Simvastatin Zentiva - instructions for use, dose, side effects, contraindications

core: lactose - 74.50 / 149.00 / 298.00 mg, corn pregelatinised corn starch - 10,00 / 20,00 / 40,00 mg, microcrystalline cellulose - 5,00 / 10,00 / 20,00 mg, talc - 1.00 / 2.00 / 4.00 mg, magnesium stearate 0.50 / 1.00 / 2.00 mg, butyl hydroxy anisole 0,02 / 0.04 / 0.08 mg; film sheath: giprolose - 0,76 / 1,65 / 3,06 mg, hypromellose - 0,76 / 1,65 / 3,06 mg, titanium dioxide - 0,69 / 1,50 / 2,78 mg, talc - 0, 28 / 0.60 / 1.11 mg.

Description:

Tablets coated with a film coating, 10 mg:

Oblong, biconvex tablets from white to almost white, film-coated, with a risk on both sides and with engraving "SVT" and "10" on one side.

Film-coated tablets, 20 mg:

Oblong, biconvex tablets from white to almost white, film-coated, with a risk on both sides and with engraving "SVT" and "20" on one of the parties.

Tablets, film-coated, 40 mg:

Oblong, biconvex tablets from white to almost white, film-coated, with a risk on both sides and with engraving "SVT" and "40" 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:

A hypolipidemic agent obtained synthetically from the product of fermentation of the fungus Aspergillus terreus, which is an inactive lactone, undergoes hydrolysis in the body to form the main hydroxy-acid metabolite, which has a high inhibitory activity against 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), an enzyme catalyzing the initial mevalonate formation from HMG -CoA.

Since the conversion of HMG-CoA to mevalonate is the earliest and most significant stage in the synthesis of cholesterol, the use of simvastatin ns causes the accumulation of potentially toxic sterols in the body. HMG-CoA is easily masturbated to acetyl-CoA, which is involved in many synthesis processes in the body.

Simvastatin causes a decrease in plasma concentrations of triglycerides (TG), low-density lipoprotein cholesterol (LDL cholesterol), very low-density lipoprotein cholesterol (LDL-C), and total cholesterol (OCS) (in cases of heterozygous familial and non-familial forms of hypercholesterolemia, when the appointment of hypocholesteroleic diet and other non-drug measures (physical activity and weight loss) is not enough to achieve a therapeutic effect.

Simvastatin increases the concentration of high density lipoprotein cholesterol (HDL cholesterol) and reduces the ratio of LDL cholesterol / HDL cholesterol and HDL-CX7XC cholesterol.

A noticeable therapeutic effect is manifested within 2 weeks from the start of the admission, the maximum therapeutic effect is achieved 4-6 weeks after the start of treatment.The effect persists with the continuation of treatment, with the cessation of therapy, the concentration of cholesterol gradually returns to the initial level.

Pharmacokinetics:

Metabolism

Simvastatin is an inactive lactone, which is rapidly hydrolyzed in vivo before β- hydroxy acids of simvastatin (L-654,969), a strong inhibitor of HMG-CoA reductase. The main metabolites of simvastatin in blood plasma are p-hydroxy acid simvastatin (L-654,969) and its 5'-hydroxy, 6'-hydroxymethyl and 6'-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) formed as a result of hydrolysis. Both types of metabolites are determined in the blood plasma when taking simvastatin.

The hydrolysis of simvastatin mainly occurs during the "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 rate of hydrolysis in human blood plasma is low enough. The maximum concentration (C_shah) in the blood plasma of simvastatin metabolites is achieved through 1,3-2,4 h after administration of a single dose. In a study using ¹⁴From the labeled simvastatin, the plasma concentration of total radioactivity (¹⁴With labeled simvastatin +¹⁴ C labeled metabolites of simvastatin) peaked at 4 hours and rapidly decreased to about 10% of the peak value within 12 hours after taking a single dose.

Pharmacokinetic properties of the drug are studied in adults. Data on pharmacokinetics in children and adolescents are absent.

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.

Simvastatin and its active metabolite bind more than 95% to blood proteins. 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. After ingestion of radioactive simvastatin, 13% of the drug was detected in the urine and 60% in the stool for 96 hours. The amount of drug withdrawn with cap drug includes equivalent amounts of the drug as absorbed and isolated with bile and nonabsorbable. After intravenous administration β-hydroxy acid, the half-life (T 1/2) of this metabolite is about 1.9 hours. On average, only 0.3% of the dose administered intravenously is excreted in the urine in active form. Simvastatin is actively captured by hepatocytes via the transport protein OATP1B1.

In a study on the proportionality of doses of simvastatin 5, 10, 20. 60. 90 and 120 mg ns, there was a significant deviation from linearity AUC in the general blood stream with increasing dose. Pharmacokinetic parameters for single and multiple administration of simvastatin showed that simvastatin Do not accumulate in tissues with repeated use.

In a study in patients with severe renal failure (creatinine clearance (CK) less than 30 ml / min), the total concentrationinhibitors of HMG-CoA reductase in plasma after receiving a single dose of the corresponding inhibitor of HMG-CoA reductase (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 isoenzyme CYP3A4. It means that simvastatin is not an inhibitor of isoenzyme CYP3A4 and suggests that the use of simvastatin does not affect the concentration in the blood plasma of drugs metabolized under the action of the isoenzyme CYP3A4.

The risk of myopathy increases with an increase in the concentration of inhibitors of HMG-CoA reductase in blood plasma. Strong inhibitors of isoenzyme CYP3A4 can increase the concentration of HMG-CoA reductase inhibitors and lead to an increased risk of myopathy (see section "Special instructions").

Individual populations

Carriers of the allele C.521T> C of the gene SLC01B1 I have a lower activity of OATP1B1. Average exposure (AUC) the main active metabolite, simvastatin acid,is 120% in heterozygous carriers (CT) of C allele and 221% in homozygous (CC) carriers, but in relation to patients who are carriers of the most common genotype (TT). Allele C is found in 18% of Europeans. In patients with polymorphism SLC01B1 There is a risk of increased exposure to simvastatin on the body, which can lead to an increased risk of rhabdomyolysis.

Indications:

1. Hyperlipidemia

- as a supplement to the diet, when the use of only diet and other non-pharmacological treatments in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson type hyperlipidemia), or mixed hypercholesterolemia (hyperlipidemia IIa type according to Fredrickson's classification) is not enough to: reduce the elevated concentrations of OXC, CHC LINI, 'GG, apolipoproteip B (apo B);

increased concentration of cholesterol;
decrease in the ratio of LDL / HDL cholesterol and LDL cholesterol / 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 concentration of OXC. HS LIPP and apo B;
primary dysbetalapoproteinemia (type III hyperlipidemia according to Fredrickson classification)

2. Patients with ischemic heart disease (CHD) 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 the preparation 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 recovery operations

coronary blood flow (such as coronary artery bypass grafting and percutaneous transluminal coronary angioplasty).

Reducing the risk of need for recovery operations

peripheral blood flow and other types of non-coronary revascularization.

Reducing the risk of hospitalization due to attacks of angina pectoris.

3.Use in children and adolescents with heterozygous family

hypercholesterolemia

The drug is indicated for the reduction of elevated concentrations of total cholesterol, LDL cholesterol, triglycerides, apo B in young men 10-17 years and women 10-17 years of not less than 1 year after menarche (the first menstrual bleeding) with heterozygous familial hypercholesterolemia.

Contraindications:

Hypersensitivity to simvastatin or to other components of the drug as well as other drugs of a number of statin (HMG-CoA reductase) in history.
Liver disease in its active phase, a persistent increase in activity "liver" enzymes in the blood plasma of unclear origin (more than 3 times compared with the upper limit of normal (AIV)).
Concomitant treatment with strong inhibitors of isoenzyme CYP3A4 (E.g., itraconazole, voriconazole, keto cop azole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone and preparations containing kobitsistat) (see. The sections "interaction with other drugs," "special instructions").
Concomitant treatment with gemfibrozil, cyclosporin, or danazol (cf.sections "Interaction with other medicines", "Special instructions"),
Pregnancy or the period of breastfeeding.
Age 18 years (except for children and adolescents with heterozygous familial hypercholesterolemia) (see. Section "Indications for Use").
Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Carefully:

Be wary of patients who abuse alcohol; transplant patients undergoing immunosuppressive therapy (due to an increased risk of rabdo.mioliza and renal failure); under conditions that can lead to severe renal insufficiency, such as hypotension, acute infectious diseases heavy currents expressed metabolic and endocrine disorders, water-electrolyte balance, surgery (including dental) or trauma; patients with decreased or increased tone of skeletal muscles

unclear etiology; with simultaneous admission with fibrates, excluding gemfibrozil (cf.(more than 1 g per day), colchicine, amiodarone, dronedarone, veranamil, amlodipine, diltiazem, fusidic acid, grapefruit juice, with severe renal failure (creatinine clearance less than 30 ml / min.).

Pregnancy and lactation:

The drug Simvastatin Zentiva is contraindicated in pregnancy.

Safety of the use of simvastatin in pregnant women is not established. The drug Simvastatin Zentiva should be given to women of childbearing age only in those cases when the probability of pregnancy is very small. In the case of diagnosing pregnancy during therapy, taking Simvastatin Zentiva should be stopped immediately, and patients are warned about the potential risk to the fetus. Treatment with the drug must be suspended for the duration of the pregnancy or until the pregnancy is diagnosed. Although there is no evidence that the number of congenital malformations increases with the use of simvastatin or other inhibitors of HMG-CoA reductase, the use of Simvastatin Zentiva during pregnancy can reduce the concentration of msvalonate (a precursor in cholesterol biosynthesis) in the fetus.Atherosclerosis is a chronic disease and usually stopping the intake of hyiolinemic drugs during pregnancy has little effect on the long-term risks associated with primary hypercholesterolemia.

Data on the isolation of simvastatin and its metabolites in breast milk are absent. If you need to use the drug during breastfeeding, given the risk of serious adverse reactions in infants, you should decide whether to stop breastfeeding.

Dosing and Administration:

Before the appointment of the drug Simvastatin Zentiva, the patient should be recommended a standard hypocholesterol diet, which he must observe during the entire period of therapy.

The drug is taken orally once a day in the evening, squeezed with enough water, regardless of food intake.

The daily dose of Simvastatin Zentiva is from 5 to 80 mg once a day in the evening. The maximum daily dose is 80 mg. The change (selection) of the dose follows

spend at least 4 weeks apart. A dose of 80 mg per day is recommended to be prescribed only to patients with a high risk of cardiovascular complications,if treatment with the drug in lower doses did not allow achieving lipid profile targets, and the estimated benefit from treatment exceeds the possible risk. In most patients, the optimal effect is achieved when taking the drug at doses up to 20 mg per day.

Patients with homozygous hereditary hypercholesterolemia

The recommended daily dose of Simvastatin Zentiva is 40 mg once a day in the evening or 80 mg in three divided doses (20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening). A dose of 80 mg per day is recommended to be prescribed only if the expected benefit of therapy exceeds the possible risk. In such patients, the drug Simvastatin Zentiva is prescribed in combination with other types of lipid-lowering therapy (eg, LDL-apheresis) or without such treatment, if it is not available.

For patients taking lomitapid concomitantly with Simvastatin Zentiva, the daily dose of simvastagin should not exceed 40 mg.

Patients with ischemic heart disease (HES) or a high risk of developing PES In the treatment of patients with IHD or its high risk of development, effective doses of Simvastatin Zentiva are 20-40 mg once a day in the evening. Therefore, the recommended initial dose in such patients is 20 mg per day.Possible dose adjustment should be performed according to the recommendations above. Drug therapy should be started simultaneously with diet and exercise. If the LDL content is less than 75 mg / dL (1.94 mmol / L), the total cholesterol content is less than 140 mg / dL (3.6 mmol / L), the dose of the drug must be reduced.

Patients with hyperlipidemia who do not have the above risks The standard starting dose is 20 mg once a day in the evening. Patients who require a significant reduction in LDL cholesterol (greater than 45%) can begin with 20-40 mg / day, taken once a day in the evening. Possible dose adjustment should be performed according to the recommendations above.

Elderly patients Correction of the dose is not required.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not required.

In patients with severe renal insufficiency (KC less than 30 ml / min) the maximum recommended dose of Simvastatin Zentiva should not exceed 10 mg per day.

Concomitant therapy

The drug can be administered both in monotherapy and with bile acid chelators. For patients taking fibrates (except gemfibrozil, see the section "Contraindications"), diltiazem, dronedaron, verapamil, nicotinic acid in lipid-dosing doses (more than 1 g / day) concomitantly with the preparation Simvastatin Zentiva, the maximum daily dose of the drug should not exceed 10 mg.

W /

For patients receiving amiodarone, verapamil. Simvastatin Zentiva, the maximum daily dose should not exceed 20 mg, unless the expected benefit exceeds the risk of developing myopathy and rhabdomyolysis.

For patients receiving diltiazem or amlodipine Simvastatin Zentiva, the maximum daily dose should not exceed 40 mg, unless the expected benefit exceeds the risk of myopathy and rhabdomyolysis.

Children and adolescents 10-17 years old with heterozygous hereditary hypercholesterolemia For children and adolescents (boys in stage II or more but on the Tanner scale and girls whose menstruation started at least 1 year ago, aged 10-17 years) with heterozygous familial hypercholesterolemia, the recommended initial dose is usually 10 mg once a day in the evening . Before starting simvastatin therapy, children and adolescents should switch to a standard diet that lowers cholesterol; This diet should continue during the course of taking simvastatin.

The recommended dose ranges from 10 to 40 mg / day; the maximum recommended dose is 40 mg / day. Doses should be selected individually in accordance with the purpose of therapy, appointed on the basis of the recommendations of a specialist. The dose adjustment should be carried out with an interval of at least 4 weeks.

Ethnic groups of patients

In clinical trials, a higher than expected frequency of myopathy in Chinese patients receiving simvastatin 40 mg and nicotinic acid / laropyprant 2000 mg / 40 mg. Caution should be exercised when treating Chinese patients with simvastatin (especially doses of 40 mg or higher) given concomitantly with niacin (nicotinic acid), in lipid modifying doses (> 1 g / day), or products containing niacin. Since the risk of developing myopathy depends on the dose of statins, the use of simvastatin 80 mg with cyanine (nicotinic acid) in lipid-lowering doses (> 1 g / day) or products containing niacin is not recommended for Chinese patients.It is not known whether there is an increased risk of myopathy in other Mongoloid patients receiving treatment with simvastatin, prescribed together with niacin (nicotinic acid) in lipid-lowering doses (> 1 g / day) or with products containing niacin.

Side effects:

With the use of the drug Simvastatin Zentiva, the following side effects may occur, which are divided into systemic and organ classes in accordance with the classification of the Medical Dictionary of Regulatory Activities (MedDRA). The WHO classification was used to indicate the frequency of side effects: very often (> 10%); often (> 1% and <10%); infrequently (> 0.1% and <1%); rarely (> 0.01% and <0.1%); very rarely (<0.01%); the frequency is unknown (it is not possible to determine the incidence of side effects from the available data).

Violations from the blood and lymphatic system: rarely - anemia.

Immune system disorders: rarely - angioedema, rheumatic urolithiasis, vasculitis, urticaria, lupus-like syndrome: frequency unknown - immune-mediated necrotizing myopathy (autoimmune myopathy).

Impaired nervous system: rarely - headache, dizziness, paresthesia, peripheral neuropathy; very rarely - insomnia, memory impairment, confusion; frequency is unknown-depression.

Disorders from the side of the organ of vision: rarely - blurred vision. Heart Disease: rarely - a feeling of palpitations.

Vascular disorders: rarely - the "tides" of blood to the skin of the face.

Disturbances from the respiratory system, chest and mediastinal organs: very rarely - dyspnea; frequency unknown - interstitial lung disease. Disorders from the gastrointestinal tract: rarely - a violation of taste, constipation, abdominal pain, flatulence, dyspepsia, nausea, vomiting, diarrhea, pancreatitis.

Disorders from the liver and bile ducts: rarely - jaundice, hepatitis; very rarely - fatal and non-fatal hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues: rarely - skin rash, itching. alopecia, dermatomyositis, skin hyperemia, photosensitivity.

Disturbances from the musculoskeletal and connective tissue: rarely - arthritis, arthralgia, myalgia, muscle cramps, myopathy (including myositis) *, rhabdomyolysis; the frequency is unknown - tendonitis, possibly with a rupture of tendons.

mainly when taking a dose of simvastatin 80 mg per day.

Disorders from the kidneys and urinary tract: rarely acute renal failure (due to rhabdomyolysis).

Violations of the genitals and breast: frequency is unknown - erectile dysfunction.

General disorders and disorders at the site of administration: rarely - weakness, fever, asthenic syndrome.

Laboratory and instrumental data: rarely - increased activity

"hepatic" transaminases, increased activity of alkaline phosphatase, increased activity of creatine phosphokinase (CK), thrombocytopenia, increased erythrocyte sedimentation rate (ESR), eosinophilia.

The following adverse events have been reported with the use of some statins:

sleep disturbance. including nightmares;
memory impairment;
sexual dysfunction, gynecomastia;
diabetes mellitus: the incidence will depend on the presence or absence of risk factors (fasting blood glucose> 5.6 mmol / l, BMI> 30 kg / m², increased concentration of triglycerides in blood plasma, arterial hypertension in history).

Overdose:

Symptoms: None of the several known cases of overdose (maximum accepted dose of 3.6 g) of specific symptoms have been identified.

Treatment: gastric lavage, reception of activated carbon. Symptomatic and supportive therapy. It is necessary to monitor the liver and kidney function, the activity of CKK in the blood serum.

In the development of myopathy with rhabdomyolysis and acute renal failure (a rare but severe adverse reaction), stop taking the drug immediately and inject the patient with a diuretic and sodium bicarbonate (intravenous infusion). If necessary, hemodialysis is indicated.

Rhabdomyolysis can cause hypercalcia and ul, which can be eliminated by intravenous administration of calcium chloride or calcium gluconate, glucose infusion with insulin, use of potassium ion exchangers or, in severe cases, by hemodialysis.

Interaction:

Contraindicated combinations of medicines

Contraindicated concomitant therapy with the following medicines. Strong inhibitors of isoenzyme CYP3A4

Simvastatin is metabolized by isoenzyme CYP3A4, but does not inhibit the activity of this isoenzyme.This suggests that the reception simvastatiia no effect on the concentration in the blood plasma of drugs metabolized by the action of the isoenzyme CYP3A4. Strong inhibitors of isoenzyme CYP3A4 increase the risk of myopathy by reducing the elimination rate simvastatiia. Simultaneous application of strong inhibitors of isoenzyme CYP3A4 (E.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, botseprsvira, telaprevir, nefazodone, preparations containing kobitsistat) and simvastatiia contraindicated (see. The section "Contra", "Special instructions"),

Gemfibrozil. ciclosporin or danazol

In a joint application with simvastatiia doses over 10 mg per day increases the risk of myopathy / rhabdomyolysis (see. Section "Contraindications", "Cautions").

The mechanism of interaction with cyclosporine is not fully understood, but it is known that ciclosporin leads to an increase AUC inhibitors of HMG-CoA reductase. Increase AUC for simvastatin acid is presumably due in part to inhibition CYP3A4.

Gemfibrozil increases AUC simvastatin acid in 1,9 times, perhaps, the ego is associated with the inhibition of glucuronization.

Interaction with other drugs

Other fibrates

The risk of myopathy increases with the simultaneous use of simvastagin with other fibrates, except fenofibrate (see the section "With caution"). These hypolipidemic agents can cause myopathy in monotherapy. With the simultaneous use of simvastagin with fenofibrate, the risk of developing myopathy did not exceed the amount of risks associated with monotherapy with each drug.

Amiodarone

The risk of myopathy / rhabdomyolysis increases with simultaneous use of amiodarop with simvastatin at doses of more than 20 mg per day. In a clinical study, the incidence of myopathy in patients taking both simvastatin in a dose of 80 mg and amnodaron, was 6% (see section "Method of administration and dose", "Special instructions").

Blocks of "slow" calcium channels

Bepapamil

The risk of myopathy and rhabdomyolysis increases with simultaneous the use of verapamil with simvastatin in a dose of 40 mg or 80 mg. In a pharmacokinetic study with simultaneous application of verapamil, an increase in the exposure of simvastatin acid by 2.3-fold was observed,presumably due to inhibition of the isoenzyme CYP3A4. Therefore, the dose of simvastagin should not exceed 20 mg per day in patients who simultaneously take verapamil, unless the expected benefit is greater than the harm from an increased risk of myopathy and rhabdomyolysis.

Diltiazem

The risk of myopathy and rhabdomyolysis increases with simultaneous the use of diltiazem with simvastatin in a dose of 80 mg. The risk of myopathy in patients taking simvastatin 40 mg, was not elevated when taken concomitantly with diltiazem. In a pharmacokinetic study with the simultaneous use of diltiazem, an increase in the exposure of simvastatin acid 2.7-fold was observed, presumably due to the inhibition of the isoenzyme CYP3A4. Therefore, the dose of simvastagin should not exceed 40 mg per day in patients who simultaneously take diltiazem, unless the expected benefit is greater than the harm from an increased risk of myopathy and rhabdomyolysis.

Amlodipine

An increased risk of myopathy occurs in patients taking both amlodipine and simvastatin in a dose of 80 mg. In patients receiving simvastatin in a dose of 40 mg and simultaneously amlodipine, the risk of myopathy is not increases. In the pharmacokinetic study with simultaneous use of amlodinin, an increase in the exposure of simvastatinic acid was observed 1.6 times. Therefore, the dose of simvastatin should not exceed 40 mg per day in patients taking amlodipine at the same time, unless the expected benefit exceeds the risk of an increased risk of myopathy and rhabdomyolysis.

Lomitapid

The risk of myopathy / rhabdomyolysis may increase with simultaneous application of lomitapid with simvastatin.

Moderate inhibitors of isoenzyme CYP3A4 (e.g., dronedorone).

With the simultaneous use of drugs that have moderate inhibitory activity against isoenzyme CYP3A4. and simvastatin, especially in high doses, may increase the risk of myopathy. With the simultaneous use of the drug Simvastatin Zentiva and moderate isozyme inhibitors CYP3A4 It may be necessary to reduce the dose of Simvastatin Zentiva.

Facid acid

With the simultaneous use of fusidic acid and simvastatin, the risk of myopathy may increase. It may be necessary to temporarily stop taking simvastatin.During the concomitant therapy with fusidic acid and simvastatin, the patient should be under the supervision of a physician.

Niacin (a nicotinic acid)

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

Rifampicin

Because the rifampicin is a powerful inducer of isoenzyme CYP3A4, in patients with long-term rifampicin (for example, for the treatment of tuberculosis), the effectiveness of simvastatin therapy may be reduced. In a pharmacokinetic study involving healthy volunteers, the area under the concentration-time curve (AIJC) for simvastatin acid was reduced by 93% with simultaneous application of rifampicin.

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 at a dose of 20-40 mg per day potentiates the affect 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 reached. its further definition should be conducted 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.

Fluconazole

Rare cases of rhabdomyolysis associated with simultaneous use of simvastatin and fluconazole have been reported.

Digoxin

Simvastatin increases the concentration of digoxin in the blood plasma.

Coltesiramine and colestipol

Kolestyramin and colestipol reduce the bioavailability of simvastatin (the use of simvastatin is possible 4 hours after admissionof these drugs, with an additive effect).

Other types of interactions

Grapefruit juice

Grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4 systems of cytochrome P450 and can increase the concentration in the blood plasma of isoenzyme metabolized substances CYP3A4. An increase in the activity of inhibitors of HMG-CoA reductase 1.9 times was recorded after consuming 240 ml of juice per day. The use of a large amount of juice (more than 1 liter per day) with the use of simvastatin increases the level of inhibitory activity against HMG-CoA reductase in blood plasma by 7 times. In connection with ethyl "it is necessary to avoid the consumption of grapefruit juice in large quantities on the background of simvastatin therapy.

Special instructions:

Before and during treatment, the patient should be on a hypocholesterol diet. Myopathy / Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, sometimes causes mionatation, expressed as muscle pain, muscle sensitivity or muscle weakness, accompanied by an increase in CKK activity (more than 10 times higher than UGN). Myopathy can manifest itself in the form of rhabdomyolysis, sometimes accompanied by secondary acute renal failure caused by myoglobinuria, or without it.In rare cases, reported lethal cases. The risk of myopathy increases with high concentrations of HMG-CoA reductase inhibitors in blood plasma. Risk factors for development include advanced age (65 years and over), female gender, uncontrolled hypothyroidism and impaired renal function.

As with other HMG-CoA reductase inhibitors, the risk of myopathy / rhabdomyolysis depends on the dose. According to a database of clinical trials in which 41,413 patients were prescribed simvastatin therapy, with 24747 (approximately 60%) participating in the study followed by observation for a minimum of 4 years, myopathy was approximately 0.03%, 0.08% and 0.61% at doses of 20, 40 and 80 mg per day, respectively. In the course of these studies, the patients were carefully monitored, and some medications interacting with simvastatin were excluded.

In clinical trials, during which patients with a history of myocardial infarction received a simvastatin 80 mg per day (average follow-up follow-up of 6.7 years), the incidence of myopathy was approximately 1.0% compared to 0.02% for patients taking 20 mg per day.Approximately half of these cases of myopathy occurred during the first year of treatment with the drug. The incidence of myopathy in each subsequent year of treatment was about 0.1%.

Measurement of CK

CK can not be measured after intensive physical exertion or if there is another probable cause of increased activity of CKK, as this makes it difficult to interpret its values. If the value of CK is significantly higher than the baseline value (more than 5 times), they need to be measured again after 5-7 days to confirm the results.

Before treatment

Before starting or increasing the dose of the drug, Simvastatin Zentiva should inform the patient about the possibility of developing myopathy and recommend to consult a doctor immediately if there is unclear muscle pain, increased sensitivity of the muscles or muscle weakness.

Caution should be used in patients with predisposing factors for the development of rhabdomyolysis. In order to establish reference baseline values, the concentration of CK should be determined before starting treatment in the following situations:

elderly age (age> 65 years);
women;
impaired renal function;
uncontrolled hypothyroidism;
congenital muscular pathology in a personal or family anamnesis;
a history of muscle toxicity when using statins or fibrates;
alcohol abuse.

In such situations, the risk of treatment should be compared with the potential advantage, and clinical monitoring is also recommended. If a patient has previously experienced muscle disorders in the treatment of fibrates or stasas, treatment with various drugs of this class should be started with caution. If the baseline CPK is significantly elevated (more than 5 times compared with the VGN), treatment with Simvastatin Zentiva should not begin.

During treatment

If the patient is suffering from muscle pain, weakness, or muscle spasms when treating with Simvastatin Zentiva, the patient needs to measure the level of CK in the blood plasma. If, in the absence of physical activity, the CKF values appear to be significantly elevated (more than 5 times compared with the VGN), treatment should be discontinued. If the muscle symptoms are very pronounced and cause daily discomfort, even in the event that,when the CK values exceed the baseline values by less than 5 times compared with the VGN, consideration should be given to discontinuing the treatment with Simvastatin Zentiva. If the myion can be caused by other causes, treatment should be discontinued.

If the symptoms have disappeared and the CKF rates have returned to normal, you can consider re-applying the statin or using an alternative statin at a lower dose with careful monitoring.

An increased risk of myopathy is observed in patients taking simvastatin in a dose of 80 mg. It is recommended to conduct periodic measurements of activity

CK, as this is very important in the recognition of subclinical cases of myopathy. Therapy with Simvastatin Zentiva should be temporarily discontinued several days before routine surgery and / or after extensive medical and surgical interventions.

Measures to reduce the risks of myion / rhabdomyolysis caused by interactions with other medications

The risk of development of myopathy and rhabdomyolysis increases significantly with the simultaneous use of the drug Simvastatin Zentiva with potent inhibitors of the isoenzyme CYP3A4 (such as itraconazole, kstoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg, nelfinavir), boceprevir, telaprevir, nefazodone, gemfibrozil, ciclosporin and danazol, preparations containing a cobicystate) (see the section "Contraindications", "Interaction with other medicinal products"). If you can not avoid short-term treatment with the above drugs, the therapy with Simvastatin Zentiva should be interrupted for the period of their use.

The risk of myopathy and rhabdomyolysis also increases with the simultaneous administration of fibrates, amiodarone or verapamil with high doses of simvastatin. The risk can also increase with the simultaneous use of diltiazem or amlodipine with 80 mg of Simvastatin Zentiva per day. The risk of developing myopathy, including the development of rhabdomyolysis, may increase with concomitant administration of fusidic acid preparations and Simvastatin Zentiva (see "Contraindications", "Interaction with other medicines").

In addition, caution should be exercised when combining Simvastatin Zentiva with certain other less potent inhibitors CYP3A4: flucose, verapamil, diltiazem (see Fig.section "Contraindications", "Interaction with other medicinal products").

It is necessary to avoid simultaneous reception of grapefruit juice and Simvastatin Zentiva.

Caution should be exercised when prescribing fenofibrate with Simvastatin Zentiva, as each of the drugs taken separately can cause myopathy.

Combined use of Simvastatin Zentiva in doses above 20 mg / day with amiodarone or verapamil should be avoided. Excess daily dose of simvastatin more than 20 mg per day is only possible if the expected benefit from

therapeutic effect exceeds the risk of myopathy (see "Contraindications", "Interaction with other drugs").

Doctors considering the possibility of using combination therapy with the drug Simvastatin Zentiva and niacin (nicotinic acid) in lipid-lowering doses (at least 1 g per day) or products containing niacin should carefully evaluate the potential benefit and risk, and also carefully monitor patients on the appearance signs and symptoms of myopathy, especially during the first months of the course of therapy and with an increase in the dose of one of the medications taken.

In an international clinical study, a higher incidence of myopathy in Chinese patients with simvastatin in a daily dose of 40 mg or simvastatin at a dose of 40 mg per day along with sustained-release laropiprant / nicotinic acid at a dose of 40 mg / 2000 mg per day was noted in an international clinical study. Despite the fact that in this clinical study the only representatives of the Mongoloid race were Chinese patients, simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g per day) in patients of the Mongoloid race is not recommended, since the incidence of myopathy is higher in patients of Chinese nationality than in patients of other nationalities (see section "Interaction with other drugs").

Simultaneous use of fusidic acid and Simvastatin Zentiva may increase the risk of myopathy (see "Interaction with other drugs"). 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 use of the drug Simvastatin Zentiva and fusidic acid should be considered individually in each individual case and combined therapy should be performed under close medical supervision.

Diabetes

There is evidence of an increase in plasma glucose in the intake of statins, and in some patients predisposed to developing diabetes, they can cause hyperglycemia. However, this risk does not exceed the benefit of the therapeutic effect of statins, reducing the risk of developing cardiovascular diseases, therefore, it is not the reason for stopping the use of statins. Patients who are predisposed to developing diabetes (fasting blood glucose concentration 5.6-6.9 mmol / l.

-the

BMI> 30 kg / m, elevated plasma triglyceride concentration, presence of hypertension) should regularly monitor biochemical blood counts and undergo a clinical examination.

Exposure to the liver

In some patients receiving simvastatin, there was a steady increase in the activity of "hepatic" transaminases (more than 3 times higher than UGN).When interrupting or stopping the reception of simvastatin by these patients, the indicators of "hepatic" transaminases usually gradually decreased to the initial values.

At the beginning of therapy with Simvastatin Zentiva, a transient increase in the activity of "liver" transaminases is possible. The increase in these indicators 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 treatment and / or alcohol abuse.

Before the start of treatment, and then for clinical reasons, all patients are recommended to conduct a study of liver function. Patients who are scheduled to increase the dose of Simvastatin Zentiva to 80 mg per day should perform additional liver function tests before switching to 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 study of liver function in the near future and subsequently conduct regularly until the normalization of the activity of "liver" transaminases. In case of further increase in the activity of "hepatic" transaminases, especially when the excess of VGP is 3 times, the drug should be stopped. 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.

There were rare post-registration reports of 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 Simvastatin Zentiva, stop therapy immediately. If another cause of the development of this pathology has been identified, the repeated administration of the drug Simvastatin Zentiva 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 an unexplained increase in the activity of "liver" transaminases (more than 3 times compared with IGN) are contraindications to the prescription of the drug Simvastatin Zentiva.

In the course of treatment with simvasgatine, 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 initiation of treatment, often were transient, were not accompanied by any symptoms, and required discontinuation of treatment.

The decrease in the function of the transport anolyte of organic anions (OATP) can increase the degree of systemic exposure to simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduction in function can occur as a result of inhibition by interacting drugs (eg, cyclosporine) or in patients that carry genotype SLCOl B1 p.521T> C. Patients who are carriers of the gene allele SLCOIBI (p.521T> C) encoding the less active protein OATP1B1, are more susceptible to systemic exposure to simvastatin on the body, and they have a higher risk of developing myopathy.However, the absence of this gene in genotyping ns excludes the risk of myopathy. Ophthalmological examinations

There is no evidence of adverse effects of simvastatin on the lens of the eye. Interstitial lung disease

When statins were used, cases of interstitial lung disease were reported, especially with prolonged therapy (see "Side effect" section). When patients have symptoms of lung damage (shortness of breath, unproductive cough) against the background of the general! symptoms (fatigue, weight loss, fever) it is necessary to stop taking the drug and contact a specialist.

Use in children and adolescents (aged 10-17 years)

The safety and efficacy of simvastatin in children aged 10-17 years with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial involving boys of adolescence (stage II and higher on the Tanner scale) and girls with a menstrual cycle at least 1 year old. In patients who took simvastatin, the profile of adverse reactions was, in general, comparable to that of patients taking placebo.The use of a dose of more than 40 mg per day has not been studied in patients of childhood and adolescence.

In this limited controlled study, there is an effect on the growth or puberty of adolescent boys and girls, as well as any effect on the length of the menstrual cycle in girls. Adolescent girls should be counseled about the use of effective contraceptive methods during treatment with simvastatin (see "Contraindications", "Pregnancy and Breastfeeding"). In patients under the age of 18 years, the efficacy and safety of the drug in the course of treatment for more than 48 days ns have been studied, and the delayed effects regarding physical, intellectual and sexual development are unknown.

The use of simvastatin has not been studied in patients younger than 10 years, as well as in pre-pubertal children and girls before menarche.

Elderly patients

In patients over 65 years of age, the efficacy of taking simvasatin, judged 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 trial with simvastatin 80 mg / day in patients older than 65 years, there was an increased risk of myopathy compared with patients younger than 65 years of age.

Patients with rare hereditary diseases

Patients with rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption, the use of this drug is contraindicated.

Effect on the ability to drive transp. cf. and fur:

The drug Simvastatin Zentiva does not have a significant adverse effect on the management of vehicles and occupations of other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions. However, it should be taken into account that in the post-marketing period, rare cases of dizziness development were reported.

Form release / dosage:

Tablets, film-coated, 10 mg, 20 mg and 40 mg.

For 14 tablets in a blister of PVC / PE / PVDC / A1.For 2 or 6 blisters are placed in a cardboard box together with instructions for use.

Packaging:

For 14 tablets in a blister of PVC / PE / PVDC / A1. For 2 or 6 blisters are placed in a cardboard box together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children

Shelf life:

3 years.

Do not use after the expiry date printed on the package!

Terms of leave from pharmacies:On prescription

Registration number:П N013557 / 01

Date of registration:29.12.2001

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Information update date: & nbsp12/05/15

Illustrated instructions

Instructions

Simvastatin Zentiva (Simvastatin Zentiva)