Expiration date: 06/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains active substance:

simvastatin 10 or 20 mg

excipients (tablets 10 mg): lactose monohydrate — 75,5 mg corn starch — of 10.18 mg starch pregelatinization — 1,25 mg carboximetilkrahmal sodium (type A) 7.5 mg of colloidal silicon dioxide, and 1.2 mg butylhydroxytoluene 0.02 mg citric acid monohydrate — 1.25 mg ascorbic acid — 2.5 mg MKC — 9,4 mg magnesium stearate — 1,2 mg 

excipients (tablets 20 mg): lactose monohydrate powder — 151 mg of corn starch — 20,36 mg starch pregelatinization — 2.5 mg carboximetilkrahmal sodium (type A) 15 mg silica colloidal anhydrous — 2,4 mg butylhydroxytoluene — 0.04 mg citric acid monohydrate — 2.5 mg ascorbic acid — 5 mg MKC — 18,8 mg of magnesium stearate and 2.4 mg 

shell film (tablets 10 mg): hypromellose — 1.2 mg talc — 0,52 mg titanium dioxide — 0,52 mg dye iron oxide yellow — 0.002 mg dye iron oxide red — 0,038 mg of macrogol 400 and 0.12 mg 

shell film (tablets 20 mg): hypromellose — 2.4 mg talc — 1,04 mg of titanium dioxide — 1,04 mg dye iron oxide yellow — 0,044 mg dye iron oxide red — 0,036 mg macrogol 400 — 0,24 mg 

blister of aluminum foil and PVC/PVDC for 10 or 14 pieces per pack carton 2 blisters to 14 PCs. or 3 to 10 PCs.

Description pharmaceutical form:

Tablets 10 mg: oval biconvex, film-coated light pink color with etched "BL" on one side and "10" on the other in cross section - from white to almost white with a yellowish sheen color.

Tablets 20 mg: oval biconvex, film-coated light pink with a faint yellowish tint, engraved "BL" on one side and "20" on the other in cross section - from white to almost white with a yellowish sheen color.

Pharmacokinetics:

Simvastatin lactones presented in an inactive form, which is relatively well absorbed (from 61 to 85%) from the gastrointestinal tract. Bioavailability less than 5%. After intake of therapeutic Cmax in plasma achieved through 1-2 h and is reduced by 90% through 12 h. Simultaneous eating does not affect the absorption of simvastatin. Chronic administration of cumulation of simvastatin in the body occurs.

Relationship with blood plasma proteins is 98%.

Simvastatin is a substrate of CYP3A4. Metabolized in the liver, has the effect of first passage through the liver (mainly gidrolizuyutza into its active form beta-hydrocyclone). The penetration of simvastatin across the BBB and gematoplatzentarnyi barrier has not been studied. Mainly excreted via the intestine (60%) as metabolites. About 13% is excreted by the kidneys in an inactive form. T1/2 active metabolites is 1.9 h.

Description pharmacological action:

The active ingredient of the drug Simla — simvastatin, the main effect of which is to decrease total cholesterol and LDL cholesterol in plasma. It is an inhibitor of HMG-COA reductase, the enzyme catalyzing the conversion of HMG-COA in mevalonova acid (the early stage of cholesterol synthesis). Simvastatin reduces the concentration of total cholesterol, LDL cholesterol and triglycerides. The concentration of cholesterol in VLDL is also reduced, while the HDL concentration moderately increased. Reduces the concentration of total cholesterol and LDL in the heterozygous cases, family and non-family forms of cholesterolemia, with mixed hyperlipidemia, when high cholesterol is a risk factor. Simvastatin reduces the concentration of total cholesterol and LDL cholesterol in patients with coronary artery disease, thereby reducing the risk of myocardial infarction and lethal outcome for these patients.

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

Anti-atherosclerotic effect of simvastatin is a consequence of the effects of simvastatin on the vascular wall and blood components. Simvastatin alters the metabolism of macrophages, inhibiting the activation of macrophages and destruction of atherosclerotic plaques. Simvastatin 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 influence of simvastatin improves endotelinzawisimogo vasodilation. The therapeutic effect develops in 2 weeks, the maximum effect is observed after 4-6 weeks of treatment.

Indications:

• hyperlipidemia (type IIA and IIb according to Frederickson) the poor diet low in cholesterol and other non-pharmacological interventions (physical activity and reducing body weight in patients with increased risk of coronary atherosclerosis)
  
• combined hypercholesterolemia and hypertriglyceridemia, hyperlipoproteinemia, not amenable to correction special diet and physical activity
  
• homozygous familial hypercholesterolemia (as an adjunct to lipid-lowering therapy)
  
• Coronary artery disease (secondary prevention) — a drug prescribed for patients to reduce overall mortality, reduce the risk of coronary mortality and prevention of myocardial infarction, reduce the risk of stroke and transient disorders of cerebral circulation, slowing the progression of coronary atherosclerosis.
  

Contraindications:

• hypersensitivity to simvastatin or other components of the drug and other drugs statinovogo series (inhibitors of HMG-COA reductase) in history
  
• lactase deficiency, lactose intolerance, syndrome of glucose-galactose malabsorption
  
• liver disease in active phase or persistent increase in liver transaminaz unclear etiology
  
• diseases of skeletal muscles (myopathy)
  
• concomitant use of inhibitors of the cytochrome P450 isoenzymes CYP3A4 (e.g. Itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, and nefazodone telithromycin), treatment with gemfibrozil, cyclosporine or danazol
  
• pregnancy and lactation
  
• the age of 18 years (the efficacy and safety of application not been studied).
  

Caution: patients with alcoholism patients after organ transplantation who have undergone the therapy immunodepressantami (due to the increased risk of rabdomioliza and kidney failure) that may lead to the development of severe deficiency of kidney, such as hypotension, acute infectious diseases heavy currents, expressed metabolic and endocrine disorders, violations vodno-elektrolitnogo balance, surgical interventions (including dental), or injury patients with low or high tone skeletal muscles unclear etiology of epilepsy, uncontrolled seizures concomitant use with fibrates (except gemfibrozil), nicotinic acid lipidnami doses (>1 g/day), amiodarone, verapamil, diltiazem, amlodipine, ranolazine grapefruit juice severe renal insufficiency (Cl creatinine <30 ml/min).

Application of pregnancy and breast-feeding:

The drug is contraindicated in pregnancy. No proven increase in the frequency of birth defects in children of women taking simvastatin or another inhibitor of HMG-COA reductase during pregnancy. When taken by pregnant woman drug Simla 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.

Simla should not be used during pregnancy, women planning pregnancy, or suspected pregnancy. If the treatment process pregnancy does occur, the drug should be withdrawn, and the woman should be warned about the potential hazard to the fetus.

Data on the excretion of simvastatin in breast milk are absent, but because a small number of other drugs of this class are excreted in human milk, women receiving the drug Simla, it is not recommended breast-feeding in connection with the possibility for serious adverse reactions in children.

Side effects:

Classification of frequency of side effects (according to who): very often (>1/10), often (>1/100, <1/10) uncommon (>1/1000, <1/100) rare (>1/10000, <1/1000) very rare (<1/10000), including individual messages.

From the digestive system: rarely — constipation, abdominal pain, flatulence, dyspepsia, nausea, vomiting, diarrhea, acute pancreatitis, hepatitis, cholestatic jaundice, increase in liver transaminases, alkaline phosphatase, creatine phosphokinase (CPK).

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

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

Allergic and immunopathological reactions: rare: syndrome of hypersensitivity (angioedema, Volcanology syndrome, polymyalgia rheumatic, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increase, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing to the face, shortness of breath and extreme weakness).

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

Other: rarely — anemia, palpitations, reduced potency, acute renal failure as a consequence of rhabdomyolysis.

Drug interactions:

Pharmacodynamic interaction

The simultaneous use of simvastatin with fibrates, nicotinic, acid lipidnami doses (>1 g/day) increases the risk of myopathy, including rhabdomyolysis (while the use of fenofibratom not proven to increase risk of myopathy in comparison with the monotherapy with each drug separately).

Pharmacokinetic interaction

Inhibitors of 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. With caution should appoint with less potent inhibitors of CYP3A4 verapamil and diltiazem. 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.

The maximum daily dose of simvastatin should not exceed 20 mg when it is combined with amlodipine.

In patients receiving fuseboy acid simultaneously with the drug, may increase the risk of myopathy, therefore it is necessary to closely monitor the condition of these patients.

Data on the possible interaction of simvastatin with colchicine no.

Simvastatin at a dose of 20-40 mg/day in volunteers and patients with hypercholesterolemia potentiates the effects of coumarin anticoagulants (e.g. warfarin), particularly 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 activity of CYP3A4. 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.

Once in the evening. The drug should not be linked with food intake. Before starting treatment with the drug Simla the patient should be assigned a standard gipoholesterinovu diet that must be adhered to throughout the course of treatment. The recommended dose for the treatment of hypercholesterolemia ranged from 5 to 80 mg. Most often, the initial dose of the drug Simla — 10 mg. Change (selection) the dose should be held at intervals of not less than 4 weeks.

The maximum daily dose — 80 mg. Dose of 80 mg should be administered only to those patients who have not achieved the desired result, the level of LDL at the dose of 40 mg in most patients the optimal effect is achieved when taking the drug at a dose of 20 mg/day. The maximum daily dose is only recommended in patients with severe hypercholesterolemia, or high risk of cardiovascular complications. The duration of the drug determined by the physician individually.

Hypercholesterolemia. The recommended initial dose for patients with hypercholesterolemia is 10 mg for a more pronounced decrease in the concentration of LDL cholesterol (more than 45%), treatment may be initiated with 20-40 mg/day (once in the evening).

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

Cardiovascular prevention. In the treatment of patients with CHD or high risk of CHD administered in an initial dose of 20 mg/day in the evening if necessary dose gradually increased every 4 weeks to 40 mg If the LDL less than 75 mg/DL (1,94 mmol/l) and the concentration of total cholesterol less than 140 mg/DL (3.6 mmol/l), the dose should be reduced.

Concomitant therapy. Drug Simla effective in monotherapy or in combination with bile acid resins (e.g. cholestyramine and colestipol). Patients receiving treatment with fibrates or nicotinic acid in Lipetskaya doses (>1 g/day), the recommended initial dose of 5 mg, the maximum daily dose of the drug is 10 mg. Shimla Further increase of the dose in such situations is not recommended. In patients concurrently receiving amiodarone or verapamil, daily doses of the drug Simla should not exceed 20 mg. For patients simultaneously taking diltiazem, amlodipine, daily dose of the drug Simla should not exceed 40 mg.

Elderly patients and patients with moderate renal failure changes dosage not required. In patients with severe renal insufficiency (Cl creatinine <30 ml/min) the recommended dose of the drug Simla should not exceed 10 mg/day. If necessary, increase dose careful monitoring of such patients.

Overdose:

Symptoms: any one of several known cases of overdose (maximum accepted dose 3.6 g) specific symptoms have been identified.

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). Recommended monitoring of liver function and activity of creatine kinase in serum. There is no specific antidote.

In the development of myo with rhabdomyolysis and acute renal failure (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 a 5% solution of dextrose (glucose) with short-acting insulin, the use of potassium ion-exchangers or, in severe cases, using hemodialysis.

Precautions:

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

Patients with severe renal insufficiency treatment to control kidney function.

During the period of drug treatment Simla 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 increases with increasing drug doses Simla and in patients with severe renal insufficiency. Among predisposing factors for myopathy isolated elderly age (>65 years), belonging to the female gender, uncontrolled hypothyroidism, and impaired renal function.

In the treatment of drug Simla is possible to increase the concentration of serum CPK, that should be considered in the differential diagnosis of pain behind the breastbone and after intense exercise.

Before starting drug therapy Simla 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.

The initial activity of ck before starting therapy to determine in the following cases:

• elderly patients
  
• kidney damage
  
• uncontrolled hypothyroidism
  
• positive family history of hereditary muscle diseases
  
• a history of toxic effects on muscle statins or fibrates
  
• patients with alcoholism.
  

It is necessary to evaluate possible risks and expected benefits and during therapy. Recommended clinical monitoring during therapy. If the initial activity of CPK significantly increased (more than 5 times the ULN), the measurement should be repeated after 5-7 days for confirmation of results. With a significant initial increase in the activity of CPK (>5 times the ULN), the drug is administered not recommended.

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

During treatment, the drug Simla the appearance of muscle pain, weakness or cramps, you must determine the concentration of CPK. The criterion for discontinuation of the drug is the increase of the concentration of CPK in the serum of more than 5 times the ULN. If muscle symptoms are pronounced and cause discomfort, even if CPK activity less than 5 times the ULN, you may need to stop treatment. If you suspect a myopathy therapy should be stopped regardless of the cause of myopathy.

If the symptoms disappear and CPK activity 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 drug Simla necessary to temporarily stop a few days before extensive 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 significantly increased with simultaneous use of the drug Simla 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 combined use of fibrates and high dose Niacin in Lipetskaya doses (>1 g/day) or in concurrent therapy with amiodarone or verapamil with high doses of the drug Simlo (see "Interactions"). Risk also increases slightly with concomitant administration of diltiazem and high doses of the drug Simla (80 mg). Consequently, the use of the drug Simla concurrently with Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone is contraindicated (see "Contraindications"). If you cannot abandon therapy listed inhibitors of CYP3A4, you should refrain from prescribing Simla. Simla also need to be careful to combine it with another, less potent inhibitors of CYP3A4 — verapamil and diltiazem (see "Interactions"). Should avoid the simultaneous reception of the drug Simla and grapefruit juice.

In patients receiving high-dose nicotinic acid in Lipetskaya doses (>1 g/day), the daily dose of the drug Simla should not exceed 10 mg. Benefits of combined use of the drug Simlo 10 mg/day with other fibrates (except phenofibrate), nicotinic acid lipidnami doses (>1 g/day) should be carefully weighed given the potential risk of such combinations.

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

When receiving Simla in doses exceeding 20 mg/day, should be avoided co-administration of amiodarone or verapamil.

The effect on the liver

Treatment with Simla can cause a rise in liver enzymes in the blood serum. This increase is usually negligible and clinically insignificant. After preparation, the activity of transaminases usually slowly decreases 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 for the remaining 9 months, then 1 every six months). If necessary, increase the dose to 80 mg mandatory monitoring of liver function before dose escalation 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 ULN, treatment with Simla should be discontinued.

Used with caution in patients with alcoholism and/or persons with a history of liver disease.

These modern long-term clinical studies do not contain information regarding adverse effects of simvastatin on the lens of the human eye.

No specific effects at the first appointment or cancel Simlo not registered.

No special actions of the doctor (paramedic) or patient when skipping one or more doses of the drug are required.

Effects on ability to drive or to perform work requiring high speed physical and mental reactions. During the period of treatment must be careful when driving vehicles and occupation of other potentially hazardous activities, require high concentration and psychomotor speed reactions.