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

Excipients: lactose - 74.25 mg, pregelatinized starch - 10.0 mg, cellulose microcrystalline 5.0 mg, talc (magnesium hydrosilicate) 1.0 mg, magnesium stearate 0.75 mg, butyl hydroxy anisole 0.02 mg;

shell: giprolose (hydroxypropylcellulose) 0.76 mg, hypromellose 0.76 mg, titanium dioxide E-171 0.69 mg, talc (magnesium hydrosilicate) 0.28 mg.

One tablet, coated with 20 mg,contains active substance: simvastatin 20 mg; auxiliary substances: lactose 148.5 mg, pregelatinized starch 20.0 mg, cellulose microcrystalline 10.0 mg, talc (magnesium hydrosilicate) 2.0 mg, magnesium stearate 1.5 mg, butyl hydroxy anisole 0.04 mg; shell: giprolose (hydroxypropyl cellulose) - 1.65 mg, hypromellose - 1.65 mg, titanium dioxide E-171 - 1.5 mg, talc (magnesium hydrosilicate) - 0.6 mg.

Description:

Round, biconvex tablets, coated with a coat of white color with a risk on one side.

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 the fermentation product of 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), very low density lipoproteins (VLDL) and total cholesterol (in cases of heterozygous familial and non-family forms of hypercholesterolemia, with mixed hyperlipidemia, when high cholesterol is a risk factor) .

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

The onset of the effect is 2 weeks after the start of the admission, the maximum

The therapeutic effect is achieved in 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%.

Metabolised in the liver,has the effect of a "first pass" through the liver (hydrolyses to form an active derivative: beta-hydroxy acid, other active as well as inactive metabolites are found). 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 Pa and NL) with ineffectiveness of diet therapy with low cholesterol and other non-medicamentous measures (physical activity and weight loss) in patients with an increased risk of coronary atherosclerosis;

combined hypercholesterolemia and hypertriglyceridemia, not corrected by a 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, as well as to other drugs of the statin series (inhibitors of HMG-CoA reductase) in the anamnesis;
liver disease in the active phase, persistent increase in the activity of "liver" transaminases of unclear etiology;
diseases of skeletal muscles (myopathy);
simultaneous application with strong inhibitors of isoenzyme CYP3A4 (itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, bocetrevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone);

- concomitant treatment with gemfibrozil, cyclosporin or danazol;

- age to 18 years (effectiveness and security not established);

- lactose intolerance, deficiency lactase or glucose-galactose malabsorption (the preparation contains lactose).

Carefully:

With caution appoint a patient, alcohol abusers, patients after organ transplantation who undergo immunosuppressant therapy (due to an increased risk of rhabdomyolysis and kidney failure); with simultaneous application with dronedarone (increased risk of myopathy andrhabdomyolysis); at conditions that can lead to the development of severe renal function deficiency, such as arterial hypotension, acute infectious diseases of severe course, expressed metabolic and endocrine disorders, violations of the water-electrolyte balance, surgical interventions (including dental) or trauma; patients with a decreased or increased tone of skeletal muscles of unknown etiology; epilepsy.

Pregnancy and lactation:FROMImvastatin is contraindicated in pregnant women. AT connection with the fact that inhibitors of HMG-CoA-reductase inhibit the synthesis of cholesterol, and Cholesterol and other products of its synthesis play an essential role in the development of fetus, including the synthesis of steroids and cell membranes, simvastatin can have adverse effects on

Fetus when he is pregnant. There are several reports of the development of anomalies in newborns whose mothers were taking simvastatin. Women of childbearing 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.

The abolition of lipid-lowering drugs during pregnancy does not have a significant effect on the results of long-term treatment of primary hypercholesterolemia.

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 development 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 hypocholesterolemic diet, which should be observed throughout the course of treatment.

Simvastatin should be taken 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 5 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. Have most patients the optimal effect is achieved when taking the drug in 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 from ischemic heart disease (CHD) or high risk of CHD development Effective dosages 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 made at intervals of 4 weeks, if necessary, dIt 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.

Have elderly patients and in patients with mild shea moderately expressed degree of renal failure changes in the dosage of the drug are not it takes.

In patients with chronic renal failure of severe severity (creatinine clearance less than 30 ml / min) the maximum recommended dose of simvastatin should not exceed 10 mg per day.

When Simvastatin is used together with verapamil, dithiasem, dronedarone, fibrates (except fenofibrate), as well as with

nicotinic acid in lipid-lowering doses (> 1 g / day), the dose of simvastatin should not exceed 10 mg per day.

With the simultaneous use of simvastatin with drugs amiodarone, amlodipine, ranolazine, The dose of Simvastatin should not exceed 20 mg per day.

Side effects:

Digestive system: are possible abdominal pain, constipation, flatulence, nausea, diarrhea, pancreatitis, vomiting, hepatitis.

Nervous system and senses: asthenic syndrome, loss or loss of memory, depression, sleep disturbances, including insomnia and nightmarish dreams, headache, dizziness, muscle cramps, paresthesia, peripheral neuropathy, blurred vision, impaired taste.

Allergic and immunopathological reactions: angioedema, rheumatic polymyalgia, vasculitis, thrombocytopenia, increased ESR, fever, arthritis, urticaria, photosensitivity, skin hyperemia, blood flushes to the skin of the face, dyspnea, lupus-like syndrome, eosinophilia.

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

From the musculoskeletal system: myopathy, myalgia, muscle cramps, weakness; rarely - rhabdomyolysis; cases of development of immuno-mediated necrotizing myopathy with the use of inhibitors of HMG-CoA reductase were revealed.

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

Laboratory and instrumental data: rise activity of "hepatic" transaminases, alkaline phosphatase and creatine phosphokinase (CK), hyperglycemia, increased concentration of glycosylated hemoglobin, thrombocytopenia.

Other: anemia, palpitations, acute renal failure (due to rhabdomyolysis), sexual dysfunction. gynecomastia, single cases of interstitial Lung diseases (especially when long-term use).

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. 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, potassium ion exchangers or, in severe cases, hemodialysis.

Interaction:

Cytostatics, antifungal agents (ketoconazole, itraconazole, voriconazole, posaconazole), immunosuppressants, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, other lipid-lowering agents, which are not potent inhibitors CYP3A4, but are able to cause myopathy under conditions of monotherapy, such as gemfibroz (see "Contraindications") and others fibrates (except fenofibrate), as well as nicotinic acid in lipid-lowering doses (> 1 g per day), increase the risk of myopathy. Ciclosporin shea danazol: The risk of myopathy / rhabdomyolysis increases with the simultaneous administration of cyclosporine or danazol with high doses of simvastatin. Simultaneous use of simvastatin with fusidic acid, with colchicine increases the risk of myopathy. Amiodarone, dronedaron, ranolazine, blockers of "slow" calcium channels: the risk of myopathy and rhabdomyolysis increases with simultaneous use of amiodarone, dronedarone, ranolazine or blockers of "slow" calcium channels, such as verapamil, diltiazem, amlodipine with high doses of simvastatin.

Simvastatin potentiates the action oral anticoagulants (eg, fenprokumone, warfarin) and increases risk of bleeding that requires control of coagulation blood before the treatment, and quite often in the initial period therapy. Once reached stable indicator level prothrombin time or International Normalized Relationship (MNO), its further monitoring should be carried out at intervals, recommended for patients, receiving therapy with anticoagulants.

When changing the dosage or discontinuation of simvastatin also should monitor prothrombin time or INR by the above scheme.

Therapy with simvastatin does not cause changes in prothrombin time and risk of bleeding in patients not taking anticoagulants.

Increases concentration digoxin at blood plasma.

Kolestyramine and colestipol reduce bioavailability of simvastatin (use simvastatin is possible after 4 hours. after administration of said drugs, while there is an additive effect).

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the concentration in the blood plasma of metabolic agents CYP3A4. Increased activity inhibitors of HMG-CoA reductase 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 the administration of simvastatin significantly increases the 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, it is possible transient increase in the activity of "liver" transaminases. Before starting therapy, continue to regularly investigate the function of baking (monitor the activity of "liver" transaminases every 6 weeks for the first 3 months, then every 8 weeks for the remainder of the first year, and then 1 time in 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 initial activity), the reception of simvastatin should be discontinued. Simvastatin, as well as other inhibitors of HMG-CoA reductase, should not be used at an increased risk of rhabdomyolysis and renal insufficiency (against severe acute infection, arterial hypotension, planned large surgery, trauma, severe metabolic disorders).

In patients with reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephroticsyndrome) with an increase in the level of cholesterol should first be carried out therapy underlying the disease.

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, one should avoid their simultaneous administration.

Simvastatin is not indicated in those cases, when there is hypertriglyceridemia I, IV and V types.

Treatment with simvastatin can cause Myopathy, leading to rhabdomyolysis and renal failure. The risk of this pathology increases with the simultaneous use of simvastatin with the following drugs: itraconazole, ketoconazole, voriconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone.

The combination of these drugs with simvastatinom is contraindicated. If treatment with these drugs can not be avoided, drug therapy should be interrupted for the period of their use simvastatin. Simultaneous use of simvastatin with gemfibrozil, cyclosporine or danazolum is contraindicated. Caution should be exercised while using simvastatin and other fibrates (except fenofibrate), since these drugs can cause myopathy under monotherapy. The benefits of simultaneous use of simvastatin with the following drugs should be carefully weighed against the potential risk of such combinations: other lipid-lowering drugs (other fibrates or a nicotinic acid (> 1 g per day), amiodarone, dronedaron, verapamil, diltiazem, amlodipine or ranolazine.

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.

In the treatment with simvastatin, an increase in serum CKF is possible, 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 a marked increase in the activity of CKK, treatment with the drug is stopped.

PThe drug is effective both in the form of monotherapy, and in combination with bile acid sequestrants. If the current dose is skipped, the drug should be taken as soon as possible. If it's time to take the next dose, do not double the dose. Patients with severe renal failure receive treatment under the control of kidney function.

Duration of drug administration determined by the attending physician individually.

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

The adverse effects of simvastatin on the ability to drive vehicles and work with mechanisms were not reported.

Form release / dosage:

Tablets coated with 10 mg and 20 mg.

For 10 tablets, coated in a white blister of PVC / PVDC / AL. Two blisters together with instructions for use are placed in a pack of cardboard.

Packaging:

For 10 tablets, coated in a white blister of PVC / PVDC / AL. Two blisters together with instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of 15 to 25 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003203/07

Date of registration:15.10.2007

The owner of the registration certificate:Hemofarm ADHemofarm AD Serbia

Manufacturer: & nbsp

HEMOFARM, A.D. Serbia

Information update date: & nbsp03.08.2015

Illustrated instructions

Instructions

Simvastatin (Simvastatin)