor® is recommended in a dose of 40 mg per day, taken once in the evening. A dose of 80 mg is recommended to be prescribed only if the intended benefit of therapy exceeds the possible risk (see SPECIFIC INDICATIONS, Myopathy / Rhabdomyolysis).In such patients, Zocor® is used in combination with other lipid-lowering treatments (eg, LDL-apheresis) or without such treatment if it is not available.
For patients taking lomitapid concomitantly with Zocor®, the daily dose of Zocor® should not exceed 40 mg (see INTERACTION WITH OTHER MEDICINES, SPECIFIC INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Concomitant therapy
Zocor® can be given both in monotherapy and in combination with bile acid sequestrants.
In patients taking Zocor® simultaneously with fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate, the maximum recommended dose of Zocor® is 10 mg per day.
For patients receiving amiodarone, verapamil, diltiazem or amlodipine simultaneously with the drug Zokor®, the daily dose of Zokor8 should not exceed 20 mg.
(See INTERACTION WITH OTHER MEDICINES, SPECIFIC INDICATIONS, Myopathy / Rhabdomyolysis)
With renal insufficiency
Since Zocor® is excreted by the kidneys in small amounts, there is no need to change the doses in patients with moderate renal impairment.In patients with severe renal failure (CK <30 ml / min), the expediency of prescribing the drug in doses exceeding 10 mg per day should be carefully weighed. If such dosages are considered necessary, they should be administered with caution (see Cautiousness).
Application in children and adolescents 10-17 years with heterozygous familial hypercholesterolemia
The recommended initial dose is 10 mg per day in the evening. The recommended dosage regimen is 10-40 mg per day, the maximum recommended dose of Zocor® is 40 mg per day. The choice of doses is carried out individually in accordance with the goals of therapy.

Side effects:Zokor® is generally well tolerated, and most side effects are mild and transient. Less than 2% of patients who participated in clinical trials discontinued treatment due to the development of adverse events characteristic of Zocor®.
In pre-registration clinical trials, undesirable events that occurred at a frequency of at least 1%, which were evaluated by researchers as possible, probably or definitely associated with taking the drug, were abdominal pain, constipation, and flatulence.Other adverse events that occurred in 0.5-0.9% of patients were asthenia and headache.
There were rare reports of the development of myopathy (see SPECIAL INSTRUCTIONS.Myopathy / Rhabdomyolysis).
In a clinical study (HPS) in which 2,0550 patients took Zocor® (n = 10269 patients) at a dose of 40 mg per day or placebo (n = 10267 patients) for an average of 5 years, the nature of the adverse events was similar in the drug groups Zocor® and placebo. The incidence of discontinuation due to adverse events was also comparable in the two groups (4.8% in the Zocor® group and 5.1% in the placebo group). The incidence of myopathy in patients taking Zocor® was less than 0.1%. An increase in the activity of "hepatic" transaminases (more than 3 times higher than the upper limit of the norm (VGN), confirmed in a follow-up study) was observed in 0.21% of patients in the Zocor® group and 0.09% in the 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 impossible to estimate the frequency based on available data):
On the part of the organs of hematopoiesis
Rare: anemia.
From the skin
Rare: skin rash, itching, alopecia.
From the digestive system
Rare: indigestion, nausea, vomiting, diarrhea, pancreatitis, hepatitis / jaundice.
Very rare: fatal and non-fatal hepatic insufficiency.
From the central nervous system and sense organs Rare: dizziness, peripheral neuropathy, paresthesia.
Very rare: insomnia.
The frequency is not established: depression.
From the side of the musculoskeletal system
Rare: myalgia, muscle cramps, rhabdomyolysis.
The frequency is not established: tendonopathy, possibly with a rupture of tendons.
On the part of the respiratory system
Frequency not established: interstitial lung disease.
From the side of the reproductive system
Frequency not established: erectile dysfunction.
Allergic and immunopathological reactions: seldom developed a hypersensitivity syndrome, which manifested itself as angioedema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, blood flushes to the skin of the face, shortness of breath and general weakness.
Very rare reports were received on the development of immuno-mediated necrotizing myopathy (autoimmune myopathy), caused by taking statins. Immunopreparated myopathy is characterized by weakness of proximal muscles and increased activity of creatine phosphokinase (CK) in the serum, which persist despite the withdrawal of statin treatment. On muscle biopsy, necrotizing myopathy is seen without significant inflammation. Improvement is observed in the therapy with immunosuppressive drugs (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Also, rare post-registration reports of cognitive impairments (for example, various memory disorders - forgetfulness, memory loss, amnesia, confusion) associated with the use of statins have also been obtained. These cognitive impairments were recorded with all statins. Messages in general were classified as non-serious, with different duration before the onset of symptoms (from 1 day to several years) and the time of their resolution (median 3 weeks). The symptoms were reversible and passed after the withdrawal of statin therapy.The following adverse events were reported with the use of some statins:
- sleep disturbances, including nightmares;
- Sexual dysfunction, gynecomastia.
Laboratory indicators
There are rare reports of the development of a pronounced and persistent increase in the activity of "liver" transaminases. An increase in the activity of alkaline phosphatase and gamma-glutamyl transpeptidase was also reported. Deviations in the indicators of functional hepatic samples are usually weakly expressed and are of a transient nature. There are cases of increased activity of CKF (see SPECIAL INSTRUCTIONS).
An increase in the concentration of glycosylated hemoglobin (HbAlc) and fasting serum glucose in statin use, including Zocor®, has been reported.
Children and adolescents (10-17 years)
In a clinical study involving patients aged 10-17 years with heterozygous familial hypercholesterolemia, the safety profile and tolerability of treatment in the Zocor® group was comparable to the safety profile and tolerability of treatment in the placebo group (see SPECIFIC INDICATIONS, children and adolescents aged 10-17 years).

Overdose:Several cases of overdose were reported, the maximum dose taken was 3.6 g. None of the patients had an overdose effect.
For the treatment of overdose, general measures are taken, including maintenance and symptomatic therapy.

Interaction:Contraindicated combinations of medicines
Contraindicated concomitant therapy with the following medicines.
Strong inhibitors of the isoenzyme CYP3A4. Simvastatin is metabolized by the CYP3A4 isoenzyme, but does not inhibit the activity of this isofermpt. This suggests that the use of simvastatin does not affect the concentration in the blood plasma of drugs metabolized by the isozyme CYP3A4. Strong inhibitors of the CYP3A4 isoenzyme increase the risk of myopathy by decreasing the rate of withdrawal of simvastatin. Simultaneous use of strong inhibitors of the isoenzyme CYP3A4 (for example, itraconazole, kegocopazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, bocetrevir, telaprevir, nefazodone, preparations containing co-bicystate) and simvastatin is contraindicated (see CONTRAINDICATIONS, SPECIFIC INDICATIONS, Myopathy / Rhabdomyolysis).
Gemfibrozil, ciclosporin or danazol.
See CONTRAINDICATIONS; SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis.
Interaction with other drugs
Other fibrates. The risk of myopathy increased with concomitant use of simvastatin with gemfibrozil (see. CONTRA) and other fibrazami (except fenofibrate). These hypolipidemic agents can cause myopathy in monotherapy. With simultaneous use of fenofibrate with simvastatin risk of myopathy risk does not exceed the sum of each drug in monotherapy (see CONTRA;. Specified, Myopathy / Rhabdomyolysis).
Amiodarone. The risk of myopathy / rhabdomyolysis increases with simultaneous use of amiodarone with simvastatin. In a clinical study, the incidence of myopathy in patients taking both simvastatin in a dose of 80 mg and amiodarone, was 6% (see METHOD OF APPLICATION AND DOSES: SPECIFIC INDICATIONS, Myopathy / Rhabdomyolysis).
Blockers of "slow" calcium channels. The risk of developing myopathy / rhabdomyolysis increases with the simultaneous use of verapamil, diltiazem or amlodipine with simvastatin (see DOSAGE AND ADMINISTRATION, SPECIFIC INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Lomitapid. The risk of myopathy / rhabdomyolysis may increase with concomitant use of lomipid with simvastatin (see DOSAGE AND ADMINISTRATION, SPECIFIC INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Moderate inhibitors of the isoenzyme CYP3A4 (eg, dronedaron). When using drugs with moderate inhibitory activity against CYP3A4 isozyme and simvastatin, especially at higher doses, the risk of myopathy may increase (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis). With simultaneous use of Zocor®, and moderate inhibitors of CYP3A4 isozymes, a dose reduction of Zocor® may be required.
Ranolazine (moderate inhibitor of the isoenzyme CYP3A4). With the simultaneous use of ranolazine and simvastatin, the risk of myopathy may increase (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis). With the simultaneous use of Zocor® and ranolazine, a dose reduction of Zocor® may be required.
Inhibitors of transport protein OATP1B1. The hydroxy acid of simvastatin is a substrate of the transport protein OATP1B1. Simultaneous application of transport protein inhibitors OATP1B1 and simvastatin may lead to an increase in the plasma concentration of the hydroxy acid of simvastatin and an increased risk of myopathy (see: CONTRAINDICATIONS, SPECIFIC INSTRUCTIONS, Myopathy / rhabdomyolysis).
Fusidic acid. With the simultaneous use of fusidic acid and simvastatin, the risk of myopathy may increase (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Nicotinic acid (not less than 1 g / day). With the simultaneous use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g / day), cases of development of myopathy / rhabdomyolysis have been described (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Colchicine. With the simultaneous use of colchicine and simvastatin in patients with renal insufficiency, cases of myopathy and rhabdomyolysis have been described.
When combined therapy with these drugs, such patients should be carefully monitored.
Indirect anticoagulants (coumarin derivatives). Simvastatin in 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 the start of simvastatin therapy, and also often enough during the initial treatment period to exclude significant changes in this indicator. Once a stable indicator of INR is achieved, its further definition should be carried out at intervals recommended for the control of patients receiving anticoagulant therapy. When changing the dose of simvastatin or after its withdrawal, regular measurement of prothrombin time is also recommended. In patients who did not take anticoagulants, therapy with simvastatin was not associated with the occurrence of bleeding or changes in prothrombin time.
Other types of interaction
Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme and can increase the plasma concentration of drugs metabolized by the CYP3A4 isoenzyme. When the juice is consumed in the usual amount (1 glass of 250 ml per day), this effect is minimal (an increase in the activity of HMG-CoA reductase inhibitors by 13% in AUC assessment) and has no clinical significance.However, the consumption of grapefruit juice in large volumes significantly increases the activity of HMG-CoA reductase inhibitors in blood plasma. In this regard, you should avoid the use of grapefruit juice with simvastatin (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Special instructions:Myopathy / Rhabdomyolysis
Simvastatin, like other statins, can cause myopathy, which manifests itself in the form of muscle pain, soreness or weakness, and is accompanied by an increase in the activity of CKK (more than 10 times higher than UGN). Myopathy can manifest itself in the form of rhabdomyolysis, sometimes accompanied by secondary acute renal failure due to myoglobinuria. In rare cases, a lethal outcome was observed. The risk of myopathy increases with an increase in the concentration in the blood plasma of substances that have an inhibitory effect on HMG-CoA reductase. Risk factors for myopathy include the elderly (65 years and older), female gender, uncontrolled hypothyroidism and impaired renal function.
As with other HMG-CoA reductase inhibitors, the risk of myopathy / rhabdomyolysis depends on the dose.In clinical studies (the median duration of follow-up was 4 years), the incidence of myopathy with 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 can interact with simvastatin were not used.
In a clinical study in which patients with a history of myocardial infarction took Zocor® at a dose of 80 mg per day (mean follow-up of 6.7 years), the incidence of myopathy was approximately 1.0%, and in patients taking the drug at a dose of 20 mg per day - 0.02%. Approximately half of the cases of myopathy development were registered during the first year of treatment. The incidence of myopathy during each next year of treatment was approximately 0.1%.
In patients taking Zocor® 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. Therefore, Zocor® at a dose of 80 mg per day should be administered only to patients with a high risk of cardiovascular complications in whom therapy with lower doses does not achieve the desired therapeutic effect, and the perceived benefit of treatment exceeds the potential risk.If a patient taking Zocor® at a dose of 80 mg needs treatment with another drug that can interact with simvastatin, then it is necessary to reduce the dose of Zocor® or to prescribe another statin that has less potential for possible drug interaction (see CONTRAINDICATIONS, USE AND USE DOSES).
All patients who start Zokor® therapy, as well as patients who need to increase the dose, should be warned about the possibility of myopathy and are informed of the need to immediately seek medical attention in the event of any unexplained muscle pain, tenderness in the muscles or muscle weakness. Therapy with Zocor® should be stopped immediately if myopathy is suspected or diagnosed. The presence of the above symptoms and / or more than 10-fold compared with UGN increase in activity of CKK indicate the presence of myopathy. In most cases, after immediate discontinuation of Zocor®, the symptoms of myopathy are resolved, and the activity of CK decreases. In patients,beginners taking Zocor® or switching to higher doses of the drug, it is advisable to periodically determine the activity of CKK, but there is no guarantee that such monitoring can prevent the development of myopathy.
Many patients who underwent rhabdomyolysis during Zocor® therapy had a complicated history, including impaired renal function, usually due to diabetes mellitus. Such patients require more careful observation.
Therapy with Zocor® should be temporarily discontinued several days before major surgical interventions are performed, as well as in the postoperative period.
In a clinical study in which patients with a high risk of developing cardiovascular diseases were taking simvastatin in a dose of 40 mg once a day (median follow-up time 3.9 years), the incidence of myopathy was approximately 0.24% among Chinese patients (n = 5468) and 0.05% among patients of another nationality (n = 7367) . Despite the fact that in this clinical study the only representatives of the Mongoloid race were Chinese patients, caution should be exercised when prescribing simvastatin to patients of the Mongoloid race, in particular to prescribe it in low doses.
The risk of developing myopathy / rhabdomyolysis increases with the simultaneous use of Zocor® with the following medicines.
Contraindicated combinations of medicines
- Strong inhibitors of the isoenzyme CYP3A4. Concomitant therapy with strong inhibitors of the CYP3A4 isoenzyme at therapeutic doses (eg, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevirov, telaprevir, nefazodone, or preparations containing a co-cystitis) is contraindicated. If short-term treatment with strong inhibitors of the CYP3A4 isoenzyme can not be avoided, Zocor® therapy should be discontinued for the period of their use (see CONTRAINDICATIONS, INTERACTION WITH OTHER MEDICINES).
- Gemfibrozil, ciclosporin or danazol. The simultaneous use of these drugs with the drug Zokor® is contraindicated (see CONTRAINDICATIONS, INTERACTION WITH OTHER MEDICINAL PRODUCTS).
Other medicines
- Other fibrates. In patients taking fibrates, except gemfibrozil (see Fig.CONTRAINDICATIONS) or fenofibrate, the dose of simvastatin should not exceed 10 mg per day. With the simultaneous use of simvastatin and fenofibrate, the risk of developing myopathy does not exceed the amount of risks when treating each drug individually. Assign fenofibrate in combination with simvastatin should be cautious, since both drugs can cause the development of myopathy. The adherence of fibrate therapy to simvastatin therapy usually leads to a slight additional decrease in LDL cholesterol, but allows a more pronounced decrease in TG concentration and an increase in HDL-C concentration. In small short clinical trials in which both drugs were used under close supervision, combined therapy with fibrates with simvastatin was not accompanied by the development of myopathy (see INTERACTION WITH OTHER MEDICINES).
- Amiodarone. In patients receiving amiodarone, the dose of simvastatin should not exceed 20 mg per day (see INTERACTION WITH OTHER DRUGS).
- Blockers of "slow" calcium channels. In patients receiving verapamil, dlltiazem or amlodipine, the dose of simvastatnna should not exceed 20 mg per day (see INTERACTION WITH OTHER DRUGS).
- Lomitapid. In patients with homozygous familial hypercholesterolemia taking lomitapid, the dose of simvastatna should not exceed 40 mg per day (see INTERACTION WITH OTHER DRUGS).
- Moderate inhibitors of the isoenzyme CYP3A4. With the simultaneous use of drugs with moderate inhibitory activity against the isoenzyme CYP3A4, and simvastatna, especially at higher doses, the risk of developing myopathy may increase. Simultaneous application of simvastatna with moderate inhibitors of the isoenzyme CYP3A4 may require dose adjustment simvastatnna.
- Fusidic acid. The simultaneous use of fusidic acid and simvastatna can increase the risk of myopathy (see INTERACTION WITH OTHER MEDICINES). Simultaneous application of simvastatna and fusidic acid is not recommended. If the use of systemic fusidic acid preparations is considered necessary, Zocor® should be withdrawn for the duration of this therapy.In exceptional cases where long-term therapy with fusidic acid systemic drugs is necessary, for example for the treatment of severe infections, the simultaneous use of Zocor® and fusidic acid should be considered individually in each individual case and combined therapy should be carefully monitored.
- A nicotinic acid (in lipid-lowering doses not less than 1 g / day). With the simultaneous use of Zocor® and nicotinic acid in lipid-lowering doses (at least 1 g / day), cases of myopathy / rhabdomyolysis have been described. In a clinical study (median follow-up of 3.9 years) involving patients with a high risk of cardiovascular disease and a well-controlled concentration of LDL-C with simvastatin 40 mg / day with or without ezetimibe 10 mg / day, no additional positive effect on outcomes of cardiovascular diseases with simultaneous use of nicotinic acid in lipid-lowering doses (not less than 1 g / day). Thus, the advantage of simultaneous application of simvastatin with nicotinic acid in lipid-lowering doses (notless than 1 g / day) should be carefully weighed against the potential risks of combination therapy. In addition, 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 in a dose of 40 mg or simvastatin / ezetimibe at a dose of 40/10 mg concurrently with sustained-release laropiprant / nicotinic acid at a dose of 40 mg / 2 g. Although in this clinical trial the only representatives of the Mongoloid race would be whether patients of Chinese nationality are not recommended simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g / day) in patients of Mongoloid race, since the incidence of myopathy is higher in patients of Chinese nationality than in patients of other nationalities (see INTERACTION WITH OTHER DRUGS).
Effects on the liver
In some adult patients taking Zocor®, there was a steady increase in the activity of "hepatic" enzymes (more than 3 times higher than UGN).With the termination or interruption of Zocor® therapy, the activity of the "hepatic" transaminases usually returns gradually to the baseline 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 abnormalities in the results of functional liver tests before starting treatment with Zocor® and / or abusing alcohol.
Before beginning treatment, and then in accordance with clinical indications, all patients are recommended to conduct a study of liver function. Patients who plan to increase the dose of Zocor® to 80 mg per day should perform additional liver function tests before proceeding to take the indicated dosage, then 3 months after the start of its use and then regularly repeat (for example, once every six months ) during the first year of treatment. Particular attention should be given to patients with increased activity of "liver" transaminases. These patients need to repeat the liver function tests in the near future and subsequently carry out regularly to normalize the activity of "liver" transaminases.In those cases, when the activity of "hepatic" transaminases increases, especially when the excess of IUH is 3 times, the drug should be canceled. The cause of increased activity of alanine aminotransferase (ALT) may be muscle damage, so the increase in activity of ALT and CK may indicate the development of myopathy (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
There were rare post-registration reports of fatal and non-fatal cases of liver failure in patients taking statins, including simvastatin. If a severe liver injury with clinical symptoms and / or hyperbilirubinemia or jaundice develops with Zocor®, immediate therapy should be discontinued. If there is no other cause of the development of this pathology, re-administration of Zokor® is contraindicated.
In patients who abuse alcohol and / or patients with impaired liver function, the drug should be used with extreme caution. Active liver disease or unexplained increase in the activity of "liver" transaminases are contraindications to the appointment of Zocor®.
During the treatment with Zokor®, as in the treatment with other lipid-lowering drugs, there was a moderate increase (exceeding the VGN by less than 3 times) in the activity of "liver" transaminases. These changes appeared soon after the start of treatment, often were transient, were not accompanied by any symptoms and did not require interruption of treatment.
Ophthalmological examination
The data of modern long-term clinical trials do not contain information on the adverse effects of Zocor® on the lens of the human eye.
Use in children and adolescents aged 10-17 years
The safety and effectiveness of Zocor® in children and adolescents aged 10-17 years with heterozygous familial hypercholesterolemia were evaluated in controlled clinical trials involving 10-17 year olds and 10-17 year olds not less than 1 year after menarche. In patients who were taking Zocor®, the profile of adverse events was comparable to that in patients taking placebo. The use of Zocor® in a dose of more than 40 mg per day has not been studied in patients of childhood and adolescence.In this study, there was no significant effect of Zocor® on the growth and sexual maturation of young men and girls or any effect on the length of the menstrual cycle in girls. Girls should be consulted about proper methods of contraception during treatment with Zocor® (see CONTRAINDICATIONS, APPLICATION WITH PREGNANCY AND PERIOD OF BREASTFEEDING). The use of Zocor® was not studied in children younger than 10 years and in girls 10-17 years before menarche.
Use in elderly patients
In patients over the age of 65 years, the effectiveness of Zocor®, evaluated by the level of decrease in the concentration of OXC and LDL-C, was similar to that observed in the population as a whole. There was no significant increase in the incidence of adverse events or changes in laboratory parameters. However, in a clinical study of the use of Zocor® at a dose of 80 mg per day in patients older than 65 years, there was an increased risk of myopathy compared with patients younger than 65 years.

Effect on the ability to drive transp. cf. and fur:Zokor® has little or no effect on the ability to drive vehicles and work with machinery.Nevertheless, when driving vehicles or working with machinery, it should be taken into account that in the post-marketing period, rare cases of dizziness development have been reported.

Form release / dosage:Tablets film-coated 10 mg, 20 mg.

Packaging:For 14 tablets in a blister of PVC / PE / PVDC film and aluminum foil. For 1 or 2 blisters with instructions for use in a cardboard box.

Storage conditions:Store at a temperature not exceeding 25 ° C.
Keep out of the reach of children.

Shelf life:2 years.
Do not use the product after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013094 / 01

Date of registration:24.10.2011 / 26.02.2016

Expiration Date:Unlimited

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

MERCK SHARP & DOHME, Ltd. United Kingdom

AKRIKHIN HFK, JSC Russia

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp2016-11-09

Illustrated instructions

Instructions

Zocor® (Zocor®)