Simvastatin - instructions for use, doses, side effects, contraindications

0.75 / 1.50 mg, polyvinyl alcohol 2.33 / 4.66 mg, macrogol (polyethylene glycol) - 1.18 / 2.36 mg, iron dye oxide black - 0.02 / 0.04 mg, talcum powder 0.86 / 1.72 mg, iron oxide pigment yellow 0.28 / 0.56 mg, iron oxide red dye 0.19 / 0.38 mg, titanium dioxide 0.97 / 1.94 mg.

Description:

round biconvex tablets, covered with a film coating of white color.

Pharmacotherapeutic group:lipid-lowering agent - HMG-CoA reductase inhibitor

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.01 Simvastatin

Pharmacodynamics:

A hypolipidemic agent obtained synthetically from a fermentation product Aspergillus terreus, is an inactive lactone in the body undergoes hydrolysis with the formation of a hydroxy-acid derivative. The active metabolite inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), an enzyme that catalyzes the initial reaction of mevalonate formation from HMG-CoA. Since the conversion of HMG-CoA to mevalonate is an early stage in the synthesis of cholesterol, the use of simvastatin does not cause the accumulation of potentially toxic sterols in the body. HMG-CoA is easily metabolized to acetyl-CoA, which is involved in many synthesis processes in the body.

It causes a decrease in the plasma levels of triglycerides (TG), low-density lipoproteins (LDL),lipoproteins of very low density (VLDL) and total cholesterol (in cases of heterozygous familial and non-family forms of hypercholesterolemia, with mixed hyperlipidemia, when elevated cholesterol is a risk factor).

Increases the high-density lipoprotein (HDL) content and reduces the ratio of LDL / HDL and total cholesterol / HDL.

The onset of the effect is 2 weeks after the start of the treatment, the maximum therapeutic effect is achieved after 4-6 weeks. The effect persists with the continuation of treatment, with the cessation of therapy, the cholesterol content gradually returns to the baseline level.

Pharmacokinetics:

Absorption of simvastatin is high. After oral administration, the maximum concentration in the blood plasma is reached after approximately 1.3-2.4 hours and decreases by 90% after 12 hours. The connection with plasma proteins is about 95 %.

Metabolized in the liver, has the effect of a "first pass" through the liver (hydrolyses to form an active derivative: beta-hydroxy acid, found other active, as well as inactive metabolites). The half-life of active metabolites is 1.9 hours.

It is excreted mainly with feces (60%) in the form of metabolites. About 10-15 % is excreted by the kidneys in an inactive form.

Indications:

Hypercholesterolemia:

Primary hypercholesterolemia (type Ha and IL) with ineffectiveness of diet therapy with low cholesterol and other non-drug measures (physical activity and weight loss) in patients with an increased risk of coronary atherosclerosis;
Combined hypercholesterolemia and hypertriglyceridemia, not corrected by special diet and exercise.

Cardiac ischemia:

for the prevention of myocardial infarction, to reduce the risk of death, reduce the risk of cardiovascular disorders (stroke or transient ischemic attacks), slow the progression of coronary artery atherosclerosis, reduce the risk of revascularization procedures.

Contraindications:

Hypersensitivity to simvastatin or to other components of the drug (including hereditary lactose intolerance), as well as to other drugs of the statin series (inhibitors of GMC-CoA reductase) in the anamnesis;
Diseases of the liver in the active phase, persistent increase in the activity of "hepatic" enzymes of unclear etiology;
Diseases of skeletal musculature (myopathy);
Age to 18 years (efficiency and safety not established)

Carefully:

FROM caution prescribe patients who abuse alcohol, patients after organ transplantation, who undergo immunosuppressant therapy (due to an increased risk of rhabdomyolysis and kidney failure); at conditions that can lead to the development of severe renal failure, such as arterial hypotension, acute infectious diseases of severe course, severe metabolic and endocrine disorders, violations of electro-electrolyte balance, surgical interventions (including dental), or trauma; patients with decreased or increased tone of skeletal muscles of unknown etiology; epilepsy.

Pregnancy and lactation:

Simvastatin may adversely affect the fetus and is contraindicated in pregnant women. There are several reports of the development of anomalies in newborns whose mothers were taking Simvastatin.

Women of reproductive age who receive Simvastatin, should avoid conception.

The use of simvastatin is not recommended in women of childbearing age who do not use contraceptives. If in the course of treatment the pregnancy nevertheless has come, Simvastatin should be canceled, and a woman should be warned about the possible danger to the fetus.

Data on the isolation of simvastatin with mother's milk are absent. If it is necessary to prescribe Simvastatin during breastfeeding, it should be borne in mind that many drugs are excreted in breast milk and there is a threat of severe reactions, so breast-feeding during taking the drug is not recommended.

Dosing and Administration:

Before the treatment with Simvastatin, the patient should be prescribed a standard hypocholesterol diet, which should be observed throughout the course of treatment. Simvastatin should be taken orally 1 time per day in the evening, with plenty of water.

The time of taking the drug should not be associated with eating.

The recommended dose of simvastatin for treatment hypercholesterolemia varies from 10 to 80 mg once a day in the evening.The recommended initial dose of the drug for patients with hypercholesterolemia is 10 mg. The maximum daily dose is 80 mg.

Changes (selection) of the dose should be carried out at intervals of 4 weeks. In most patients, the optimal effect is achieved when taking the drug at doses up to 20 mg per day.

In patients with homozygous hereditary hypercholesterolemia the recommended daily dose of Simvastatin is 40 mg once a day in the evening or 80 mg in three divided doses (20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening).

In the treatment of patients with ischemic heart disease (CHD) or a high risk of CHD effective doses of simvastatin are 20-40 mg per day. Therefore, the recommended initial dose in such patients is 20 mg per day. Changes (selection) of the dose should be carried out at intervals of 4 weeks, if necessary, the dose can be increased to 40 mg per day. If the LDL content is less than 75 mg / dL (1.94 mmol / L), the total cholesterol content is less than 140 mg / dl (3.6 mmol / L), the dose of the drug should be reduced.

In elderly patients and in patients with mild or moderate degree of renal failure, no dosage adjustment is required.

In patients with chronic renal failure (creatinine clearance less than 30 ml / min) or receiving ciclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate), nicotinic acid in lipid-lowering doses (> 1 g / day) in combination with simvastatin, the maximum recommended dose of simvastatin should not exceed 10 mg per day.

For patients receiving amiodarone or verapamil Simvastatin simultaneously, the daily dose should not exceed 20 mg.

Side effects:

From the digestive system: abdominal pain, constipation, flatulence, nausea, diarrhea, pancreatitis, vomiting, hepatitis, increased activity of "liver" enzymes, alkaline phosphokinase and creatine phosphokinase (CKF).

From the nervous system and sensory organs: asthenic syndrome, headache, dizziness, insomnia, muscle cramps, paresthesia, peripheral neuropathy, blurred vision, impaired taste sensations.

From the side of the musculoskeletal system: myopathy, myalgia, muscle cramps, weakness; rarely rhabdomyolysis.

Allergic and immunopathological reactions: angioedema, rheumatic polymyalgia, vasculitis, thrombocytopenia, increased ESR, fever, arthritis, urticaria,

photosensitivity, skin hyperemia, hot flashes, dyspnea, lupus-like syndrome, eosinophilia.

Dermatological reactions: rarely skin rash, itching, alopecia, dermatomyositis.

Other: anemia, palpitations, acute renal failure (due to rhabdomyolysis), decreased potency.

Overdose:

In none of the known few cases of overdose (the maximum dose of 450 mg) specific symptoms were identified.

Treatment: induce vomiting, take Activated carbon, to carry out symptomatic therapy. It is necessary to monitor the liver and kidney function, the level of CK in the blood serum. With the development of myopathy with rhabdomyolysis and acute renal failure (a rare but severe side effect), the drug should be stopped immediately and the diuretic and sodium bicarbonate (intravenous infusion) administered to the patient. If necessary, hemodialysis is indicated.

Rhabdomyolysis can cause hyperkalemia, which can be eliminated by intravenous administration of calcium chloride or calcium gluconate, glucose infusion with insulin, the use of potassium ion-exchange sorbents or, in severe cases, by hemodialysis.

Interaction:

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

Cyclosporine or danazol: the risk of myopathy / rhabdomyolysis increases with the simultaneous administration of cyclosporine or danazol with high doses of simvastatin.

Other hypolipidemic agents that can cause the development of myopathy: the risk of myopathy increases with the co-administration of other lipid-lowering drugs that are not potent inhibitors CYP3A4, but capable of causing myopathy under conditions of monotherapy. Such as gemfibrozil and other fibrates (except fenofibrate), as well as a nicotinic acid in a dose> 1 g per day.

Amiodarone and verapamil: the risk of myopathy increases with the simultaneous administration of amiodarone or verapamil with high doses of simvastatin.

Diltiazem: the risk of developing myopathy is slightly increased in patients receiving diltiazem Simvastatin simultaneously in a dose of 80 mg.

Simvastatin potentiates the effect of oral anticoagulants (for example, fenprokumone, warfarin) and increases the risk of bleeding, which requires the need to monitor the coagulability of the blood before the treatment, and often enough in the initial period of therapy. Once a stable level of prothrombin time or International Normalized Ratio (MNO) is reached, its further control should be performed at intervals recommended for patients receiving anticoagulant therapy. When changing the dosage or stopping the intake of simvastatin, it is also necessary to monitor prothrombin time or INR in the above scheme.

Therapy with simvastatin does not cause changes in prothrombin time and the risk of bleeding in patients who do not take anticoagulants.

Increases the level of digoxin in the blood plasma.

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

Grapefruit juice contains one or more ingredients that inhibit CYP3A4 and can increase the concentration in the blood plasma of metabolic agents CYP3A4.

The increase in the activity of HMG-CoA reductase inhibitors after consuming 250 ml of juice per day is minimal and has no clinical significance. However, consumption of a large amount of juice (more than 1 liter per day) with Simvastatin significantly increases the level of inhibitory activity against HMG-CoA reductase in blood plasma. In this regard, it is necessary to avoid the consumption of grapefruit juice in large quantities.

Special instructions:

At the beginning of Simvastatin therapy, a transient increase in the level of "liver" enzymes is possible.

Before starting therapy, continue to conduct regular liver function tests (monitor the activity of liver enzymes every 6 weeks for the first 3 months, then every 8 weeks for the remainder of the first year, and then once every six months), as well as with increasing doses a liver function test should be performed. When the dose is raised to 80 mg, a test should be performed every 3 months. With a persistent increase in the activity of transaminases (3-fold compared with the baseline level), Simvastatin should be discontinued.

Simvastatin, like other inhibitors of HMG-CoA reductase,should not be used at an increased risk of rhabdomyolysis and renal failure (on the background of severe acute infection, hypotension, planned major surgery, trauma, severe metabolic disorders).

The abolition of lipid-lowering drugs during pregnancy does not have a significant effect on the results of long-term treatment of primary hypercholesterolemia. In patients with a reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephrotic syndrome), when the level of cholesterol is increased, the underlying disease should first be treated.

Simvastatin is cautiously prescribed to people who abuse alcohol and / or have a history of liver disease.

Before and during treatment, the patient should be on a hypocholesterol diet. Simultaneous reception of grapefruit juice can increase the severity of side effects associated with taking simvastatin, therefore, they should be avoided at the same time.

Simvastatin is not indicated in cases where there is hypertriglyceridemia I, IV and V types.Treatment with simvastatin can cause myopathy, leading to rhabdomyolysis and kidney failure. The risk of this pathology increases in patients receiving simultaneously with Simvastatin one or more of the following medicines: fibrates (gemfibrozil, fenofibrate), ciclosporin, nefazadone, macrolides (erythromycin, clarithromycin), antifungal agents from the group of "azoles" (ketoconazole, itraconazole) and HIV protease inhibitors (ritonavir). The risk of developing myopathy is also increased in patients with severe renal failure.

All patients starting therapy with simvastatin, as well as patients who need to increase the dose of the drug, should be warned about the possibility of myopathy and the need to immediately seek medical attention in the event of unexplained pain, muscle soreness, lethargy or muscle weakness, especially if accompanied by malaise or fever. The drug should be discontinued immediately if myopathy is diagnosed or suspected.

In order to diagnose the development of myopathy, it is recommended that CK values be measured regularly.

When treating Simvastatin, it is possible to increase the content of serum CK, which should be taken into account in the differential diagnosis of chest pain. The criterion for the discontinuation of the drug is an increase in serum levels of CK in more than 10 times the upper limit of the norm. In patients with myalgia, myasthenia gravis and / or pronounced

increasing the activity of CKK treatment with the drug is stopped.

The drug is effective both in the form of monotherapy, and in combination with sequestrants of bile acids.

If the current dose is skipped, the drug should be taken as soon as possible. If it's time for the next dose, do not double the dose.

Patients with severe renal failure receive treatment under the control of kidney function.

Duration of the drug is determined individually by the attending physician.

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

The adverse effect of the drug on the ability to drive and work with machinery has not been reported.

Form release / dosage:

Tablets film-coated 10 mg and 20 mg.

Packaging:

For 10 tablets in a contour mesh box made of PVC film and aluminum foil printed lacquered.

1,2, 3,4 or 5 contour squares with instruction in a pack of cardboard.

Storage conditions:

List B. In a dry, the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002033/08

Date of registration:21.03.2008

The owner of the registration certificate:ALSI Pharma, ZAO ALSI Pharma, ZAO Russia

Manufacturer: & nbsp

ALSI Pharma, ZAO Russia

Representation: & nbspALSI Pharma CJSC ALSI Pharma CJSC Russia

Information update date: & nbsp01.08.2015

Illustrated instructions

Instructions

Simvastatin (Simvastatin)