Simvastatin

General characteristics. Structure:

Active ingredient: 10 mg or 20 mg of a simvastatin.

Excipients: cellulose microcrystallic, lactoses monohydrate (sugar milk), starch prezhelatinizirovanny (starch 1500), silicon dioxide colloid (aerosil), ascorbic acid, butylhydroxyanisole, stearic acid, magnesium stearate, polyvinyl alcohol, macrogoal (polyethyleneglycol), dye ferrous oxide black, talc, dye ferrous oxide yellow, dye ferrous oxide red, titanium dioxide.

Drug for decrease in level of the cholesterol of blood serum which is contained in lipoproteids of low density. Drug allows to reduce cholesterol level in blood if its indicators are exceeded, and the low-cholesteric diet in combination with physical exercises does not give due effect or its use is impossible. At ischemia reception of a simvastatin prevents development of a myocardial infarction, reduces risk of death, and also probability of attacks or a stroke. Drug slows down development of the prime cause of cardiovascular diseases: the atherosclerosis affecting coronary arteries. Reduces risk when holding procedures for recovery of affected areas of vessels.

Additional effect of drug – in increase in antitrombotichesky activity of vessels, a rassasyvaniya of blood clots, antiinflammatory and antioxidant action, suppression of process of emergence of new growths because of growth of cells, stabilization of function of an endothelium. Simvastatin – one of the most studied drugs of the group and therefore which are often appointed. Among statines differs in high degree of safety, efficiency and availability. Successfully slows down progressing of atherosclerosis and reduces percent of development of cardiovascular complications.

Pharmacological properties:

Pharmacodynamics. The hypolipidemic means received in the synthetic way from Aspergillus terreus fermentation product is an inactive lactone, in an organism is exposed to hydrolysis with formation of hydroxyacid derivative. The active metabolite inhibits 3-гидрокси-3-метил-глутарил-КоА-редуктазу (GMG-KOA-reduktazu), the enzyme catalyzing initial reaction of formation of a mevalonat from GMG-KOA. As transformation GMG-KOA in мевалонат represents an early stage of synthesis of cholesterol, Simvastatin's use does not cause accumulation in an organism of potentially toxic sterol. GMG-KOA it is easily metabolized to atsetil-KOA which participates in many processes of synthesis in an organism.

Causes decrease in contents in a blood plasma of triglycerides (TG), lipoproteids of the low density (LPNP), lipoproteids of very low density (LPONP) and the general cholesterol (in cases of heterozygous family and single forms of a hypercholesterolemia, at the mixed lipidemia when the increased content of cholesterol is risk factor).

Increases the maintenance of lipoproteids of the high density (LPVP) and reduces a ratio of LPNP/LPVP and the general cholesterol / LPVP.

The beginning of manifestation of effect - in 2 weeks from the beginning of reception, the maximum therapeutic effect is reached in 4-6 weeks. Action remains at treatment continuation, at the therapy termination the content of cholesterol gradually is returned to initial level.

Pharmacokinetics. Simvastatin's absorption high. After intake the maximum concentration in a blood plasma is reached approximately in 1,3-2,4 hours and decreases by 90% in 12 hours. Communication with proteins of a blood plasma makes about 95%.

It is metabolized in a liver, has effect of "the first passing" through a liver (it is hydrolyzed with formation of active derivative: beta hydroxyacids, are found also other active, and also inactive metabolites). The elimination half-life of active metabolites makes 1,9 hours.

It is removed preferential with a fecal masses (60%) in the form of metabolites. About 10-15% are removed by kidneys in an inactive form.

Indications to use:

Hypercholesterolemia:

• primary hypercholesterolemia (IIa and IIb type) at inefficiency of a dietotherapy with the low content of cholesterol and other non-drug actions (an exercise stress and decrease in body weight) at patients with the increased risk of developing of coronary atherosclerosis;

• the combined hypercholesterolemia and the gipertriglitseridemiya which are not adjusted by a special diet and an exercise stress.

Coronary heart disease:

• for prevention of a myocardial infarction, for reduction of risk of death, reduction of risk of cardiovascular disturbances (a stroke or tranzitorny ischemic attacks), delay of progressing of atherosclerosis of coronary vessels, reduction of risk of procedures of revascularization.

Route of administration and doses:

Prior to treatment by Simvastatin the patient should appoint a standard hypocholesteric diet which has to be observed during all course of treatment.

Simvastatin it is necessary to accept in 1 times a day in the evening, washing down with enough water.

Time of administration of drug should not be connected with meal.

The recommended Simvastatin's dose for treatment of a hypercholesterolemia varies from 10 to 80 mg of 1 times a day in the evening. The recommended initial dose of drug for patients with a hypercholesterolemia makes 10 mg. The maximum daily dose – 80 mg.

Changes (selection) of a dose should be carried out bucketed in 4 weeks. At most of patients the optimum effect is reached at administration of drug in doses to 20 mg a day.

At patients with a homozygous hereditary hypercholesterolemia the recommended daily dose of Simvastatin makes 40 mg of 1 times a day in the evening or 80 mg in three steps (20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening).

At treatment of patients with the coronary heart disease (CHD) or high risk of development of an ischemic heart disease effective doses of Simvastatin make 20-40 mg a day. Therefore the recommended initial dose at such patients – 20 mg a day. Changes (selection) of a dose should be carried out bucketed in 4 weeks, if necessary it is possible to increase a dose to 40 mg a day. If the maintenance of LPNP less than 75 mg/dl (1,94 mmol/l), content of the general cholesterol - less than 140 mg/dl (3,6 mmol/l), a dose of drug it is necessary to reduce.

And at patients with the easy or moderately expressed degree of a renal failure of changes of a dosage of drug it is not required from patients of advanced age.

At patients with a chronic renal failure (clearance of creatinine less than 30 ml/min.) or receiving cyclosporine, даназол, gemfibrozit or other fibrata (except a fenofibrat), niacin in lipidsnizhayushchy doses (≥ 1 g/days) in a combination with Simvastatin, the maximum recommended Simvastatin's dose should not exceed 10 mg a day.

For the patients accepting Amiodaronum or verapamil along with Simvastatin, the daily dose should not exceed 20 mg.

Features of use:

Simvastatin can make an adverse effect on a fruit and is contraindicated to pregnant women. There are several messages on development of anomalies in newborns which mothers accepted Simvastatin.

The women of reproductive age accepting Simvastatin have to avoid conception. Simvastatin's use is not recommended at the women of childbearing age who are not using contraceptive means. If in the course of treatment pregnancy nevertheless occurred, Simvastatin has to be cancelled, and the woman has to be warned about possible danger to a fruit.

Data on Simvastatin's allocation with maternal milk are absent. In need of Simvastatin's appointment during feeding by a breast it is necessary to consider that many medicines are allocated with breast milk, and there is a threat of development of heavy reactions therefore feeding by a breast during administration of drug is not recommended.
At the beginning of therapy by Simvastatin perhaps passing increase in level of "hepatic" enzymes.

Before therapy and further regularly to conduct a research of function of a liver (to control activity of "hepatic" enzymes each 6 weeks within the first 3 months, then each 8 weeks within the remained first year, and then 1 time in half a year), and also at increase in doses it is necessary to carry out the test for definition of function of a liver. At increase in a dose to 80 mg it is necessary to carry out the test each 3 months. At permanent increase in activity of transaminases (by 3 times in comparison with initial level) Simvastatin's reception should be stopped.

Simvastatin, as well as other inhibitors of GMG-KOA-reduktazy, it is not necessary to apply at the increased risk of development of a rabdomioliz and a renal failure (against the background of a heavy acute infection, arterial hypotension, the planned big surgery, injuries, heavy metabolic disturbances).

Cancellation of hypolipidemic means during pregnancy has no significant effect on results of prolonged treatment of primary hypercholesterolemia.

At patients with the lowered function of a thyroid gland is (hypothyroidism) or in the presence of some diseases of kidneys (a nephrotic syndrome) at increase in level of cholesterol it is necessary to carry out therapy of the cornerstone disease at first.

Simvastatin with care appoint to persons who abuse alcohol and/or have in the anamnesis of a disease of a liver.

Prior to the beginning of and during treatment the patient has to be on a hypocholesteric diet.

The concomitant use of grapefruit juice can strengthen degree of manifestation of the by-effects connected with Simvastatin's reception therefore it is necessary to avoid their concomitant use.

Simvastatin is not shown when there is a gipertriglitseridemiya I, IV and V types.

Treatment by Simvastatin can cause the myopathy leading to a rabdomioliz and a renal failure. The risk of developing of this pathology increases at the patients receiving one or several of the following medicines along with Simvastatin: fibrata (gemfibrozit, фенофибрат), cyclosporine, нефазадон, macroleads (erythromycin, кларитромицин), antifungal means from group of "azoles" (кетоконазол, итраконазол) and inhibitors of HIV proteases (ритонавир). The risk of development of a myopathy increases also at patients with a heavy renal failure.

All patients beginning therapy by Simvastatin and also patients who need to increase a drug dose have to be warned about possibility of a myopathy and need of the immediate address to the doctor in case of emergence inexplicable pains, morbidity in muscles, slackness or muscular weakness, especially if it is followed by an indisposition or fever. Therapy by drug has to be immediately stopped if the myopathy is diagnosed or is supposed.

For diagnosing of development of a myopathy it is recommended to take measurements of size KFK regularly.

At treatment by Simvastatin increase of maintenance of serumal KFK is possible that should be considered at differential diagnosis of pains behind a breast. As criterion of drug withdrawal serves increase in maintenance of KFK in blood serum more than by 10 times of rather upper bounds of norm. At patients with a mialgiya, a myasthenia and/or the expressed increase in activity of KFK treatment with drug is stopped.

Drug is effective both in the form of monotherapy, and in combination with sekvestrant of bile acids.

In case of the admission of the current dose drug needs to be accepted as soon as possible. If came time of the following dose, a dose not to double.

To patients with a heavy renal failure treatment is carried out under control of function of kidneys.

Duration of use of drug is defined by the attending physician individually.

Influence on ability of driving and work with mechanisms. About adverse influence of drug on ability to drive the car and work with mechanisms it was not reported.

Side effects:

From a digestive sistemy:vozmozhna of an abdominal pain, lock, meteorism, nausea, diarrhea, pancreatitis, vomiting, hepatitis, increase in activity of "hepatic" enzymes, alkaline phosphokinase and kreatinfosfokinaza (KFK).

From a nervous system and bodies chuvstv:astenichesky syndrome, headache, dizziness, sleeplessness, muscular spasms, paresthesias, peripheral neuropathy, sight vagueness, disturbance of flavoring feelings.

From a musculoskeletal system: myopathy, mialgiya, myotonia, weakness; seldom - рабдомиолиз.

Allergic and immunopathological reaktsii:angionevrotichesky hypostasis, rheumatic polimialgiya, vasculitis, thrombocytopenia, increase SOE, fever, arthritis, urticaria, photosensitization, dermahemia, inflows, asthma, volchanochnopodobny syndrome, eosinophilia.

Dermatological reactions: seldom skin rash, itch, alopecia, dermatomyositis.

Prochiye:anemiya, heartbeat, an acute renal failure (owing to a rabdomioliz), decrease in a potentiality.

Interaction with other medicines:

Cytostatics, antifungal means (кетоконазол, итраконазол), fibrata, high doses of niacin, immunodepressants, erythromycin, кларитромицин, телитромицин, HIV protease inhibitors, нефазодон increase risk of development of a myopathy.

Cyclosporine or даназол: the risk of development of a myopathy / рабдомиолиза increases at joint purpose of cyclosporine or a danazol with high doses of Simvastatin.

Other hypolipidemic means capable to cause development of a myopathy: the risk of development of a myopathy increases at joint purpose of other hypolipidemic means which are not powerful CYP3A4 inhibitors, but capable to cause a myopathy in the conditions of monotherapy. Such as gemfibrozit also other fibrata (except a fenofibrat), and also niacin in a dose ≥ 1 g a day.

Amiodaronum and verapamil: the risk of development of a myopathy increases at joint reception of Amiodaronum or verapamil with high doses of Simvastatin.

Diltiazem: the risk of development of a myopathy slightly increases at the patients receiving diltiazem along with Simvastatin in a dose of 80 mg.

Simvastatin exponentiates effect of peroral anticoagulants (for example, фенпрокумон, warfarin) and increases risk of developing of bleedings that demands need of monitoring procedure of indicators of coagulability of blood prior to treatment, and also is rather frequent during an initial stage of therapy. As soon as the stable level of an indicator of a prothrombin time or the International Normalized Relation (INR) is reached, its further control should be carried out bucketed, recommended for the patients receiving therapy by anticoagulants. At change of a dosage or the termination of reception of Simvastatin it is also necessary to carry out control of a prothrombin time or MNO according to the above scheme.

Therapy by Simvastatin does not cause changes of a prothrombin time and risk of bleedings in the patients who are not accepting anticoagulants.

Increases digoxin level in a blood plasma.

Colestyraminum and колестипол reduce bioavailability (Simvastatin's use is possible in 4 hours after reception of the specified medicines, at the same time the additive effect is noted).

Juice of grapefruit contains one or more components which inhibit CYP3A4 and can increase concentration in a blood plasma of the means which are metabolized CYP3A4. Increase in activity of inhibitors of GMG-KOA-reduktazy after the use of 250 ml of juice a day is minimum and has no clinical value. However consumption of large volume of juice (more than 1 liter a day) at Simvastatin's reception considerably increases the level of the inhibiting activity concerning GMG-KOA-reduktazy in a blood plasma. In this regard it is necessary to avoid grapefruit juice consumption in large numbers.

Contraindications:

• Hypersensitivity to a simvastatin or to other components of drug (including a hereditary lactose intolerance), and also to other drugs of a statinovy row (GMK-KOA-reduktazy inhibitors) in the anamnesis;

• Liver diseases in an active phase, permanent increase in activity of "hepatic" enzymes of not clear etiology;

• Diseases of skeletal muscles (myopathy);

• Age up to 18 years (efficiency and safety are not established).

With care appoint the patient abusing alcohol, to patients after organ transplantation which carries out therapy by immunodepressants (in connection with the increased risk of emergence of a rabdomioliz and a renal failure); at states which can lead to development of the expressed insufficiency of function of kidneys, such as arterial hypotension, acute infectious diseases of a heavy current, the expressed metabolic and endocrine disturbances, disturbances of water and electrolytic balance, surgical interventions (including dental) or injuries; to patients with the lowered or raised tone of skeletal muscles of not clear etiology; epilepsies.

Overdose:

In one of the known several cases of overdose (most accepted dose of 450 mg) of specific symptoms it was not revealed.

Treatment: to cause vomiting, to accept absorbent carbon, to carry out symptomatic therapy. It is necessary to control functions of a liver and kidneys, the KFK level in blood serum.

At development of a myopathy with rabdomiolizy and an acute renal failure (rare, but heavy side effect) it is necessary to stop immediately administration of drug and to enter to the patient diuretic and sodium bicarbonate (intravenous infusion). If necessary the hemodialysis is shown.

Rabdomioliz can cause a hyperpotassemia which can be eliminated with intravenous administration of Calcii chloridum or calcium of a gluconate, infusion of glucose with insulin, use of potassium ion-exchange sorbents or, in hard cases, by means of a hemodialysis.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 10 mg and 20 mg.

On 10 tablets in a blister strip packaging from the film of PVC and printing aluminum foil varnished.

1, 2, 3, 4 or 5 blister strip packagings with the instruction in a pack from a cardboard.