Expiration date: 01/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet cobtains:

simvastatin 10, 20 or 40 mg

excipients: lactose monohydrate starch pregelatinization butylhydroxyanisole citric acid anhydrous ascorbic acid corn starch MCC magnesium stearate 

shell film: talc hypromellose propylene glycol titanium dioxide 

in e blisters 7 PC. in the stack cartons of 2 or 4 blister.

Description pharmaceutical form:

Tablets 10 and 20 mg: round, slightly biconvex, film-coated white or nearly white, with beveled.

Pills 40 mg: round, slightly biconvex, film-coated, white or almost white, bevelled and scored on one side.

Pharmacokinetics:

Simvastatin lactones presented in an inactive form, which is relatively well absorbed from the gastrointestinal tract (61-85%). Bioavailability less than 5%. Once inside C max in plasma achieved through 1-2 h and is reduced by 90% through 12 h. Simultaneous eating does not affect the absorbability of the drug. Chronic administration of drug accumulation in the body occurs. Linking blood plasma proteins — 98%.

Simvastatin is a substrate of CYP3A4. Metabolized in the liver, has the effect of "first passage" through the liver (mainly hydrolyses in its active form, which is beta hydroxy acid). T1/2 active metabolites is 1.9 h.

Mainly excreted by the intestine (60%) as metabolites. About 13% is excreted by the kidneys in an inactive form.

Description pharmacological action:

The active substance of the drug Vasilip is simvastatin, the main effect of which is the reduction of total cholesterol and LDL cholesterol in plasma. It is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-COA) reductase — the enzyme, catalysing the transformation g-Koa in mevalonova acid (the early stage of cholesterol synthesis). Simvastatin reduces the concentration of total cholesterol, LDL cholesterol and triglycerides. The cholesterol content of very low density lipoproteins (VLDL) also decreases, whereas the content of HDL cholesterol is moderately increased. Reduces total cholesterol and LDL in the heterozygous cases, family and non-family forms of hypercholesterolemia, with mixed hyperlipidemia, when high cholesterol is a risk factor. The drug reduces total cholesterol and LDL cholesterol in patients with CHD, reducing the risk of myocardial infarction and lethal outcome for these patients.

Simvastatin significantly reduces the content of apolipoprotein B, and moderately increases HDL cholesterol concentrations and reduce plasma concentrations of triglycerides (TG). As a result of these effects of simvastatin reduced the ratio of total cholesterol (OX) HDL-C (OH/HDL) and LDL-C to LPVN cholesterol (LDL/HDL).

Anti-atherosclerotic effect of simvastatin is a consequence of the impact of the drug on the walls of blood vessels and blood components. Simvastatin alters the metabolism of macrophages, inhibiting the activation of macrophages and destruction of atherosclerotic plaques. The drug inhibits the synthesis of isoprenoids, which are the growth factors in the proliferation of smooth muscle cells of the inner lining of blood vessels. Under the action of simvastatin improves endotelinzawisimogo vasodilation.

The therapeutic effect occurs after 2 weeks, the maximum effect is observed after 4-6 weeks of treatment.

Indications:

hypercholesterolemia:

• primary hypercholesterolemia or mixed dyslipidemia (in addition to diet and the ineffectiveness of other non-pharmacological interventions (physical activity and weight loss)
  
• homozygous hereditary hypercholesterolemia (in addition to a special diet and lipid-lowering therapies including apheresis LDL), or the ineffectiveness of these measures.
  

cardiovascular prevention:

• reduction of cardiovascular mortality and morbidity in patients with clinical manifestations of atherosclerotic cardiovascular disease or diabetes mellitus with normal or elevated levels of cholesterol and as additional measures to correction of other risk factors and cardioprotective therapy.
  

Contraindications:

• hypersensitivity to simvastatin and other components of the drug
  
• liver disease in active phase or persistent increase in liver transaminaz unclear etiology
  
• concomitant use of inhibitors of cytochrome P450 3A4 (CYP3A4) (e.g. Itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, and nefazodone telithromycin)
  
• pregnancy
  
• lactation
  
• the age of 18 years (the efficacy and safety of application not been studied).
  

With caution:

• alcohol abuse prior to therapy
  
• liver disease in anamnesis
  
• severe electrolyte imbalance
  
• expressed in endocrine and metabolic disorders
  
• hypotension
  
• severe acute infections (sepsis)
  
• myopathy
  
• uncontrolled epilepsy
  
• extensive surgical intervention
  
• trauma
  
• lactase deficiency
  
• galactosemia or malabsorption syndrome of glucose-galactose (because the drug contains lactose)
  
• concomitant use with gemfibrozil, cyclosporine, nicotinic acid (more 1 g/day), amiodarone, verapamil, diltiazem, fenofibrate grapefruit juice.
  

Application of pregnancy and breast-feeding:

The drug is contraindicated in pregnancy. No proven increase in the frequency of birth defects in children whose mothers took simvastatin or another inhibitor of HMG-COA reductase. When taken by pregnant woman of simvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Cancellation of lipid-lowering drugs during pregnancy has no significant effect on the results of short-term risk associated with primary hypercholesterolemia.

Simvastatin should not be used in pregnant women, women planning pregnancy or suspected pregnancy. If in the process of pregnancy, the drug should be withdrawn, and the woman warned of the possible danger to the fetus.

It is not known whether the drug is excreted in breast milk, therefore drug therapy Vasilip in the period of breast-feeding is contraindicated.

Side effects:

Classification of frequency of side effects (who): very often — &ge1/10 often — &ge1/100–

Of the gastrointestinal tract, liver: rarely — constipation, abdominal pain, flatulence, dyspepsia, nausea, vomiting, diarrhea, pancreatitis, hepatitis, jaundice, increase in liver transaminases, alkaline phosphatase, creatine phosphokinase (CPK).

CNS, peripheral nervous system and sensory organs: rarely — headache, paresthesia, dizziness, peripheral neuropathy, asthenia, insomnia, convulsions, blurred vision, impaired taste sensation.

From the side of musculoskeletal system: rare — myopathy, rhabdomyolysis, myalgia, muscle cramps.

Allergic and immunopathological reactions: detailed syndrome of hypersensitivity (angioedema, volchanochnopodobnogo syndrome, polymyalgia rheumatic, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, flushing to the face, shortness of breath and extreme weakness).

Dermatological reactions: rarely — skin rash, pruritus, alopecia.

Other: rarely — anemia, heartbeat, acute renal failure (due to rhabdomyolysis), low potency.

Drug interactions:

Pharmacodynamic

The simultaneous use of simvastatin with fibrates, nicotinic acid (more 1 g/day) increases the risk of myopathy, including rhabdomyolysis (while the use of fenofibratom — not proven increased risk of myopathy in comparison with the monotherapy with each drug separately). Concurrent use with gemfibrozil may lead to increased concentrations of simvastatin in the blood serum.

Pharmacokinetic

Inhibitors of cytochrome CYP3A4 (Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone) involved in the metabolic conversion of simvastatin in the liver, increase the risk of myopathy and rhabdomyolysis on therapy with simvastatin. The simultaneous use of these drugs is contraindicated. Caution — while the use of less strong CYP3A4 inhibitors: cyclosporine, verapamil and diltiazem. The daily dose of simvastatin when administered simultaneously with cyclosporine should not exceed 10 mg. The daily dose of simvastatin on the background of concomitant use of amiodarone or verapamil should not exceed 20 and 40 mg on the background of the simultaneous administration of diltiazem, unless the expected benefit clearly not superior to the potential risk of myopathy and rhabdomyolysis.

Simvastatin at a dose of 20-40 mg/day in volunteers and patients with hypercholesterolemia potentiates the effects of coumarin anticoagulants (e.g. warfarin), in particular the increase in PV, MHO. Therefore, in patients taking cumarin anticoagulants, PV and MHO must be defined prior to the start of therapy with simvastatin, in the initial period of treatment, when changing dose of simvastatin or elimination of the drug. Upon reaching a stable rate of PV and MHO, further control should be spacing, recommended for patients receiving treatment with anticoagulants. Therapy with simvastatin does not cause changes in PV and risk of bleeding in patients not taking anticoagulants.

Grapefruit juice inhibits the CYP3A4 activity. Simultaneous reception of large quantities of grapefruit juice (more 1 l a day) and simvastatin leads to a significant increase in the concentration in blood plasma simvastatinaii acid. Therefore, during therapy with simvastatin should avoid drinking grapefruit juice.

Method of application and dose:

Inside,one evening.

The recommended dose of simvastatin varies from 5 to 80 mg 1 time per day in the evening. Most often the initial dose Vasilip — 10 mg. Changes (selection) the dose should be held at intervals of not less than 4 weeks. The maximum daily dose — 80 mg. This dose is only recommended in patients with severe hypercholesterolemia, or high risk of cardiovascular complications. The duration of the drug is determined by the attending physician individually.

Hypercholesterolemia

The patient should follow standard gipoholesterinovu diet throughout the period of drug treatment Vasilip. The recommended starting dose is 10 mg for a more pronounced reduction in LDL cholesterol (more than 45%) treatment may be initiated with 20-40 mg/day (once in the evening).

In patients with homozygous hereditary hypercholesterolemia recommended daily dose of 40 mg in the evening or 80 mg 3 reception (20 mg morning, 20 mg day and 40 mg in the evening) these patients Vasilip recommended for use in combination with other lipid-lowering treatment (e.g. LDL apheresis).

Cardiovascular prevention

In patients with high risk of CHD, hyperlipidemia or without effective dose of the drug Vasilip — 20-40 mg per day. Therefore, the recommended initial dose in such patients — 20 mg per day. Changes (selection) the dose should be carried out at intervals of 4 weeks, the dose can be increased to 40 mg per day. If the content of LDL less than 75 mg/DL (1,94 mmol/l), total cholesterol — less than 140 mg/DL (3.6 mmol/l), the dose should be reduced.

Concomitant therapy

The drug Vasilip effective in monotherapy or in combination with bile acid resins (such as colestipol and colestyramine). Patients receiving treatment with cyclosporine, gemfibrozil, other fibrates or nicotinic acid (more 1 g/day), the recommended initial dose of 5 mg, the maximum daily dose — 10 mg. Further increase of the dose in such situations is not recommended. In patients concurrently receiving amiodarone or verapamil, daily doses of the drug Vasilip should not exceed 20 mg.

Elderly patients and patients with moderate renal failure changes dosage not required. In patients with severe renal insufficiency (Cl creatinine <30 10="" p="">

Overdose:

Symptoms: there is evidence of several cases of overdose of simvastatin. The maximum accepted dose was 3.6 g.

Treatment: in case of overdose symptomatic treatment should be General activities: monitoring and maintaining vital functions, preventing further absorption of the medication (gastric lavage, reception activated carbon or laxatives). It is recommended to monitor liver function and CPK. There is no specific antidote.

In the development of myo with rhabdomyolysis (rare but severe side effect) should immediately stop taking the drug, enter patient diuretic and sodium bicarbonate (in/in cefuroxim). Rhabdomyolysis can cause giperkaliemia, that can be resolved/with the introduction of calcium chloride and calcium gluconate, infusion of glucose with insulin, the use of potassium ion-exchangers or, in severe cases, using hemodialysis.

Special instructions:

In patients with reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephrotic syndrome) when cholesterol, you should first treat the underlying disease.

Patients with severe renal insufficiency treatment to control kidney function.

During the period of drug treatment Vasilip women of reproductive age should use reliable contraception.

Treatment with simvastatin, like other inhibitors of HMG-COA reductase may cause myopathy, sometimes leading to rhabdomyolysis with or without renal failure due to myoglobinuria. The risk of myopathy is increased with increasing doses of simvastatin and in patients with severe renal insufficiency.

When treatment with simvastatin may increase the serum CPK, that should be considered in the differential diagnosis of pain behind the breastbone and after intense exercise.

Before the start of drug therapy Vasilip or increase the dose patients should be informed about the risk of myopathy and need immediately consult a doctor in case of unexplained pain, tension or weakness in the muscles, particularly if accompanied by malaise or fever.

Baseline ck before starting therapy to determine in the following situations:

• elderly patients
  
• if the kidney damage
  
• in decompensated hypothyroidism
  
• when burdened with family history of hereditary muscle diseases
  
• if you have a history of toxic effects on muscle statins or fibrates
  
• the abuse of alcohol.
  

In these cases it is necessary to assess the potential risks and expected benefits, it is recommended clinical monitoring during therapy. If the baseline CPK is significantly elevated (more than 5 times the upper limit of normal), the measurement should be repeated after 5-7 days for confirmation of results. Upon confirmation of a significant initial increase of CPK level (more than 5 times the upper limit of normal) the drug is administered not recommended.

Before and during the course of treatment, the patient should be on gipoholesterinovu diet.

During drug treatment Vasilip the appearance of muscle pain, weakness or cramps, you must determine the level of CPK. Criterion for drug withdrawal is the increase in levels of creatine kinase in the serum of more than 5 times the upper limit of normal. If muscle symptoms are pronounced and cause discomfort, even if CPK level is 5 times lower upper limit of normal, it may be necessary to stop treatment. If you suspect a myopathy therapy should be stopped regardless of the cause of myopathy.

If the symptoms disappear and the contents of the CPK returned to normal levels, the re-appointment of the statin or alternative drug of the same class in the minimum clinically effective dose and under close medical supervision.

Therapy with the drug Vasilip necessary to temporarily stop a few days before major surgery.

Patients with severe renal insufficiency treatment to control kidney function.

Measures to reduce the risk of myopathy caused by drug interactions

The risk of myopathy and rhabdomyolysis is considerably increased by concomitant use of simvastatin and potent inhibitors of CYP3A4 (e.g., Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), gemfibrozil, or cyclosporine (see "Interactions"). The risk of myopathy and rhabdomyolysis is also increased when sharing fibrates and high dose Niacin (>1 g/day) or in concurrent therapy with amiodarone or verapamil with high doses of simvastatin (see section "Interactions"). Risk also increases slightly with concomitant administration of diltiazem and high-dose simvastatin (80 mg).

Consequently, the use of simvastatin concurrently with Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone is contraindicated (see "Contraindications"). If you cannot abandon therapy listed CYP3A4 inhibitors, should refrain from purpose of simvastatin. Simvastatin also need to be careful to combine with certain other less potent CYP3A4 inhibitors: cyclosporine, verapamil and diltiazem (see section "Interactions").

Avoid concurrent use of simvastatin and grapefruit juice.

In patients taking cyclosporine, gemfibrozil or high-dose Niacin (>1 g/day), daily dose of simvastatin should not exceed 10 mg.

Co-administration of simvastatin and gemfibrozil is only possible in cases when the expected benefit significantly exceeds the potential risk of this drug combination. The advantages of combined use of simvastatin 10 mg/day with other fibrates (except phenofibrate), nicotinic acid (>1 g/day) or cyclosporine should be carefully weighed given the potential risk of such combinations.

There is a risk of myopathy when assigning individually phenofibrate and simvastatin, so care should be taken while taking this combination.

When receiving simvastatin in doses exceeding 20 mg/day, should be avoided co-administration of amiodarone or verapamil, with the exception of cases when the expected benefit outweighs the potential risk of myopathy.

The effect on the liver

Treatment with simvastatin can cause a rise in liver enzymes in the blood serum. This increase is usually negligible and clinically insignificant. After drug withdrawal, the levels of transaminases usually fall slowly to the original level. However, before treatment and in the future it is necessary to carry out the study of the liver (monitor activity transaminaz liver every 6 weeks for the first 3 months, then every 8 weeks during the remainder of the first year and then 1 every six months). If necessary, increase the dose to 80 mg mandatory monitoring of liver function before increasing dose after 3 months after the increase and then periodically (e.g. 1 every 6 months) during the first year of treatment. The steady increase in activity ACT and/or ALT in serum in 3 times the upper limit of normal, therapy with simvastatin should be discontinued.

Prescribed with caution in alcohol abusers and/or with a history of liver disease.

Effects on ability to drive and other complex mechanical means

About the adverse effects of the drug Vasilip on the ability to drive and work with mechanisms not reported. However, be aware that with post-marketing use of simvastatin observed isolated cases of vertigo.