Expiration date: 01/2025

The composition and form of issue:

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

simvastatin 10 mg

excipients: ascorbic acid — 2.5 mg butylhydroxyanisole — 0.02 mg citric acid (monohydrate) — 1.25 mg MKC — 5 mg pregelatinized corn starch 10 mg magnesium stearate — 1.7 mg lactose monohydrate — 100 mg 

shell: Opadry pink OY-B-34915 — 3 mg 

simvastatin 20 mg

excipients: ascorbic acid — 5 mg butylhydroxyanisole — 0.04 mg citric acid (monohydrate) 2.5 mg MKC — 10 mg pregelatinized corn starch 20 mg magnesium stearate and 3.4 mg lactose monohydrate 200 mg 

shell: Opadry pink OY-B-34917 — 6 mg 

simvastatin 40 mg

excipients: ascorbic acid — 10 mg butylhydroxyanisole — 0.08 mg citric acid (monohydrate) — 5 mg MKC — 20 mg pregelatinized corn starch 40 mg magnesium stearate and 6.8 mg lactose monohydrate — 400 mg 

shell: Opadry brown AMB 80W36564 — 12 mg

part of all film membranes composed of the following components: polyvinyl alcohol, titanium dioxide E171, talc, lecithin, xanthan gum E415, colorant iron oxide red E172, colouring agent iron oxide yellow E172 shell Opadry pink OY-B-34915 contains more in composition, the dye Indigo Carmine aluminum lacquer E132 shell Opadry pink OY-D34917 and Opadry brown AMB 80W36564 contain additionally in the composition of the colorant iron oxide black T172

in blister PVC/aluminum foil of 7 PCs. in cardboard pack 1 blister or in blister PVC/aluminum foil, 14 PCs. in cardboard pack 1, 2 or 6 blisters.

Description pharmaceutical form:

Dosage 10 mg: round biconvex tablets, film-coated light pink color.

Dosage 20 mg: round biconvex tablets, film-coated pink, scored on one side.

Dosage 40 mg: round biconvex tablets, film-coated dark pink, scored on one side.

Pharmacokinetics:

Suction. Simvastatin is absorbed in the digestive tract of 85% regardless of the meal. The maximum concentration in plasma is reached after about 1,3–2,4 h is reduced by 90% after 12 h

Distribution. Relationship with blood plasma proteins is about 95%.

Metabolism. In the primary passing through the liver is metabolized to a significant amount in the formation of beta-hydroxy acids, and 4 active and other inactive metabolites by the CYP3A4 isoenzyme of cytochrome P450. The rate of metabolism depends on blood flow in the portal vein of the liver. The bioavailability of simvastatin is less than 5%. The metabolism of simvastatin in the blood is extremely slow. For multiple doses, simvastatin does not accumulate in the body.

Excretion. T1/2 active metabolites is 1.9 h. Simvastatin is excreted primarily through the intestines (60%) as metabolites. About 10-15% of the administered the simvastatin is excreted by the kidneys unchanged.

Description pharmacological action:

Lipid-lowering means, obtained synthetically from a fermentation product of Aspergillus terreus, is an inactive lactone, the body is subjected to hydrolysis with the formation of gidrokshikislota derived. The active metabolite ingibiruet g-Koa-reductase, the enzyme catalyzing the initial reaction of formation of mevalonate from HMG-COA. Because the conversion of HMG-COA to mevalonate is an early step of cholesterol synthesis, the use of simvastatin does not cause a buildup of potentially toxic sterols. HMG-Koa easily metabolized to acetyl-COA, which is involved in many processes of synthesis in the body. Simvastatin causes a decrease in the content in blood plasma triglycerides (TG), LDL, VLDL and total cholesterol (in cases of heterozygous familial and non-family forms of hypercholesterolemia, with mixed hyperlipidemia).

Increases HDL and reduces the ratio of LDL/HDL and total cholesterol/HDL.

The therapeutic effect appears for the first time in 2 weeks after the start of regular use of simvastatin, the maximum effect is achieved after 4-6 weeks. Effect of simvastatin is kept throughout the treatment period, after discontinuation of simvastatin cholesterol gradually returning to the original value.

Indications:

Hypercholesterolemia:

• primary hypercholesterolemia (type IIA and IIb according to the classification of Frederickson) — as a Supplement to diet and other non-pharmacological treatments (e.g. increasing physical activity, correction of body weight), when these treatments aren't effective enough
  
• combined hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, intractable correction special diet and physical activity
  
• homozygous familial hypercholesterolemia as adjunct to diet and other lepidotrigla therapy (including LDL-apheresis), when these treatments aren't effective enough
  

Coronary heart disease:

• reducing the risk of total mortality by reducing mortality due to CHD
  
• reducing the risk of serious cardiovascular and coronary complications:
  
• non-fatal myocardial infarction,
  
• coronary death,
  
• stroke,
  
• surgery revascularization
  
• reducing the risk of the need for operations to restore coronary blood flow (such as coronary artery bypass grafting and percutaneous transluminal coronary angioplasty)
  
• reducing the risk of need surgery to restore peripheral blood flow and other nacionalnoj revascularization.
  

Contraindications:

• hypersensitivity to simvastatin or other components of the drug
  
• hypersensitivity reactions to other drugs statinovogo number (HMG-COA reductase inhibitors) in history
  
• diseases of skeletal muscles (myopathy)
  
• liver disease in active phase or an increase in liver transaminases in the serum unknown etiology
  
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption
  
• pregnancy
  
• lactation
  
• concomitant use of CYP3A4 inhibitors (ketoconazole, Itraconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone)
  
• severe acute infectious diseases
  
• marked reduction in blood pressure
  
• planned surgery
  
• trauma
  
• severe disorders of metabolism
  
• the age of 18 years (efficacy and safety not established).
  

Caution: if you have risk factors for myopathy/rhabdomyolysis (over 65 years of age, the use in women, uncontrolled hypothyroidism, muscle disease in the family history, impaired renal function, especially with Cl creatinine less than 30 ml/min, myopathy/rhabdomyolysis associated with the use of statins and fibrates, a history of alcoholism) while the use of cyclosporine, danazol, gemfibrozil, other fibrates (except phenofibrate) or lipidosnik doses (1 g/day) of Niacin, amiodarone, verapamil, diltiazem, grapefruit juice, fusidic acid patients after organ transplantation who have undergone the therapy immunodepressantami (due to the increased risk of rabdomioliza and kidney failure) when conditions 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 in epilepsy.

Application of pregnancy and breast-feeding:

Drug Simgal contraindicated during pregnancy. There are cases of congenital anomalies in children of mothers who took simvastatin during pregnancy. The development of such anomalies is associated with the inhibition of mevalonate synthesis in the fetus.

Women of childbearing age taking simvastatin should use reliable methods of contraception. If the treatment process pregnancy does occur or is suspected her drug Simgal should be immediately abolished. Cancellation of lipid-lowering drugs during pregnancy has no significant effect on the results of prolonged treatment of primary hypercholesterolemia.

Allocation data of simvastatin and its metabolites in breast milk are missing. In connection with the possibility of serious adverse effects in children whose mothers take the drug Simgal lactation, if necessary, such treatment breastfeeding should be discontinued.

Side effects:

The incidence of side effects is classified according to the who recommendation: very often — at least 10%, often — not less than 1% but less than 10% infrequently — no more than 0.1% but less than 1% rare — at least 0.01% but less than 0.1%, very rare — less than 0.01% (including isolated cases).

From the hematopoietic system and lymphatic system: rarely — anemia.

From the nervous system: very often — insomnia, rarely — headache, dizziness, paresthesia, peripheral neuropathy very rarely — impaired memory, sleep disturbance, nightmares, depression.

Gastrointestinal: rarely — pain in the abdomen, constipation, flatulence, nausea, diarrhea, vomiting, acute pancreatitis.

The liver and biliary tract: rarely — jaundice, hepatitis, rarely — liver failure.

The respiratory system of the chest, mediastinum: very rare — interstitial lung disease (with prolonged treatment).

From the skin: rarely — alopecia.

Allergic reactions: rarely — skin rash, pruritus, urticaria, hypersensitivity syndrome (angioedema, volchanochnopodobny syndrome, rheumatic polymyalgia, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate, arthritis, arthralgia, photosensitivity, fever, flushing skin, a rush of blood to the skin of the face, shortness of breath, feeling of malaise).

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

Laboratory parameters: rare — increase in liver transaminases (ALT, AST, GGT), alkaline phosphatase, creatine phosphokinase (CPK) in the blood serum.

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

Drug interactions:

Cytostatics, antifungal agents (ketoconazole, Itraconazole), fibrates, high doses of nicotinic acid, immunosuppressants, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone increases the risk of myopathy.

Cyclosporine or danazol: the risk of myopathy/rhabdomyolysis is increased with concomitant use of cyclosporine or danazol high doses of simvastatin.

Other lipid-lowering means to cause the development of myopathy the risk of myopathy is increased with simultaneous use of other lipid-lowering drugs that are not potent inhibitors of CYP3A4, but can cause myopathy in monotherapy. These include gemfibrozil and other fibrates (except phenofibrate), and nicotinic acid in lepidotrigla a dose of at least 1 g/day.

Amiodarone and verapamil: the risk of myopathy is increased with concomitant use of amiodarone or verapamil with high doses of simvastatin.

Amlodipine and diltiazem: the risk of myopathy is increased slightly in patients receiving amlodipine or diltiazem concurrently with simvastatin at a dose of 80 mg.

Simvastatin potentiates the effect of indirect anticoagulants (e.g. phenprocoumon, warfarin) and increases the risk of bleeding that requires the need for monitoring of indicators of blood coagulation before treatment, and quite often in the initial period of therapy. Once achieved a stable level indicators PV or MHO, further control should be spacing, recommended for patients receiving therapy with indirect anticoagulants. When changing the dose or stopping taking simvastatin you should also to monitor PV or MHO according to the above scheme.

Therapy with simvastatin does not cause changes in PV and risk of bleeding in patients not receiving indirect anticoagulants.

Increases the concentration of digoxin in plasma.

Cholestyramine and colestipol reduce the bioavailability (the use of simvastatin may through 4 h after administration of these drugs, showing an additive effect).

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the concentration in blood plasma of means, those with the participation of isoenzyme CYP3A4. Increased activity of inhibitors of HMG-COA reductase after drinking 250 ml of juice a day is minimal and has no clinical significance. However, the consumption of a large amount of juice (more 1 l a day) while taking simvastatin significantly increases the inhibitory activity against HMG-COA reductase in the blood plasma. In this regard, it is necessary to avoid consumption of grapefruit juice in large quantities.

Method of application and dose:

Inside, 1 time a day in the evening, squeezed enough water. The recommended dose varies from 5 to 80 mg/day. Change the dose if needed should be made at intervals of not less than 4 weeks. The dose of 80 mg/day is recommended for application only to patients who have not achieved the desired result of concentration of LDL at the dose of 40 mg, and patients receiving diltiazem simultaneously with the preparation of Simgal. Daily dose should not exceed 40 mg.

Hypercholesterolemia. Before treatment the patient undergoes therapy with the use of gipoholesterinovu diet. The diet should be continued during drug treatment of Simgal. The initial dose is 10-20 mg/day.

If necessary, reduce the concentration of LDL in the blood by 45% or more, the initial dose may be 20-40 mg/day.

If necessary, the dosage can be changed.

Patients with homozygous hereditary hypercholesterolemia the recommended dose is 40 mg/day once or 80 mg/day divided into 3 doses (20 mg morning, 20 mg day and 40 mg in the evening). Drug Simgal used in addition to diet and other lepidotrigla therapy, or when their ineffectiveness.

Coronary heart disease. Initial dose — 20 mg 1 time in the evening, if necessary, the dose gradually increased every 4 weeks to 40 mg.

If the content of LDL cholesterol less than 75 mg/DL (1,94 mmol/l), and total cholesterol — less than 140 mg/DL (3.6 mmol/l), the dose should be reduced. Therapy drug Simgal is applied simultaneously with diet therapy and increased physical activity. If necessary, the dose should be changed.

Combination therapy with other drugs

Combination with cyclosporine, danazol, gemfibrozil, other fibrates (except phenofibrate) or lipidosnik doses (1 g/day) of Niacin: the dose of Simgal should not exceed 10 mg/day.

Combination with amiodarone or verapamil: the dose of Simgal should not exceed 20 mg/day.

A combination with bile acid resins: drug Simgal should be taken 2 hours before or 4 hours after administration of bile acid resins.

Renal failure. Dosage adjustment in mild and moderate renal insufficiency is not required. In severe renal failure (Cl creatinine less than 30 ml/min) daily dose should not exceed 10 mg/day. It is necessary to carry out treatment under the supervision of a physician.

Old age. Dose adjustment is not required.

Overdose:

None of the few known cases of overdose (maximum accepted dose of 450 mg) specific symptoms have been identified.

Treatment: induction of vomiting, administration of activated charcoal, symptomatic therapy. Should monitor liver and kidney, the activity of CPK in serum. With the development of myopathy/rhabdomyolysis and acute renal failure (rare but severe side effect) should immediately stop taking the drug Simgal and enter patient diuretic and sodium bicarbonate (in/in cefuroxim). If necessary, shown hemodialysis.

Rhabdomyolysis can cause giperkaliemia, that can be resolved/with the introduction of calcium chloride or calcium gluconate, infusion of 5% dextrose solution with short-acting insulin, the use of potassium ion-exchangers or, in severe cases, hemodialysis.

Special instructions:

Drug Simgal, like other inhibitors of HMG-COA reductase, in rare cases, can cause myopathy, accompanied by muscle pain, muscle weakness, CPK activity in blood plasma in 10 times the ULN. Myopathy sometimes takes the form of rhabdomyolysis with acute renal failure due to myoglobinuria or without renal failure very rarely with a fatal outcome. The risk of myopathy/rhabdomyolysis is increased with increasing concentration of simvastatin in the blood. Increased activity of ck may indicate myopathy only if before the examination the patient had no physical activity and was excluded by other factors, which may cause increased activity of KFK. If the pre-treatment of Simgal CPK activity above the ULN in 5 times, it is necessary to repeat the test in 5-7 days to confirm the results.

To diagnose myopathy during treatment should regularly determining the activity of CPK in the blood. The activity of CPK 5 times the ULN, in the diagnosis of myopathy or suspicion of it the drug of Simgal stop. All patients starting therapy with the drug of Simgal, and patients who need to increase the dose of the drug Simgal should be warned about the possibility of myopathy and need immediate treatment to the doctor in case of unexplained pain, soreness in muscles, lethargy or muscle weakness, particularly if accompanied by malaise or fever.

In the presence of risk factors for myopathy/rhabdomyolysis such as age older than 65 years, use in women, uncontrolled hypothyroidism, muscle disease in the family history, impaired renal function, especially with Cl creatinine less than 30 ml/min, myopathy/rhabdomyolysis associated with the use of statins and fibrates, a history of alcoholism, the use of simvastatin is only possible in the case when the expected benefit outweighs the potential risk.

In the case that prior to drug treatment of Simgal the activity of CPK 5 times the ULN in patients with myopathy/rhabdomyolysis associated with the use of statins or fibrates, a drug treatment of Simgal should not even start.

If muscle pain, weakness or cramps during treatment with the drug Simgal, it is necessary to conduct the determination of the activity of KFK. The activity of CPK 5 times the ULN the drug treatment of Simgal should be discontinued. Provided that after preparation of Simgal the activity of ck decreased to ULN, you can continue treatment with Simgal at a lower dose with careful monitoring of activity of KFK.

In applying the drug of Simgal in a daily dose of 80 mg/day the risk for myopathy is greatly increased. Regular study of the activity of KFK in this mode of use can help to identify subclinical cases of myopathy. However, there is no guarantee that such monitoring of indicators of activity of KFK will help to prevent the development of myopathy.

Drug treatment of Simgal should be stopped several days before scheduled surgery (including dental) and shall not be conducted in the postoperative period.

At the beginning of drug therapy of Simgal possible transient moderate increase in liver transaminases (less than 3 times compared with CAH), which is usually not accompanied by any pathological symptoms and does not require interruption of therapy.

Before and during therapy is recommended to regularly pursue 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), and liver function tests should be conducted with increasing doses of Simgal. With increasing daily dose up to 80 mg/day is necessary to conduct this study every 3 months. If persistent elevations in liver transaminases (more than 3 times compared with CAH), the drug of Simgal should be discontinued.

Drug Simgal should be used with caution in patients who consume substantial quantities of alcohol.

Few reports were received about cases of interstitial lung disease associated with long-term therapy with simvastatin, which was manifested by shortness of breath, cough with sputum, deterioration of General condition (fatigue, weight loss, fever). With the development of such conditions therapy drug Simgal should be terminated.

Drug Simgal, like other inhibitors of HMG-COA reductase, it should not be used against the backdrop of severe acute infections, arterial hypotension, trauma, severe metabolic disorders.

In patients with reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephrotic syndrome) when the concentration of cholesterol, you should first treat the underlying disease. Before and during drug treatment of Simgal the patient should be on gipoholesterinovu diet.

Simvastatin is not indicated for hypertriglyceridemia the I, IV and V types.

If you skip doses of the drug must be taken as soon as possible. If it is time for your next dose, the dose is not doubled.

Patients with severe renal insufficiency treatment to control kidney function.

The duration of the drug is determined by the attending physician individually.

Effects on ability to drive and other mechanisms

Caution must be exercised in the management of transport and other mechanisms in connection with the fact that the drug Simgal can cause adverse reactions (dizziness, etc.) that affect the speed of psychomotor reactions and concentration.