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

Excipients: lactose monohydrate 67.92 mg / 135.84 mg / 271.68 mg, pregelatinized starch 10.00 mg / 20.00 mg / 40.00 mg, butyl hydroxy anisole 0.02 mg / 0.04 mg / 0.08 mg, citric acid, anhydrous 1.50 mg / 3.00 mg / 6.00 mg, ascorbic acid 0.06 mg / 0.12 mg / 0.24 mg , corn starch 5.00 mg / 10.00 mg / 20.00 mg, microcrystalline cellulose 5.00 mg / 10.00 mg / 20.00 mg, magnesium stearate 0.50 mg / 1.00 mg / 2.00 mg;

Sheath (film)

hypromellose 1.805 mg / 3.610 mg / 7.220 mg, talc 0.165 mg / 0.330 mg / 0.660 mg, propylene glycol 0.140 mg / 0.280 mg / 0.560 mg, titanium dioxide 0.390 mg / 0.780 mg / 1.560 mg.

When produced at OOO KRKA-RUS, Russia:

1 tablet of 10 mg / 20 mg / 40 mg contains:

Core

Active substance: Basilip semi-finished granule 89.50 mg / 179.00 mg / 358.00 mg, which corresponds to simvastatin 10.00 mg / 20.00 mg / 40.00 mg;

[Active substance of tablet mass-granules: simvastatin 10.00 mg / 20.00 mg / 40.00 mg;

Auxiliary substances of tablet mass-granules: lactose monohydrate 67.92 mg / 135.84 mg / 271.68 mg, pregelatinized starch 10,0 mg / 20.00 mg / 40.00 mg, butyl hydroxy anisole 0.02 mg / 0.04 mg / 0.08 mg, citric acid, anhydrous 1.50 mg / 3.00 mg / 6.00 mg, ascorbic acid 0 , 06 mg / 0.12 mg / 0.24 mg]

Excipients: corn starch 5.00 mg / 10.00 mg / 20.00 mg, microcrystalline cellulose 5.0 mg / 10.00 mg / 20.00 mg, magnesium stearate 0.50 mg / 1.00 mg / 2.00 mg;

Sheath (film)

hypromellose 1.805 mg / 3.610 mg / 7.220 mg, talc 0.165 mg / 0.330 mg / 0.660 mg, propylene glycol 0.140 mg / 0.280 mg / 0.560 mg, titanium dioxide 0.390 mg / 0.780 mg / 1.560 mg.

Description:

Tablets 10 mg and 20 mg:

Round, slightly biconcave tablets, covered with a film shell of white or almost white color, with a bevel.

Tablets 40 mg:

Round, slightly biconcave tablets covered with a film shell of white or almost white color, with a facet and a risk 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 preparation Vazilip® (simvastatin) is a lipid-lowering drug obtained synthetically from the fermentation product Aspergillus terreus.

Pharmacodynamics

After oral administration simvastatin, which is an inactive lactone, undergoes hydrolysis in the liver to form the corresponding form of the β-hydroxy acid of simvastatin, which is the main metabolite and has a high inhibitory activity against HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme catalyzing the initial and the most significant stage of cholesterol biosynthesis. Simvastatin has been shown to be effective in reducing total cholesterol (OXc) in the blood plasma, low-density lipoprotein cholesterol (LDL cholesterol), triglycerides (TG), and very low density lipoprotein cholesterol (XPSL), as well as in increasing cholesterol concentrations of high density lipoproteins HDL) in blood plasma in patients with heterozygous familial and non-family hypercholesterolemia or mixed hyperlipidemia in those cases,when the increased concentration of Xs in the blood plasma is a risk factor and the appointment of one diet is not enough. A noticeable therapeutic effect is observed within 2 weeks of taking simvastatin, the maximum therapeutic effect is within 4-6 weeks after the start of treatment. The effect persists with the continuation of therapy. When discontinuation of simvastatin intake, the concentration of Xc in the blood plasma returns to the initial value observed before the start of treatment.

The active metabolite of simvastatin is a specific inhibitor of HMG-CoA reductase, an enzyme that catalyzes the formation of mevalonate from HMG-CoA. Despite this, taking Vazilip® in therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows to preserve the production of biologically necessary amount of mevalonate. Since the early stage of the biosynthesis of Xc is the conversion of HMG-CoA into mevalonate, it is believed that the use of the drug Vazilip® should not cause the accumulation of potentially toxic sterols in the body. In addition, HMG-CoA is rapidly metabolized back to acetyl-CoA, which participates in many biosynthetic processes in the body.

Although Xc is the precursor of all steroid hormones, there was no clinical effect of simvastatin on steroidogenesis. Because the simvastatin does not cause an increase in the lithogenicity of bile, it is unlikely that it will affect the incidence of cholelithiasis.

Simvastatin reduces both elevated and normal concentrations of LDL cholesterol in the blood plasma. LDL is formed from very low density lipoproteins (VLDL). The catabolism of LDL is predominantly performed with the help of a high affinity LDL receptor. The mechanism of reducing the concentration of LDL cholesterol in the blood plasma after taking simvastatin may be due to both a decrease in the concentration of cholesterol in the plasma and activation of LDL receptors, which leads to a decrease in the formation and enhancement of LDL cholesterol catabolism. In the treatment with simvastatin, the concentration of apolipoprotein B (apo B) in the blood plasma is also significantly reduced. Since each LDL particle contains one apo B molecule, and in other lipoproteins small amounts of apo B are found, it can be assumed that simvastatin not only causes loss of Xs in LDL particles,but also reduces the concentration of circulating LDL particles in the blood plasma.

Besides, simvastatin increases the concentration of HDL cholesterol and reduces the concentration of TG in the blood plasma. As a result of these changes, the ratios of OXc / Xc HDL and HDL / HDL cholesterol are reduced.

In patients with coronary heart disease (CHD) and baseline OXC concentration of 212-309 mg / dl (5.5-8.0 mmol / L) simvastatin reduces the risk of total mortality, mortality from coronary artery disease, the incidence of nonfatal confirmed myocardial infarctions. Simvastatin also reduces the risk of the need for surgical interventions to restore coronary blood flow (aortocoronary bypass or percutaneous transluminal coronary angioplasty). In patients with diabetes, the risk of major coronary complications decreases. Furthermore, simvastatin significantly reduces the risk of fatal and non-fatal disorders of cerebral circulation (strokes and transient disorders of cerebral circulation).

The efficacy of simvastatin therapy in patients with or without hyperlipidemia, who are at a high risk of developing coronary artery disease due to concomitant diabetes, a history of anamnesis and other vascular diseases, has been proven effective. Simvastatin (including nonfatal myocardial infarction or death associated with coronary artery disease), the need for surgical interventions to restore coronary blood flow (including coronary artery bypass grafting and percutaneous transluminal angioplasty), at a dose of 40 mg per day, reduces overall mortality, the risk of death associated with coronary artery disease, the risk of major coronary events ), as well as peripheral blood flow and other types of non-coronary revascularization, the risk of stroke. The frequency of hospitalization for heart failure decreases. The risk of developing major coronary and vascular complications is reduced in patients with or without IHD, including patients with diabetes mellitus, peripheral vascular disease or cerebrovascular pathology. In patients with diabetes mellitus simvastatin reduces the risk of serious vascular complications, including the need for surgical interventions to restore peripheral blood flow, amputation of the lower extremities, and the occurrence of trophic ulcers.

Simvastatin (according to coronary angiography) slows the progression of coronary atherosclerosis and the appearance,as new areas of atherosclerosis, and new total occlusions, while patients receiving standard therapy, there was a steady progression of atherosclerotic lesions of the coronary arteries.

Pharmacokinetics:

Metabolism

Simvastatin is an inactive lactone, which rapidly hydrolyzes, transforming into the β-hydroxy acid of simvastatin (L-654.969), a potent inhibitor of HMG-CoA reductase. The main metabolites of simvastatin in blood plasma are simvastatin β-hydroxy acid (L-654.969) and its 6'-hydroxy, 6'-hydroxymethyl and 6'-exomethylene derivatives. Inhibition of HMG-CoA reductase is a measure of the quantitative evaluation of all pharmacokinetic studies of β-hydroxydeal metabolites (active inhibitors), as well as active and latent inhibitors (all inhibitors) formed as a result of hydrolysis. Both types of metabolites are determined in the blood plasma when administered simvastatin.

The hydrolysis of simvastatin mainly occurs during "primary passage" through the liver, so the concentration of unchanged simvastatin in human blood plasma is low (less than 5% of the dose taken). Maximum concentration (FROM_mOh) in the blood plasma of simvastatin metabolites is achieved through 1,3-2,4 hours after ingestion of a single dose. Plasma concentration of total radioactivity (¹⁴With a labeled simvastatin + ¹⁴C labeled metabolites of simvastatin) peaks at 4 hours and rapidly decreases to about 10% of the maximum value within 12 hours after ingestion of a single dose. Despite the fact that the range of recommended therapeutic doses of simvastatin ranges from 5 to 80 mg per day, the linear character of the area profile under the concentration-time curve (AUC) of active metabolites in the total blood flow is preserved with increasing dose to 120 mg.

Suction

About 85% an internal dose of simvastatin.

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

Distribution

After ingestion, higher concentrations of simvastatin are determined in the liver than in other tissues.

The concentration of the active metabolite of simvastatin L-654.969 in the systemic blood flow is less than 5% of the ingested dose, 95% of this amount is in the condition associated with blood plasma 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.

When taking 100 mg of simvastatin (5 capsules of 20 mg) ¹⁴With labeled simvastatin accumulates in the blood plasma, urine and feces. About 60% of the dose of labeled simvastatin was detected in the stool and about 13% in the urine. Labeled simvastatin in the fecal masses was represented by the products of the metabolism of simvastatin released with bile, and unabsorbed labeled simvastatin. Less than 0.5% of the dose of labeled simvastatin was detected in the urine as active metabolites of simvastatin. In blood plasma, 14% AUC was caused by active inhibitors and 28% by all inhibitors of HMG-CoA reductase. The latter indicates that, in the main, the products of simvastatin metabolism are inactive or weak inhibitors of HMG-CoA reductase.

There is no significant deviation of linearity AUC in the general blood stream with increasing dose in the dose range from 5 to 120 mg. Pharmacokinetic parameters with single and multiple intake of simvastatin showed that simvastatin Do not accumulate in tissues with repeated ingestion.

In patients with severe renal failure (creatinine clearance [QC] less than 30 ml / min), total concentration of HMG-CoA reductase inhibitor in blood plasma after oral administration of a single dose of the inhibitor of HMG-CoA reductase inhibitor (statin) at approximately 2 times higher than in healthy volunteers.

The use of simvastatin in a maximum dose of 80 mg in healthy volunteers had no effect on the metabolism of midazolam and erythromycin, which are substrates for isoenzyme CYP3A4. This means that simvastatin is not an inhibitor of isoenzyme CYP3A4 and suggests that the intake of simvastatin does not affect the concentration in the blood plasma of drugs metabolized by isoenzyme CYP3A4.

It is known that ciclosporin increases the AUC inhibitors of HMG-CoA reductase, although the mechanism of drug interaction has not been fully studied. Increase AUC simvastatin is presumably associated, in particular, with inhibition of the isoenzyme CYP3A4 and / or transport protein OATP1B1 (see the section "Contraindications").

With simultaneous use with diltiazem there is an increase AUC β-hydroxy acid simvastatin 2.7 times, presumably due to inhibition of the isoenzyme CYP3A4 (see section "Special instructions"). With simultaneous application with amlodipine there is an increase AUC β-hydroxy acids of simvastatin by a factor of 1.6 (see section "Special instructions").

When a single dose of 2 g of delayed-release nicotinic acid and simvastatin 20 mg are used concomitantly, a slight increase AUC simvastatin and β-hydroxy acids of simvastatin and C_max β-hydroxy acid simvastatin in blood plasma (see section "Special instructions").

Specific pathways of the metabolism of fusidic acid in the liver are unknown, but it can be assumed that there is an interaction between fusidic acid and statins that are metabolized by an isoenzyme CYP3A4 (see section "Special instructions").

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

Indications:

Patients with ischemic heart disease (CHD) or high-risk coronary artery disease

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 Vasylip preparation^® shown for:

- reducing the risk of overall mortality due to a reduction in mortality due to coronary artery disease;

- reducing the risk of serious vascular and coronary events:

non-fatal myocardial infarction,
coronary death,
stroke,
revascularization procedures;

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

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

- reducing the risk of hospitalization due to attacks of angina pectoris.

Hyperlipidemia

- As a supplement to the diet, when the use of only diet and other non-pharmacological treatments in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson type II hyperlipidemia), or mixed hypercholesterolemia (Fredrickson's IIb type hyperlipidemia) is not sufficient for:

decrease in increased concentrations of OXc, Xc LDL, TG, apolipoprotein B (apo B) in blood plasma;
increased concentration of HDL cholesterol in the blood plasma;
decrease in the ratio of LDL cholesterol / HDL cholesterol and OXC / XC HDL in blood plasma.

Hypertriglyceridemia (type IV hyperlipidemia according to Fredrickson classification).

- Supplement to the diet and other methods of treatment of patients with homozygous familial hypercholesterolemia to reduce elevated concentrations of OXc, Xc and LDL.

- Primary dysbetalapoproteinemia (type III hyperlipidemia according to Fredrickson classification).

Use in children and adolescents with heterozygous familial hypercholesterolemia

- The use of the drug at the same time as the diet is indicated to reduce the increased concentration of OXc, Xc, LDL, TG,apo B in the blood plasma in young men 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, to other drugs of the statin series in the anamnesis;

- 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;

- use in women who plan pregnancy and women with preserved reproductive potential who do not use reliable methods of contraception;

- age to 18 years (except for children and adolescents 10-17 years with heterozygous familial hypercholesterolemia) (see section "Indications for use");

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome;

- simultaneous use with potent inhibitors of isoenzyme CYP3A4 (itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, bocetrevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and preparations containing the co-bicarbonate) (see "Interactions with other drugs");

- simultaneous use with gemfibrozil, cyclosporin or danazol (see section "Interaction with other drugs").

Carefully:

Patients who underwent rhabdomyolysis during treatment with Vasilip®, with a complicated history (renal dysfunction, usually due to diabetes mellitus) require more careful observation, and simvastatin therapy should be temporarily discontinued in these patients a few days before major surgical interventions are performed, and also in the postoperative period; in patients with persistent increased activity of serum transaminases (exceeding the upper limit of the norm [VGN] 3 times), the drug should be discontinued; In severe renal failure (CK <30 ml / min), it should be carefully weighed the feasibility of prescribing the drug at doses> 10 mg per day and, if necessary, should be administered with caution; with alcohol abuse before treatment; when used simultaneously with fibrates other than gemfibrozil (see the section "Contraindications") or fenofibrate, amiodarone, blockers of "slow" calcium channels (verapamil, diltiazem or amlodipine), lomitapid, moderate isoenzyme inhibitors CYP3A4 (e.g., dronedaron, ranolazine), fusidic acid, nicotinic acid (in lipid-lowering doses not less than 1 g / day), inhibitors of the transport protein OATP1B1, colchicine (see section "Interaction with other drugs") increases the risk of myopathy and rhabdomyolysis, elderly patients years) (see section "Special instructions").

Pregnancy and lactation:

The drug is Basilip^® contraindicated in pregnancy. Since safety for pregnant women is not proven and there is no evidence that treatment with the drug during pregnancy brings obvious benefits, taking the drug should be stopped immediately after the onset of pregnancy. Vazilip® should be given to women of childbearing age only when the probability of pregnancy is very low. The use of the drug Vazilip® during pregnancy can reduce the concentration of mevalonate (a precursor in the biosynthesis of cholesterol) in the fetus. Atherosclerosis is a chronic disease and usually stopping the use of lipid-lowering drugs during pregnancy has a slight effect on the long-term risks associated with primary hypercholesterolemia.In this regard, the drug Vazilip® should not be used in women who are pregnant, trying to conceive or suspect that they are pregnant. Treatment with the drug Vazilip® should be suspended for the duration of pregnancy or until pregnancy is diagnosed, and the woman herself is warned about possible danger to the fetus (see section "Contraindications").

Data on the isolation of simvastatin and its metabolites with breast milk are absent. If it is necessary to administer Vasilip® to a woman during breastfeeding, it should be borne in mind that many drugs are excreted in breast milk and there is a threat of serious adverse reactions. As a result, with breastfeeding, taking Vazilip® should be stopped.

Dosing and Administration:

Before the beginning of treatment with Vasilip®, the patient should be prescribed a standard hypocholesterol diet, which should be observed throughout the course of treatment.

The recommended dose of Vasilip® is from 5 to 80 mg per day. The drug should be taken 1 time per day in the evening. If necessary, the dose of the drug is increased at intervals of at least 4 weeks maximum to 80 mg once a day in the evening.A dose of 80 mg per day is recommended to be administered only to patients with a high risk of cardiovascular complications if treatment with the drug at lower doses does not achieve the target lipid levels, and the perceived benefit of therapy exceeds the possible risk (see section "Special instructions").

Patients with IHD or a high risk of CHD

Standard initial dose of Vasilip^®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 once a day in the evening. Drug therapy should be prescribed simultaneously with diet and exercise therapy.

Patients with hyperlipidemia, not having the above risk factors

The standard initial dose of Vasilip® is 20 mg once a day in the evening. For patients who need a significant (more than 45%) reduction in the concentration of Xc LINI, the initial dose may be 40 mg 1 time per day in the evening. Patients with mild or moderate hypercholesterolemia with Vasilip® can be given an initial dose of 10 mg once daily.If necessary, the selection of doses should be carried out in accordance with the above scheme (see section "Method of administration and dose").

Patients with homozygous familial hypercholesterolemia

The drug Vazilip® is recommended in a dose of 40 mg per day, taken once 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 (see section "Special instructions"). In such patients, the preparation of Vasilip® 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 Lomipidum concomitantly with Vasilip®, the daily dose of Vasilip® should not exceed 40 mg (see "Interactions with Other Drugs").

Concomitant therapy

The drug Vazilip® can be administered both in monotherapy and in combination with bile acid sequestrants.

In patients taking the preparation of Vasilip® concomitantly with fibrates other than gemfibrozil (see the section "Contraindications") or fenofibrate, the maximum recommended dose of Vasilip^® is 10 mg per day.

For patients receiving amiodarone, verapamil, diltiazem or amlodipine concurrent with the preparation of Vasilip®, the daily dose of Vasilip® should not exceed 20 mg (see section "Interaction with other drugs").

In patients taking the preparation of Vasilip® concomitantly with dronedarone, the daily dose of Vasilip® should not exceed 10 mg.

Impaired renal function

Since the preparation of Vasilip® is excreted by the kidneys in small amounts, there is no need to change the dose in patients with moderate renal impairment. In patients with severe renal failure (CK <30 ml / min), the expediency of prescribing the drug in doses exceeding 10 mg per day should be carefully weighed. If these dosages are considered necessary, they should be administered with caution (see "With caution").

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 Vasilip® is 40 mg per day.The choice of doses is carried out individually in accordance with the goals of therapy.

Side effects:

Classification of the incidence of side effects recommended by the World Health Organization (WHO):

Often	≥ 1/10
often	from ≥ 1/100 to <1/10
infrequently	from ≥ 1/1000 to <1/100
rarely	from ≥1 / 10000 to <1/1000
rarely	< 1/10000
frequency unknown	can not be estimated from the available data.

Violations from the blood and lymphatic system:

rarely: anemia.

Immune system disorders:

seldom developed a hypersensitivity syndrome, which manifested itself as angioedema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, blood flushes to the skin of the face, shortness of breath and general weakness.

Very rare reports were received on the development of immuno-mediated necrotizing myopathy (autoimmune myopathy) caused by the administration of some statins. Immuno-mediated necrotizing 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 in therapy with immunosuppressive drugs (see section "Special instructions").

Disorders from the psyche:

frequency is unknown: depression.

Impaired nervous system:

rarely: dizziness, peripheral neuropathy, paresthesia;

very rarely: insomnia;

frequency is unknown: sleep disturbances, including "nightmarish" dreams.

Disturbances from the respiratory system, chest and mediastinal organs:

frequency unknown: interstitial lung disease (especially with prolonged use).

Disorders from the digestive system:

rarely: indigestion, nausea, vomiting, diarrhea, pancreatitis.

Disorders from the liver and bile ducts:

rarely: hepatitis / jaundice;

very rarely: fatal and non-fatal hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues:

rarely: skin rash, itchy skin, alopecia.

Disturbances from the musculoskeletal and connective tissue:

rarely: myalgia, muscle cramps, rhabdomyolysis;

frequency unknown: tendinopagia, possibly with a rupture of tendons.

Violations of the genitals and breast:

frequency unknown: sexual dysfunction, gynecomastia.

Laboratory and instrumental data:

there are rare reports of the development of a pronounced and persistent increase in the activity of "hepatic" transaminases in the serum. Also, an increase in the activity of alkaline phosphatase and gamma-glutamyltranspeptidase in serum was 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 CK in the serum (see section "Special instructions").

An increase in the concentration of glycosylated hemoglobin (HbA1c) and the concentration of glucose in the blood serum on an empty stomach when taking statins, including simvastatin.

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.

Children and adolescents (10-17 years)

According to a study of 1 year duration in children and adolescents (boys in the stage of Tenner II and above and girls at least one year after the first menstruation) at the age of 10-17 years with heterozygous familial hypercholesterolemia (n= 175), the safety profile and tolerability of treatment in the group receiving simvastatin, was similar to the profile of the placebo group. Long-term effects on physical, intellectual and sexual development are unknown. Currently, there is insufficient safety data.

Overdose:

Several cases of overdose were reported, the maximum dose taken was 3.6 g. None of the patients had an overdose effect.

For the treatment of overdose, general measures are taken, including maintenance and symptomatic therapy.

Interaction:

Contraindicated combinations of medicines

Contraindicated concomitant therapy with the following medicines.

Powerful inhibitors of isoenzyme CYP3A4

Simvastatin is metabolized by isoenzyme CYP3A4, but does not inhibit the activity of this isoenzyme. This suggests that the administration of simvastatin does not affect the concentration in the blood plasma of drugs metabolized by isoenzyme CYP3A4. Powerful inhibitors of isoenzyme CYP3A4 increase the risk of myopathy by decreasing the rate of excretion of simvastatin. Simultaneous use of potent inhibitors of isoenzyme CYP3A4 (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing the co-bicystate) and simvastatin is contraindicated (see "Contraindications" and "Special instructions") .

Gemfibrozil, cyclosporin or danazol (see the sections "Contraindications" and "Special instructions")

Interaction with other drugs

Other fibrates

The risk of myopathy increases with simultaneous use of simvastatin with gemfibrozil (see the section "Contraindications") and other fibrates (except fenofibrate). These hypolipidemic agents can cause myopathy in monotherapy.With the simultaneous use of simvastatin with fenofibrate, the risk of developing myopathy did not exceed the amount of risk for monotherapy with each drug (see the sections "Contraindications" and "Special instructions").

Amiodarone

The risk of myopathy / rhabdomyolysis increases with simultaneous use of amiodarone with simvastatin. In the study, the incidence of myopathy in patients taking both simvastatin in a dose of 80 mg and amiodarone, was 6% (see sections "Method of administration and dose" and "Special instructions").

Blocks of "slow" calcium channels

The risk of developing myopathy / rhabdomyolysis increases with the simultaneous use of verapamil, diltiazem or amlodipine with simvastatin (see the sections "Dosage and administration" and "Special instructions").

Lomitapid

The risk of myopathy / rhabdomyolysis may increase with concomitant use of lomipid with simvastatin (see the section on "Dosage and administration" and "Special instructions").

Moderate inhibitors of isoenzyme CYP3A4 (for examplep, dronedaron)

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 (see section "Special instructions"). With the simultaneous use of the drug Vazilip® and moderate isozyme inhibitors CYP3A4, you may need to reduce the dose of Vasilip®.

Ranolazine (moderate isoenzyme inhibitor CYP3A4)

With the simultaneous use of ranolazine and simvastatin, the risk of myopathy may increase (see section "Special instructions"). With the simultaneous use of the drug Vazilip® and ranolazine, you may need to reduce the dose of Vasylip^®.

Inhibitors of transport protein OATP1B1

The hydroxy acid of simvastatin is the substrate of the transport protein OATP1B1. Simultaneous application of inhibitors of transport protein OATP1B1 and simvastatin may lead to an increase in the plasma concentration of the hydroxy acid of simvastatin and an increased risk of myopathy (see the sections "Contraindications" and "Special instructions").

Fusidic acid

With the simultaneous use of fusidic acid and simvastatin, the risk of myopathy may increase (see section "Special instructions").

A nicotinic acid (not less than 1 g / day)

With the simultaneous use of simvastatin and nicotinic acid in lipid-lowering doses (not less than 1 g / day), cases of development of myopathy / rhabdomyolysis have been described (see section "Special instructions").

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 effect of coumarin anticoagulants: prothrombin time, defined as the international normalized ratio (INR), increases from an initial level of 1.7 to 1.8 in healthy volunteers and from 2.6 to 3.4 in patients with hypercholesterolemia. In patients taking coumarin anticoagulants, prothrombin time should be determined before the start of simvastatin therapy, and also often enough during the initial treatment period to exclude significant changes in this indicator. Once a stable indicator of INR is achieved, its further definition should be carried out at intervals recommended for the control of patients receiving anticoagulant therapy.When changing the dose of simvastatin or after its withdrawal, regular measurement of prothrombin time is also recommended. In patients who did not take anticoagulants, therapy with simvastatin was not associated with the occurrence of bleeding or changes in prothrombin time.

Other types of interaction

Grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4 and can increase the concentration in the blood plasma of drugs metabolized by isoenzyme CYP3A4. When the juice is consumed in an ordinary amount (1 glass of 250 ml per day), this effect is minimal (an increase in the activity of inhibitors of HMG-CoA reductase by 13% is observed in assessing the value AUC) and has no clinical significance. However, the consumption of grapefruit juice in large volumes significantly increases the activity of HMG-CoA reductase inhibitors in blood plasma. In this regard, you must avoid the use of grapefruit juice with simvastatin therapy (see section "Special instructions").

Special instructions:

Myopathy / Rhabdomyolysis

Simvastatin, like other statins, can cause myopathy, which manifests itself in the form of muscle pain, tenderness, or weakness, and is accompanied by an increase in the activity of CKK (more than 10 times higher than UGN) in blood plasma.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 patients with a history of myocardial infarction, when taking simvastatin at a dose of 80 mg per day, the incidence of myopathy is approximately 1.0%, and in patients taking simvastatin in a dose of 20 mg per day - 0.02%. Approximately half of cases of myopathy development are registered during the first year of treatment. The incidence of myopathy during each next year of treatment is approximately 0.1%.

In patients receiving simvastatin in 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. Consequently, the drug Basilip^® at a dose of 80 mg per day should be prescribed only to patients with a high risk of cardiovascular complications in whom therapy with a drug in lower doses did not achieve the desired therapeutic effect, and the perceived benefit of treatment exceeds the possible risk. If a patient taking a 80 mg dose of Vasilip® is required to be treated with another drug that can interact with simvastatin, then lower the dose of Vasilip® or prescribe another statin that has less potential for possible drug interaction (see "Contraindications", " "Method of administration and dose").

All patients who start therapy with Vasilip^®, as well as patients who need to increase the dose, should be warned about the possibility of myopathy and are informed of the need to immediately seek medical attention in the event of any unexplained muscle pain, tenderness in the muscles or muscle weakness. Therapy with Vasilip® should be stopped immediately if myopathy is suspected or diagnosed.

The presence of the above symptoms and / or more than 10-fold in comparison with VGN increase in the activity of CK in the blood plasma indicate the presence of myopathy. In most cases, after an immediate discontinuation of simvastatin, the symptoms of myopathy are resolved, and the activity of CK in the blood plasma is reduced. In patients starting to take the drug Vazilip® or switching to higher doses of the drug, it is advisable to periodically determine the activity of CK in the blood plasma, but there is no guarantee that such monitoring can prevent the development of myopathy.

Many patients who underwent rhabdomyolysis during simvastatin therapy had a complicated history, including impaired renal function, usually as a result of diabetes mellitus. Such patients require more careful observation.

Therapy with Vasilip^® should be temporarily discontinued a few days before the implementation of large surgical interventions, as well as in the postoperative period.

In patients with a high risk of developing cardiovascular disease with the use of simvastatin 40 mg once a day, the incidence of myopathy was slightly higher among patients of Chinese nationality.

Care should be taken when prescribing simvastatin to patients of the Mongoloid race, in particular to prescribe it in low doses.

The risk of developing myopathy / rhabdomyolysis increases with the simultaneous use of simvastatin with the following drugs.

Contraindicated combinations of medicines

- Powerful inhibitors of isoenzyme CYP3A4

Concomitant therapy with potent inhibitors of isoenzyme CYP3A4 at therapeutic doses (eg, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevirov, telaprevir, nefazodone or preparations containing a co-bicarbonate) is contraindicated. If we avoid short-term use of potent inhibitors of isoenzyme CYP3A4 can not, therapy with the drug Vazilip® should be interrupted for the period of their use (see the sections "Contraindications", "Interactions with other drugs").

- Gemfibrozil, ciclosporin or danazol

The simultaneous use of these drugs with the drug Basilip^®it is contraindicated (see the sections "Contraindications", "Interactions with other medicinal products").

Other medicines

- Other fibrates

In patients taking fibrates other than gemfibrozil (see the section "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 Simvastatin should be treated with caution, 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 the concentration of LDL cholesterol in the blood plasma, but allows a more pronounced decrease in TG concentration and an increase in HDL cholesterol concentration in the blood plasma. Combination therapy with fibrates with simvastatin is not accompanied by the development of myopathy (see section "Interactions with other drugs").

- Amiodarone

In patients receiving amiodarone, the dose of simvastatin should not exceed 20 mg per day (see section "Interactions with other drugs").

- Blocks of "slow" calcium channels

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

- Lomitapid

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

- Moderate inhibitors of isoenzyme CYP3A4 (e.g., dronedaron)

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 myopathy. With the simultaneous use of simvastatin with moderate isoenzyme inhibitors CYP3A4 may require dose adjustment for simvastatin.

- Fusidic acid

The simultaneous use of fusidic acid and simvastatin may increase the risk of myopathy (see section "Interactions with other drugs"). Simultaneous use of simvastatin and fusidic acid is not recommended. If the use of systemic preparations of fusidic acid is considered necessary, the drug Vazilip^® should be canceled for the period of this therapy. In exceptional cases where long-term therapy with fusidic acid systemic drugs is necessary, for example for the treatment of severe infections, the simultaneous use of the drug Vazilip® and fusidic acid should be considered individually in each case, and combined therapy should be carefully monitored.

- Nicotinic acidsa (at lipid-lowering doses not less than 1 g / day)

With the simultaneous use of Vasilip® and nicotinic acid in lipid-lowering doses (at least 1 g / day), cases of myopathy / rhabdomyolysis have been described. In patients with a high risk of cardiovascular disease and a well-controlled concentration of Xc LH1NP using simvastatin 40 mg / day with or without ezetimibe 10 mg / day, there is no additional positive effect on the outcome of cardiovascular disease with the simultaneous use of nicotinic acid in lipid-lowering doses (not less than 1 g / day). Thus, the advantage of simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g / day) should be carefully weighed against the potential risks of combination therapy.The incidence of myopathy in Chinese patients treated with simvastatin 40 mg or simvastatin / 40 mg / 10 mg ezetimibe is slightly higher with simultaneous application with sustained-release laropiprant / nicotinic acid at a dose of 40 mg / 2 g.

It is not recommended simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g / day) in patients of the Mongoloid race, since the incidence of myopathy is higher in patients of Chinese nationality than in patients of other nationalities (see "Interactions with Other Drugs" ).

Effects on the liver

In some adult patients taking simvastatin, there is a steady increase in the activity of "hepatic" enzymes (more than 3 times higher than UGN) in blood plasma. With the termination or interruption of simvastatin therapy, the activity of "hepatic" transaminases in blood plasma usually gradually returns to the baseline level. Increased activity of "liver" transaminases in blood plasma was not associated with jaundice or other clinical symptoms. No hypersensitivity reactions were detected.Some of the above patients may have abnormalities in the results of functional hepatic samples before initiating treatment with Vasilip® 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 Vasilip^® up to 80 mg per day, additional liver function tests should be performed before proceeding to take this dosage, then 3 months after the start of its use and then repeat regularly (for example, once every six months) during the first year of treatment.

Particular attention should be given to patients with increased activity of "liver" transaminases in blood plasma. These patients need to repeat the liver function tests in the near future and subsequently conduct regularly until the normalization of the activity of "liver" transaminases in the blood plasma. In those cases, when the activity of "hepatic" transaminases in the blood plasma increases, especially when the excess of IGN is 3 times, the drug should be canceled.The cause of increased activity of alanine aminotransferase (ALT) in the blood plasma can be muscle damage, so the growth of ALT and CK activity in the blood plasma may indicate the development of myopathy (see section "Special instructions").

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 with clinical symptoms and / or hyperbilirubinemia or jaundice occurs in the treatment of simvastatin, immediate therapy should be discontinued. If another cause of the development of this pathology has not been identified, reassignment of simvastatin is contraindicated.

In patients who abuse alcohol and / or patients with impaired liver function, the drug should be used with extreme caution.

Active liver disease or unexplained increase in the activity of "liver" transaminases in blood plasma are contraindications to the appointment of the drug Vazilip®.

During the treatment with simvastatin, as in the treatment with other lipid-lowering medications, a moderate increase (exceeding the VGN by less than 3 times) was observed in the increase in the activity of "liver" transaminases in the blood plasma.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 studies do not contain information on the adverse effects of simvastatin on the lens of the human eye.

Use in elderly patients

In patients over the age of 65 years, the efficacy of the drug Vazilip®, estimated by the level of decrease in the concentration of OXC and LDL-C in plasma, 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 Vasylip^® at a dose of 80 mg per day in patients older than 65 years, there was an increased risk of myopathy compared with patients younger than 65 years.

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

The drug Vazilip® does not have or has little effect on the ability to drive vehicles and work with machinery.Nevertheless, when driving vehicles or operating machinery, it should be taken into account that there have been reports of rare cases of dizziness.

Form release / dosage:

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

Packaging:

7 tablets per blister (contour mesh packaging) made from a combined material of aluminum foil - PVC / PE / PVDC (Al/PVC/PE/PVDC) or PVC / PE / PVDC / PE / PVC (Al/PVC/PE/PVDC/PE/PVC).

For 2 or 4 blisters (contour mesh packages), together with the instructions for use, are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N011803 / 01

Date of registration:17.06.2009 / 11.01.2016

Expiration Date:Unlimited

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

VECTOR-MEDICA, CJSC Russia

KRKA-RUS, LLC Russia

Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Information update date: & nbsp04.02.2017

Illustrated instructions

Instructions

Vazilip® (Vasilip®)