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

Excipients: butyl hydroxy anisole 0.08 mg, ascorbic acid 10.0 mg, lactose monohydrate 283.0 mg, citric acid 5.0 mg, pregelatinized starch 40.0 mg, microcrystalline cellulose 20.0 mg, magnesium stearate 2.0 mg.

Tablet casing: hypromellose 3.30 mg, giprolose 3.30 mg, titanium dioxide 3.0 mg, talc 1.20 mg, ferric oxide red oxide E172 0.12 mg.

Description:

Oval-shaped tablets covered with a film shell, pink, engraved "MSD 749 "on one side.

Pharmacotherapeutic group:Hypolipidaemic agent - HMG-CoA-reductase inhibitor

ATX: & nbsp

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

C.10.A.A.01 Simvastatin

Pharmacodynamics:

The drug Zokor "Forte (simvastatin) is a lipid-lowering drug obtained synthetically from the fermentation product Aspergillus lerreus.

Farmakodipumpka

After oral administration simvastatin. which is an inactive lactone, undergoes hydrolysis in the liver with the formation of the corresponding form of the 3-hydroxy acid simvastatin, which is the main metabolite and has a high inhibitory activity against HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme that catalyzes the initial and the most significant stage of biosynthesis of cholesterol.Clinical studies have shown the effectiveness of Zocor Forte in reducing the concentration of total cholesterol (OXC) in blood plasma, lipoprotein cholesterol low density (CH LINY), triglyceri(TG) and lipoprotein cholesterol very low density (CHELP), and also increase the concentration of cholesterolon high-density lipoproteins (HDL cholesterol) in patients with heterozygous family and non-family hypercholesterolor mixed hyperlipidemia in those cases when the increased concentrationcholesterol is a risk factor and the appointment of one diet is not enough. BehindMeteorological effect observedis taken within 2 weeks of taking the drug, maximum therapeutic effect - within 4-6 weeks after the start of treatment. The effect is preserved when continuingRapi. When you stop receiving the simvastatype concentration of cholesterol returnto the original value observedbefore the beginning of treatment. The active metabolite of simvastatin isspecific inhibitor of HMG-CoA-reductase, an enzyme catalyzing rethe formation of a mevalonate from HMG-CoA. Despite this, the drug intakeand Zokor Forte in therapeutic doses is not leads to complete inhibition HMG-CoA reductase. which allows us to preserveThe thread is biologically necessaryth amount of mevalonate. Since woundsstage of biosynthesis of cholesterolconversion of HMG-CoA into a mevalonate, countingis used. that the use of Zocor FIt should not cause accumulation in the body of a potentially toxic sterofishing. In addition, HMG-CoA is rapidly metabolizedlysed back to acetyl-CoA. whoparticipates in many bio processessynthesis in the body. Although cholesterol is a precursorcom of all steroid hormones, not observedclinical effect of simvastatin was given on steroidogenesis. Because the simvastatin did not cause an increase in the lithogenicity of bile, It is unlikely that it will influence the increase incidence of cholelithiasis disease.

Simvastatin reduces both increased and the normal concentration of LDL-C. LDL are formed from lipoproteins very low density (VLDL). Catabolism LDL is predominantly performed with using high-affinity LDL-receptor. The mechanism for reducing the concentrationafter taking simvastatin may be due to both a decrease concentration of cholesterol VLDL. and activationher LDL receptors, which leads to reduction of education and strengthening of the kataof CSLNP. With simvasta therapytype also significantly reduces theadipoliprotein 13 (apo 13) entrapment. BySince each particle of the RFP contains one apo molecule.but in other lipoproteinslittle quantities are found apo 13. we can assume that the simvastatin not only causes loss of cholesterol in LDL particles, by and lowers the concentrationcirculating LDL particles.

Besides, simvastatin increases the concentrationHDL cholesterol and reduces concentration TG in the blood plasma. As a result of these changesratios of CX / HDL cholesterol and LDL cholesterol / HDL cholesterol decreased.

In the Scandinavian study of influence simvastapa for survival (4S) impacttherapy simvastatin on a common mortality (median time of participation naceps 5.4 years) was estimated at 4444 pacients with ischemic heart disease (IHD) and the initial concentration of OXC 212-309 mg / dl (5.5-8.0 mmol / l). In this multicenter randomized doubleblind, placebo-controlledfollowing simvastatin reduced the risk ofmortality rate by 30%. mortality from ischemic heart disease on 42%. frequency of non-fatal confirmationof myocardial infarctions by 37%. Simvastatin also reduced the risk ofsurgical interventioncoronary blood flow (coronary artery bypass grafting or a percutaneous transluminal coronapaired angioplasty) by 37%. Patients with diabetes, the risk of major coronary complications was reduced by 55%. Furthermore, simvastatin significantly (by 28%) reduced the risk offatal and non-fatal disturbancescerebral circulation (strokes and transient disorders of cerebral bloodfraternization).

In a 5-year, multicenter randomizedbath with a double-blind placebo-controlled study of protection hearts (HPS) the effectiveness of therapy Simvastatin was demonstrated in 20536 patients with hyperlipidemia or without her. in the high risk of CHD development due to concomitantdiabetes, stroke in anamnesis and other vascular diseasesyami. Before starting therapy in 33% of patientsthe concentration of LDL was less 116 mg / dl, in 25% of patients the concentration LDL was from N6 mg / dl up to 135 mg / dl and 42% of patients had an LDL concentration more than 135 mg / dl. In this study simvastatin in a dose 40 mg per day compared with placebo reduced overall mortality by 13%, the risk of death, related to CHD - by 18%, the risk arosemajor coronary events (including non-fatal myocardial infarction or death associated with ischemic heart disease) - by 27%, need for surgical interventioncoronary blood flow (including aortocoronary shuntiropepey and percutaneous traysluminalangioplasty), as well as peripheralblood flow and other types of pecoronarby 30% and 16% withresponsibly, the risk of stroke 25%. The frequency of hospitalization for heart failure (JV) decreased on 17%. The risk of developing a major coronaryand vascular complications was reduced by 25% in patients with or without IHD, including patients with diabetes, diseaseperipheral vessels or cerebrospinal fluidrovascular pathology. In patients with diabetes mellitus simvastatin by 21% reduced risk of developing a serious vascular systemcomplications, including the need forsurgical interventionrestoration of peripheralth blood flow, lower amputationtions. as well as the emergence of trophic ulcers.

In another multicenter placebo-controlled trial involving

404 patients using quantitativecoronary blood flow assessment simvastatin (according to coronary angiodecanter) slowed the progression of the coronapaired atherosclerosis and the appearance of bothatherosclerosis, and new total occlusions, whereas in patientswho received standard therapy, there was a steady progression atherosclerotic lesions of coronasartery arteries.

Analysis of subgroups from two studies, in which included 147 patients with ginertriglyceridemia (hyperlipidemia IV type according to Fredrickson's classification), showed that simvastatin in a dose of 20 to 80 mg per day reduced the concentration of Tg in 21-39% (in the placebo group by 11-13%).

LDL-cholesterol was 23-35% (in the placebo group 1-3%). cholesterol non-HDL cholesterol (non-HDL cholesterol, calculated as the difference between the concentration of OXC and the concentration of HDL cholesterol) by 26-43% (in the placebo group by 1-3%) and increases HDL cholesterol by 9-14% (in the group placebo by 3%).

In 7 patients with disbetalipoproteinemia (hyperlipidemia III type according to Fredrickson's classification) simvastatin in a dose of 80 mg per day reduced the concentration of CHLDL. Including intermediate-density lipoprotein (LDL) by 51% (in the placebo group by 8%). and the concentration of CHELP and ALPP - by 60% (in the placebo group by 4%)

Pharmacokinetics:

FROMImvastatin is an inactive lactom, which rapidly hydrolyses, transforming into (͐β-hydrocyanic acid simvastatin (L-654.969), a strong inhibitor of HMG-CoA reductase. The main metabolites of simvastatin in blood plasma are P-hydroxy acid simvastatin (1.-654.969) and eth b'-hydroxy, b'-hydroxymethyl and b'-exomethylene derivatives. Inhibition of HMG-CoA reductase is a criterion for quantifying all pharmacokinetic studies β-hydroxy acid metabolites (active inhibitors), as well as active and latent inhibitors (all inhibitors) resulting from hydrolysis. Both types of metabolites are definedin blood plasma when taken inwards simvastatin. The hydrolysis of simvastatin is mainlywalks in the "primary passage" through liver, so the concentration is unchangedsimvastatin in human blood plasma low (less than 5% of the dose). Poppysimalpaya concentration (cmax) in plasma blood metabolites of simvastatin reaches1.3-2.4 hours after admission inwards single dose. In the study withby patience (14From labeled simvastatin plasma concentration of total radioactivityactivity (14With a tagged simvastat-type + 14With labeled metabolites of simvasttin) peaked in 4 hours and rapidly declined to about 10% of poppyof the simal values within 12 hours bybarely admission inwards single dose. Notlooking at something. that the range is recommendedtherapeutic doses of simvastatin withfrom 5 to 80 mg per day, linear character profile AUC (area under the Cree"concentration - time") activetubolites in the general blood stream persists when the dose is increased to 120 mg.

Suction

Suction is subjected to about 85% withfifth inside the dose of simvastatin. Eating (within the standard hypocholesterol diet) immediately after taking simvastatin does not affect the pharmacokineticssic profile of the preparation.

Distribution

After oral administration in the liver, thehigher simvast concentrationsthan in other tissues. The concentration of active metabolite simVastatin 1.-654.969 in the systemic circulation is less than 5% of the taken orally dose; 95% of this amount is in protein-related condition. The result of active metabolism is the symbolstatin in the liver (more than 60% in men)its low concentration in generalrovoke. The possibility of penetration of simvastapa through the blood-brain barrier andthe placental barrier has not been studied.

Excretion

At the "primary passage" through nechen simvastatin metabolized fromthe next deduction of simvastapa and its metabolites with bile.

In the study, when taken 100 mg of the drug (5 capsules of 20 mg), 14C labeled simvastatin accumulated in the blood, urine and calciumof the masses. About 60% of the dose labeled simvastapa was determined in kaand about 13% in urine. Swordthe simvastatin in the feces was is represented as metabolic products simvastapa. separated from the gall, so and a nonabsorbed labeled symbolstatin. Less than 0.5% of the accepted dose of a swordsimvastapa was found in the urine in the form of active metabolites of simvastapa.

In blood plasma, 14% AUC was conditionalbut active inhibitors and 28% - allinhibitors of HMG-CoA reductase. Bythe latter indicates that at mostly metabolic products of simvastatin isare inactive or weak inhibitorsof HMG-CoA reductase. In the study but the study of the proportionof the dose of simvastatin 5, 10, 20. 60. 90 and 120 mg was not significantlyclannings from linearity AUC in generalwith increasing dose. Pharmacokinethe single and multiple admission inwards simvastatin showed that simvastatii does not accumulatein tissues at multiple admission inside.

In a study in patients with severeChest insufficiency (clearance of creatineson (KC) less than 30 ml / min) the total concentrationThe inhibition of HMG-CoA reductase inhibitors in blood plasma after taking inwards onefold dose of the corresponding inhibitorHMG-CoA reductase (statin) was approximately 2 times higher than in healthyvolunteers.

In a study involving healthy extapplication of simvastatin in poppySimal dose of 80 mg did not affect metaboliteslism of midazolam and erythromycin,with isozyme substrates CYP3A4.

This means that the simvastatia is not inhibitor of isoenzyme CYP3A4 and posturessuggests that inwards 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 AIJC of simvastatin is presumably associated, in particular, with the inhibition of the CYP3A4 isoenzyme and / or the transport protein of OATP1B1 (see CONTRAINDICATIONS).

In a pharmacokinetic study with simultaneous use with diltiazem, an increase in the AUC of the P-hydroxy acid of simvastatin was 2.7-fold, presumably due to inhibition of the isoenzyme CYP3A4 (see SPECIAL INSTRUCTIONS I. Myopathy / rhabdomyolysis).

In a pharmacokinetic study with concomitant use with amlodipine, an increase in the AUC of the P-hydroxy acid of simvastatin was observed 1.6-fold (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

In a pharmacokinetic study, while applying a single dose of 2 g of delayed-release nicotinic acid and simvastatin 20 mg, there was a slight increase in the AUC of simvastatin and P-hydroxy acids of simvastatin and Stach P-hydroxy acids of simvastatin in blood plasma (see SPECIAL I SPECIFIED AND I. Myopathy / Ribdomyolysis).

Specific pathways of fusid metabolism acids in the liver are unknown, butbut assume the existence of an interactioncoupling between fusidic acid and statiWe metabolize the isoferritement CYP3A4 (see SPECIAL INSTRUCTIONSAND I, Myopathy / Rhabdomyolysis).

The risk of developing myopathy increases with increased concentration of inhibitors HMG-CoA reductase in blood plasma. Strengthinhibitors of isoenzyme CYP3A4 moto increase the concentration of inhibitors HMG-CoA reductase inhibitors and lead to increasesrisk of developing myopathy (see VZAIMAGING WITH OTHER DRUGSCTBENNESWITH MEANS; SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Indications:

Patients with ischemic heart disease or high-risk CHD

Patients with high risk for coronary heart disease (with hyperlipidemia or without it), for example, patients with diabetes, patients with a stroke or other cerebrovascular diseases in history, in patients with peripheral vascular disease, or in patients with ischemic heart disease or predisposition to coronary artery disease Zocor Forte is indicated for:

Reducing 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 need for surgical interventions on the restoration of coronary blood flow (such as aortocoronary bypass and percutaneous transluminal coronary angioplasty).
Reducing the risk of need for surgical interventions on the restoration of peripheral blood flow and other types of non-coronary revascularization.
Reducing the risk of hospitalization due to attacks of angina pectoris.

Hyperlipidaemia

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 type Pa hyperlipidemia), or mixed hypercholesterolemia (FH type hyperlipidemia type) is not sufficient for:

reduce increased concentrations of OXC, XSLNP, TG,

apolipoprotein B (apo B);

enhancing the concentration of HDL cholesterol;
reduce relations LDL / HDL cholesterol and OXC / HDL cholesterol.

hypertriglyceridemia (type IV hyperlipidemia according to Fredrickson classification).
supplement to diet and other methods of treatment patients with homozygous familial hypercholesterolemia to reduce the elevated concentrations of OXC, CSLDPP, and apo B.
primary dysbetalapoproteinemia (type III hyperlipidemia according to Fredrickson classification).

Use in children and adolescents with heterozygous familial hypercholesterolemia

The use of Zocor Forte along with diet is shown to reduce the increased concentration 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 (the first menstrual bleeding) with heterozygous familial 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 under 18 years (excluding children and adolescents 10-17 years old with heterozygous familial hypercholesterolemia) (see INDICATIONS FOR APPLICATION).
Lactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Concomitant treatment with strong inhibitors of isoenzyme CYP3A4 (itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, bocetrevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and preparations containing a co-bicystate) (see INTERACTION WITH OTHER DRUGS, SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).
Concomitant treatment with gemfibrozil, cyclosporin or danazol (see INTERACTION WITH OTHER MEDICINES, SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Carefully:

Patients who underwent rhabdomyolysis during therapy with Zocor Forte, with a complicated anamnesis (impaired renal function, usually due to diabetes mellitus) require more careful observation, and simvastatin therapy should be temporarily discontinued in such patients a few days before performing large surgical interventions , as well as 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; (QC <30 mL / min) should carefully weigh the feasibility of prescribing simvastatin in doses> 10 mg per day and, if necessary, should be administered with caution; with alcohol abuse prior to treatment.

Pregnancy and lactation:

Zocor "Forte is contraindicated for pregnant women, since safety for pregnant women has not been proved and there is no evidence that treatment with the drug during pregnancy brings obvious benefits, the drug should be stopped immediately when pregnancy occurs. Zocor 'Forte should be prescribed to women of childbearing age only in those cases, when the probability of pregnancy is very small.The use of the drug Zocor Forte during pregnancy can reduce the concentration of mevalonate (a precursor in the biosynthesis of cholesterol) in the fetus. eroz is a chronic disease and is usually discontinuation of lipid-lowering drugs during pregnancy has little effect on long-term risk associated with primary hypercholesterolemia. In this regard, drug Zocor⁸Forte should not be used in women who are pregnant, trying to conceive or suspect that they are pregnant. Treatment with Zocor Forte should be suspended for the duration of pregnancy or untilpregnancy is not 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 prescribe Zokor Forte 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, which means that when breastfeeding the drug should be stopped.

Dosing and Administration:

Before the start of treatment with Zocor Fort, the patient should be prescribed a standard hypocholesterolemic diet, which must be observed throughout the course of treatment.

The recommended dose of Zocor 'Forte 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 only patients with a high risk of cardiovascular complications if treatment with the drug at lower doses did not achieve the target lipid levels, and the perceived benefit of therapy exceeds the possible risk (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

If necessary, the intake of simvastatin in doses 10 mg and 20 mg, it is advisable to use the drug Zocor⁸ (tablets contain 10 mg or 20 mg of simvastatin). Patients with ischemic heart disease or a high risk of CHD The standard initial dose of Zocor Forte for patients with a high risk of 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 ischemic heart disease is 40 mg 1 time per day in the evening, and medication should be administered concomitantly with diet and exercise therapy.

Patients with hyperlipidemia who do not have the above risk factors

The standard initial dose simvastatin 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. For patients with mild or moderate hypercholesterolemia The initial dose of simvastatin is 10 mg once a day. 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

Zokor preparation⁸ Forte is recommended in a dose 40 mg per day, taken once in the evening. Dose 80 mg is recommended only in case the intended benefit of therapy exceeds the possible risk (see SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis). In such patients, Zocor⁸ Forte is used in combination with other methods of lipid-lowering treatment (for example, LDL-apheresis) or without such treatment, if it is not available.

For patients taking lomitapid concomitantly with Zocor⁸ Forte, daily dose of Zocor⁸ Forte should not exceed 40 mg (see INTERACTION WITH OTHER MEDICINES, SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Concomitant therapy

Zocor ~ Forte can be administered both in monotherapy and in combination with bile acid sequestrants.

In patients receiving simvastatin concurrent with fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate, the maximum recommended dose simvastatin is 10 mg per day.

For patients receiving amiodarone, verapamil, diltiazem or amlodipine at the same time with simvastatin, daily dose simvastatin should not exceed 20 mg. (See INTERACTION WITH OTHER MEDICINES, SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis)

With renal insufficiency

Since the Zocor Forte preparation is excreted in small amounts by the kidneys, there is no need to change the doses in patients with moderate renal dysfunction. In patients with severe renal failure (CK <30 mL / min) simvastatin in doses exceeding 10 mg per day. 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 the drug Zocor Forte is 40 mg per day. The choice of doses is carried out individually in accordance with the goals of therapy.

Side effects:

Zocor's Forte is generally well tolerated, and most side effects are mild and transitory.Less than 2% of patients who participated in clinical trials discontinued treatment due to the development of adverse events characteristic of Zocor⁸ Forte.

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 20536 patients took Zocor Forte (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 Zocor Forte and placebo groups. The incidence of discontinuation due to adverse events was also comparable in the two groups (4.8% in the Zocor Forte group and 5.1% in the placebo group) .The incidence of myopathy in patients taking Zocor ~ Forte 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 by a second study) was observed in 0.21% of patients in the Zocor Forte group and 0.09% in the placebo group.

There are reports of the possibility of developing the following undesirable 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.

On the side of the cohesive covers 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 disease lungs.

From the side of the reproductive system Frequency not established: erectile dysfunction.

Allergic and immunopathological reactions: rarely developed syndrome

hypersensitivity, which manifested itself in angioneurotic edema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, blood flushes to the skin of the face, dyspnea and general weakness.

Very few development reports were received immuno-mediated necrotizing myopathy (autoimmune myopathy), caused by taking statins. Immuno-mediated Myopathy is characterized by weakness of proximal muscles and increased activity of creatine phosphokinase (CK) in the blood serum, which persist despite the withdrawal of statin treatment. On muscle biopsy, necrotizing myopathy is seen without significant inflammation. Improvement is observed with 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 undesirable phenomena 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 the concentration of glucose in the blood serum on an empty stomach with the taking of statins, including the drug Zokor "Forte.

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® Forte group was comparable to the safety profile and tolerability of treatment in the placebo group (see SPECIFIC INDICATIONS, Application in 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 drug combinationsfunds

Contraindicated concomitant therapy following medicines.

Strong inhibitors of isoenzymes CYP3A4. Simvastatin is metabolized

isofarmed CYP3A4. but does not inhibitactivity of this isoenzyme. it allowthe suggest that the reception simvastidoes not affect the concentration in blood plasma medicines, metaisozyrazedmenta CYP3A4. Strong inhibitors ofenzyme CYP3A4 increase the risk ofof myopathy due to decreased speed deducing the simvastatia. Simultaneous use of strong inhibitors of isoferrmenta CYP3A4 (e.g., itraconazoda, ketocobalase, posacoiazole, vorpkonazola, erythromycin, clarntromptone, thoselum romycin, inhibitors HIV-protease, boceprevir, body-transfusion, notphasodone, preparations containing kobitsnstat) and simvasmagin contraindicated (see CONTRAINDICATIONS;CASH. Myopathy / Rhabdomyolysis).

Gemfibrozil, ciclosporin or danazl.

See CONTRAINDICATIONS; SPECIAL INDICATIONS. Myopathy / Rhabdomyolysis.

Interaction with other drugsby means of

Other fibrils. Risk of development of myopathy increases with simultaneous applicationSymvastatia with gemfibrozil (see below).CONTRAINDICATIONS) and other fibratami (except fenofibrate). Data gipolinidemic agents can cause myopathy in monotherapy. At one-timeapplication of simvastatiya with phenomfibrate risk of myopathyhe raised the amount of risks when monoterating with each drug (see CONTRAINDICATIONNOTE; SPECIAL INSTRUCTIONS, Myopa/ rhabdomyolysis).

Amiodarone. Risk of myopic developmentthi / rhabdomyolysis increases with onetemporary use of amiodarone with simvastatin. In a clinical study the incidence of myopathy in patients, who simultaneously simvastatin at dose of 80 mg and amiodarone, was 6% (see Fig. METHOD OF APPLICATION AND DOSES; CCABOTH INSTRUCTIONS, Myopa/ rhabdomyolysis).

Blockers of "slow" calciumof the taxes. Risk of myopic developmentthi / rhabdomyolysis increases with onetemporary use of verapamil. diltiAzem or amlodipine with simvastap (see Fig. METHOD OF APPLICATION AND DOSES; CCABOTH INSTRUCTIONS, Myopashta / rhabdomyolysis).

Lomitapid. Risk of myopic developmenttia / rhabdomyolysis may increase with simultaneous application of lomitapid with simvastapom (see METHOD OF APPLICATIONNIIA AND DOSES; SPECIAL INSTRUCTIONS, Myopathy / Rhabdomyolysis).

Moderate inhibitors of isoenzymeCYP3A4 (eg, dronedaron). At onetime-based application of drugs, onof moderate inhibitoryIsoenzyme resistance CYP3A4. and simvastatin. especially in high doses, can increase the risk oftion of myopathy (see SPECIAL INDICATIONSAND I, Myopathy / Rhabdomyolysis). At onetemporary use of Zocor Forte and moderate isoferrin inhibitorscops CYP3A4 may requiredose of simvastatin.

Ranolazine (mild inhibitor of isophoresment of CYP3A4). With the simultaneous use of ranalasia and simvastatin, the risk of developing myopathy may increase (see SPECIFIC INSTRUCTIONS, MULTIPLE / rhabdomyolysis). 11 Simultaneous application of simvastatin and ranolazia may require a reduction in the dose of simvastatin.

Inhibitors of transport protein OATP1B1. The hydroxy acid of simvastatin is a substrate of OATPIBI transport protein. Simultaneous use of transport protein inhibitors OATP1BI and simvastatin may lead to an increase in the plasma concentration of hydroxy acid of simvastatin and an increased risk of myopathy (see CONTRAINDICATIONS: SPECIFIC INSTRUCTIONS., Mionation / Rabonomolt).

Fusidic acid. With the simultaneous use of fusidic acid and simvastatin, the risk of developing myopathy may increase (see SPECIAL INSTRUCTIONS, Multiple / Rabdominal).

Nicotinic acid (not less than 1 g / day).When simvastatin and nicotinic acid are simultaneously used in lipid-lowering doses (at least 1 g / day), cases of myopathy / rhabdomyolysis have been described (see SPECIAL INSTRUCTIONS, Mionation / Rhabdomyolysis).

Colchicine. With simultaneous application of colchicine and simvastatin in patients with renal insufficiency,teas of development of myopathy and rhabdomyolysis.

When combined therapy with data such patients shouldunder close supervision.

Indirect anticoagulants (derivatives coumarin). Simvastatin in a dose of 20-40 mg in day potentiates the effect of coumarin anticoagulants: prothrombin time defined as the international normalsThe ratio (MNO) increases from baseline 1.7 to 1.8 in healthy volunteers between 2.6 and 3.4 in patients with hypercholesterolemia. In patients withCoumarin anticoagulants prothrombin time should determinebefore the start of simvastatin therapy, and sosame often enough in the initial period treatment to exclude significantthis indicator. As soon asa stable indicator MN0, its further definition should be with intervals recommended for the control of patients receiving therapyticoagulants. When changing the dose of simVastatin or, after its cancellation, alsoA regular measurement ofthrombin time. Patients who do not who took anticoagulants, therapy simvastatin was not associated with the arisingbleeding or changes in prothrombin time.

Other types of interaction

Grapefruit juice contains one or more components that inhibit the isoferMent CYP3A4 and can increase the concentration in the blood plasma of drugs metabolized by the isoenzyme CYP3A4. 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. 13 Due to this, it is necessary to avoid the consumption of grapefruit juice during the treatment with simvasgatine (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 a drug Zocor Forte 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 simvastatin in a dose of 20 mg per day - 0.02%. About half of the cases of myopathy was 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 Forte 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, the drug Zokor "Forte in a dose of 80 mg per day should be prescribed only patients with a high risk of cardiovascular complications in whom drug therapy at lower doses did not achieve the desired therapeutic effect, and the perceived benefit of treatment exceeds the possible risk. If the patient taking the drug Zokor Forte in a dose of 80 mg. requires treatment with another drug that can interact with simvastatin,it is necessary to reduce the dose of Zocor Forte or to prescribe another statin, which has less potential for possible drug interaction (see CONTRAINDICATIONS, APPLICATION METHOD AND DOSES).

All patients who start Zokor Forte 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 immediate medical attention in the event of any unexplained muscle pain, tenderness in the muscles or muscle weakness. Therapy with Zocor Forte should be discontinued 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 Fort, the symptoms of myopathy are resolved, and the activity of CK decreases. Patients starting to take ZocorForte or passing to increased 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 therapy with Zokor Forte had a complicated history, including impaired renal function, usually due to diabetes mellitus. Such patients require more careful observation. Therapy with Zocor Forte should be temporarily discontinued a few days before performing large surgical interventions, 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 patients of Chinese nationality, care must be taken when appointment simvastatin to patients of the Mongoloid race, in particular to assign it to low doses.

The risk of myopathy / rhabdomyolysis increases with simultaneous use of Zocor Forte with the following medicines.

Contraindicated combinations of medicines

- Strong inhibitors of isoenzyme CYP3A4. Concomitant therapy with potent inhibitors of isoenzyme CYP3A4 in therapeutic doses (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromcin, HIV protease inhibitors, bocetrevir, telaprevir, nefazodone or preparations containing a co-bicystate) is contraindicated. If short-term treatment with strong inhibitors of isoenzyme is avoided CYP3A4 it is impossible, therapy with Zocor Forte should be interrupted for the period of their application (see p. CONTRAINDICATIONS; INTERACTION WITH OTHERS DRUGS).

Gemfibrozil, ciclosporin or danazol. The simultaneous application of these preparations with Zocor® Forte is contraindicated (see CONTRAINDICATIONS, INTERACTION WITH OTHERS

DRUGS).

Other medicines

Other fibrates. In patients taking fibrates, except gemfibrozil (cm. 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 addition of fibrate therapy to simvastatin therapy usually leads to a slight additional decrease in LDL cholesterol, but allows a more pronounced decrease in the concentration of TE and an increase in the concentration of HDL cholesterol. 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, diltiazem or amlodipine, the dose of simvastatin should not exceed 20 mg per day (see INTERACTION WITH OTHER DRUGS).
Lomitapid.In patients with homozygous familial hypercholesterolemia taking lomitapid, the dose of simvastatin should not exceed 40 mg per day (see INTERACTION WITH OTHER DRUGS).
Moderate inhibitors of isoenzyme CYP3A4. With the simultaneous use of drugs that have moderate inhibitory activity against isoenzyme CYP3A4, and simvastatin, especially at higher doses, may increase the risk of developing myopathy. At simultaneous the use of simvastatin with moderate isoenzyme inhibitors CYP3A4 a dosage adjustment of simvastatin may be required.

Fusidic acid. The simultaneous use of fusidic acid and simvastatin may increase the risk of myopathy (see INTERACTION WITH OTHER MEDICINES). Simultaneous use of simvastatin and fusidic acid is not recommended. If the use of systemic fusidic acid preparations is deemed necessary, Zokor forort should be withdrawn for the duration of this therapy. In exceptional cases, when long-term therapy with systemic fusidic acid preparations is necessary, for example, for the treatment of severe infections, the possibility of simultaneous application of Zocor Forte and fusidic acid should be considered individually in each individual case and combined therapy should be performed under close medical supervision.
A nicotinic acid (in lipid-lowering doses not less than 1 g / day). When simultaneous application of Zokor Forte and nicotinic acid in lipid-lowering doses (at least 1 g / day), cases of myopathy / rhabdomyolysis have been described. In a clinical study (a median follow-up of 3.9 years) involving high-risk patients cardiocardiovascular diseases and a well-controlled concentration LDL-C with using simvastatin in a dose of 40 mg / day with or without ezetimibe 10 mg / day It was The absence of an additional positive effect on outcomes cardiovascular diseases with simultaneous use of nicotinic acid in lipid-lowering doses (not less than 1 g / day). Thus, way, the advantage of simultaneous use of simvastatin with nicotine acid in lipid-lowering doses (not less than I g / day) should be carefully weighed concerning the potential risks of combination therapy. Besides the one in this study, the incidence of myopathy was approximately 0.24% among patients of Chinese nationality when taking simvastatin in a dose of 40 mg or simvastatin / ezetimibe at a dose of 40/10 mg compared to 1.24% among patients of Chinese nationality when taking simvastatin in a dose 40 mg or simvastatin / ezetimibe in a dose of 40/10 mg at a time with laropypirant / nicotinic acid of delayed liberation in a dose of 40 mg / 2 in Despite the fact that in this clinical study, the only representatives of the Mongoloid race patients Hoa, without the simultaneous application of simvastatin with nicotinic acid in a lipid-lowering doses (at least 1 g / day) in the Mongoloid race of patients, since the incidence of myopathy is higher in patients Chinese nationality than in patients of other nationalities (see INTERACTION WITH OTHER DRUGS).

Effects on the liver

Some adult patients taking the drug Zocor Forte has been a steady increase in the activity of "liver" enzymes (more than 3 times the ULN). At the termination or interruption of therapy with Zocor "Forte Activity" liver "enzymes usually gradually returned to baseline.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 hepatic samples before initiating treatment with Zocor® Forte 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 Forte 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, 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 with a stable excess of VEN 3 times, the drug should be canceled. The cause of increased activity of alanine aminotransferase (ALT) can 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 severe liver damage develops with clinical symptoms and / or hyperbilirubinemia or jaundice during treatment with Zocor Fort, it is necessary to immediately stop therapy. If there is no other cause of the development of this pathology, the repeated administration of Zokor Forte is contraindicated.

In patients who abuse alcohol and / or patients with impaired liver function, the drug should be used with extreme caution. Active disease liver or unexplained increase in the activity of "liver" transaminases are contraindications to the appointment of Zocor Forte.

In the process of treatment with Zocor Forte, as well as in the treatment with other lipid-lowering drugs, there was a moderate (greater than 3-fold increase in IGN) increase 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 Forte on the lens of the human eye.

Use in children and adolescents aged 10-17 years

Safety and efficacy of Zocor Forte 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 of childhood, who took the drug Zokor Forte, the profile of adverse events was comparable to that of patients taking placebo. The use of Zokorv Forte 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 taking Zocor® Forte 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® Forte (see CONTRAINDICATIONS, PREGNANCY APPLICATION AND BREASTFEEDING PERIOD). The use of Zocor® Forte has not been 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 Forte, 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 Forte at a dose of 80 mg per day in patients older than 65 years of age 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 preparation Forte has little or no influence on the ability to drive vehicles and work with machinery. However, less, when driving vehicles or working with mechanisms, it should be taken into account that in the post-marketing period, rare cases of dizziness development were reported.

Form release / dosage:

Film coated tablets 40 mg. For 14 tablets in a blister of PVC / PE / PVDC and aluminum foil. 1 or 2 blisters with instructions for use in a cardboard box

Packaging: For 14 tablets in a blister of PVC / PE / PVDC and aluminum foil. 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 N016251 / 01

Date of registration:31.03.2010

The owner of the registration certificate:MERC SHARP and DOMA IDEA, Inc. MERC SHARP and DOMA IDEA, Inc. Switzerland

Manufacturer: & nbsp

MERCK SHARP & DOHME, B.V. Netherlands

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp27.02.2013

Illustrated instructions

Instructions

Zokor® forte (Zocor® forte)