Simvakor-Darnitsa

General characteristics. Structure:

Active ingredient: simvastatin;

1 tablet contains a simvastatin of 10 mg;

excipients: butylhydroxyanisole (Е 320), ascorbic acid, citric acid monohydrate, starch prezhelatinizirovanny, lactose monohydrate, cellulose microcrystallic, calcium stearate, opadray II 85 F pink.

Pharmacological properties:

Pharmacodynamics. Simvastatin – the hypolipidemic means received in the synthetic way from Aspergillus terreus fermentation product is an inactive lactone. Simvastatin in an organism is exposed to hydrolysis with education hydroxyacid derivative which blocks 3-гидрокси-3-метил-глутарил-КоА-редуктазу (GMG KOA reductase), the enzyme catalyzing initial reaction of formation of a mevalonat from GMG KOA. As transformation of GMG KOA in мевалонат represents an early stage of synthesis of cholesterol, use of a simvastatin does not cause accumulation in an organism of potentially toxic sterol. GMG KOA is easily metabolized to atsetil-KOA which participates in many biosynthetic processes in an organism. Simvastatin reduces the content of triglycerides (TG), lipoproyeid of the low density (LPNP), lipoproteids of very low density (LPONP) and the general cholesterol in plasma (in cases of heterozygous family and single forms of a hypercholesterolemia, at the mixed lipidemia when the increased content of cholesterol is risk factor). Drug increases the maintenance of lipoproteids of the high density (LPVP), reduces a ratio of LPNP/LPVP and the general cholesterol / LPVP. Slows down progressing of coronary atherosclerosis and reduces both the frequency of emergence of new defeats, and probability of development of total occlusions of vessels.

The beginning of effect of drug is observed in 2 weeks after the beginning of its reception, the maximum therapeutic effect – in 4-6 weeks. Action remains at treatment continuation; at the therapy termination the content of cholesterol is returned to the initial level which was observed prior to treatment. It is effective both in the form of monotherapy, and in combination with sekvestrant of bile acids.

Pharmacokinetics. Absorption of a simvastatin high. After oral administration of drug time of achievement of the maximum concentration of active ingredient in a blood plasma makes 1,3-2,4 h and decreases by 90% in 12 h after its first reception. Concentration of an active form in a system blood-groove makes less than 5% of orally accepted dose. Communication with proteins of plasma makes 95%. Simvastatin is metabolized in a liver, has effect of "the first passing" through a liver (it is generally hydrolyzed in the active form – beta hydroxyacid, also other active, and also inactive metabolites are found) with the subsequent excretion in bile. Biological half-life of its active metabolites makes about 3 hours. Mainly 60% of a simvastatin are removed with a fecal masses in the form of metabolites. About 10-15% of a simvastatin are removed by kidneys in an inactive form

Pharmaceutical characteristics.

Main physical and chemical properties: tablets, coated, pink color, a round form, with a biconvex surface.

Indications to use:

Primary hypercholesterolemia (heterozygous family and single, the types IIa, IIb and mixed) – at inefficiency of a dietotherapy at patients with the increased risk of development of coronary atherosclerosis, the combined hypercholesterolemia and a gipertriglitseridemiya, the giperlipoproteinemiya which is not giving in to correction by a special diet and an exercise stress.

Homozygous family hypercholesterolemia and gipertriglitseridemiya (in combination with a diet and non-drug methods).

Secondary lipidemias: a hypercholesterolemia, a gipertriglitseridemiya (the IV type, as addition to a dietotherapy), a disbetalipoproteinemiya (the III type, in cases at inadequacy of a dietotherapy), the mixed forms.

Diseases of cardiovascular system (including symptomless coronary heart disease) – secondary prevention for the purpose of decrease in total risk of lethal outcomes, a myocardial infarction (for delay of progressing of coronary atherosclerosis), a stroke and passing disturbances of cerebral circulation.

High risk of development of coronary heart disease (in the presence of a lipidemia or without it), for example, at patients with a diabetes mellitus, at patients with a stroke or other cerebrovascular diseases in the anamnesis, at patients with diseases of peripheral vessels or at patients with coronary heart disease.

Route of administration and doses:

It is necessary to apply daily doses of Simvakora® (from 5 to 80 mg) 1 time a day in the evening. During selection of a dose of Simvakora® of its change it is necessary to carry out bucketed not less than 4 weeks, before achievement of the maximum daily dose of 80 mg, once a day is accepted in the evening.

Patients with the coronary heart disease (CHD) or high risk of development of coronary heart disease.

The standard initial dose of Simvakora® for patients with high risk of development of an ischemic heart disease (in combination with a lipidemia or without it), – patients with a diabetes mellitus, patients with a stroke or other cerebrovascular diseases in the anamnesis, patients with diseases of peripheral vessels, and also for patients with coronary heart disease – makes 40 mg once, in the evening. Medicamentous therapy can be begun along with use of a diet and physiotherapy exercises.

Patients with a hypercholesterolemia (who do not enter above-mentioned categories of risk)

Prior to treatment of Simvakorom® the patient should appoint a standard hypocholesteric diet which has to proceed during all course of treatment.

Usually initial dose makes 20 mg/days, is appointed once in the evening. For patients who need considerable (more than for 45%) decrease in the LPNP level, an initial dose can make 40 mg of 1 times a day in the evening. Patients with an easy or moderate hypercholesterolemia can appoint Simvakor® in an initial dose of 10 mg. Selection of doses, if necessary, is made by the way stated above (see the section "Route of Administration and Doses", Coronary heart disease).

Patients with a homozygous family hypercholesterolemia

Proceeding from results of a controlled research, to patients with a homozygous family hypercholesterolemia симвастатин it is recommended in the dose of 40 mg a day accepted once in the evening or 80 mg a day in 3 receptions: 20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening. To such patients of Simvakor® appoint as addition to other treatment reducing cholesterol level (for example, LPNP a plasma exchange) or without other treatment if it is unavailable.

The accompanying therapy

Симвакор® it is effective in the form of monotherapy, and also in combination with sekvestrant of bile acids.

For the patients accepting cyclosporine gemfibrozit either other fibrata, or lipidosnizhayushchy doses (≥ 1 g/days) Niacinum together with Simvakorom®, the maximum recommended dose of Simvakora® makes 10 mg a day. For patients who along with Simvakorom® accept Amiodaronum or verapamil the daily dose of Simvakora® should not exceed 20 mg (see the sections "Features of Use", subsection a myopathy / рабдомиолиз and "Interaction with other medicines").

Dosage at a renal failure

As Simvakor® is removed by kidneys in a small amount, there is no need of change of a dosage for patients with moderately expressed renal failure.

At a heavy renal failure (clearance of creatinine less than 30 ml/min.), it is necessary to weigh carefully expediency of purpose of drug in the doses exceeding 10 mg a day. If such dosage is considered necessary, it is necessary to appoint them with care.

Dosage at children (10-17 years) with a heterozygous family hypercholesterolemia

Usually initial recommended dose makes 10 mg a day in the evening. It is recommended to accept 10-40 mg a day, the maximum recommended dose makes 40 mg a day. The dose is selected individually according to the recommended treatment.

Features of use:

Use during pregnancy or feeding by a breast.

It is contraindicated during pregnancy, at drug use breastfeeding should be stopped.

Children.

Safety and efficiency of a simvastatin at teenagers (boys, and also at girls who have at least 1 year as periods began) at the age of 10-17 years with a heterozygous family lipidemia was estimated in controlled clinical trial. The profile of side effects at the patients accepting симвастатин was similar to that at the patients accepting placebo. Doses more than 40 mg were not investigated at this group of patients. In a research influence of a simvastatin on growth and sexual development of teenagers, and also on duration of a menstrual cycle at girls was not recorded (see. "Route of administration and doses", "Side reactions").

Girls have to be consulted about contraception methods at use of a simvastatin.

Simvastatin was not investigated at patients more young than 10 years, and also at girls at whom periods did not begin yet.

Myopathy / рабдомиолиз

Simvastatin, as well as other inhibitors of GMG-KOA-reduktazy, can cause development of a myopathy which is shown in the form of muscular pain, of morbidity or the general weakness and is followed by growth of activity of a kreatinfosfokinaza of norm more than 10 times higher than the upper bound. The myopathy can be shown in the form of the rabdomioliz which sometimes is followed by the acute renal failure caused by a myoglobinuria. The risk of a myopathy increases due to increase in the inhibiting activity concerning GMG-KOA-reduktazy in a blood plasma.

The risk of development of a myopathy / рабдомиолиза at therapy simvastatiny increases at a concomitant use of the following drugs:

Powerful CYP3A4 inhibitors итраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, inhibitors of HIV protease and нефазодон, especially in combination with high doses of a simvastatin (see. "Interaction with other medicines and other types of interactions").

Gemfibrozil and other fibrata (except a fenofibrat), especially in combination with high doses of a simvastatin (see. "Interaction with other medicines and other types of interactions"). There are no proofs that at purpose of a simvastatin along with fenofibraty the risk of development of a myopathy exceeds the total risk created by reception of each of these drugs.

Cyclosporine or даназол in combination with high doses of a simvastatin (see. "Interaction with other medicines and other types of interactions").

Amiodaronum or verapamil in combination with high doses of a simvastatin ("Interaction with other medicines and other types of interactions"). During clinical trials it was reported about development of a myopathy in 6% of the patients receiving симвастатин in a dose of 80 mg along with Amiodaronum.

Diltiazem. At the patients receiving diltiazem along with simvastatiny in a dose of 80 mg a day risk of development of a myopathy increases and makes about 1%. The risk of development of a myopathy in the patients receiving diltiazem along with simvastatiny in a dose of 40 mg a day is approximately equal to that at reception of a simvastatin in a dose of 40 mg a day without accompanying diltiazem reception (see. "Interaction with other medicines and other types of interactions").

Niacinum (≥ 1 g a day).

Fuzidinova acid: patients who receive fuzidinovy acid along with simvastatiny can have the increased risk of development of a myopathy (see. "Interaction with other medicines and other types of interactions").

As well as in a case with other inhibitors of GMG-KOA-reduktazy, the risk of development of a myopathy / рабдомиолиза depends on a drug dose.

In clinical trials in which patients did not receive the accompanying therapy the frequency of emergence of a myopathy / рабдомиолиза made about 0,02% at the patients receiving симвастатин in a dose of 20 mg a day, the patients receiving симвастатин in a dose of 40 mg a day have 0,08% and the patients receiving симвастатин in a dose of 80 mg a day have 0,53%.

Measures for decrease in risk of development of a myopathy / рабдомиолиза:

1. It is necessary to avoid a concomitant use of a simvastatin with such drugs: итраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, inhibitors of HIV protease and нефазодон. If therapy by the listed drugs cannot be cancelled, reasonablly to stop therapy simvastatiny for the period of reception of these drugs. The accompanying reception of any of the listed CYP3A4 inhibitors has to be excluded if advantages of a combination therapy do not exceed possible risk.

2. The dose of a simvastatin should not exceed 10 mg a day for the patients accepting cyclosporine даназол or gemfibrozit, other fibrata (except a fenofibrat), or lipidosnizhayushchy doses (≥ 1 g/days) Niacinum (niacin). It is necessary to avoid co-administration of a simvastatin with these drugs if advantages of influence on the level of lipids do not exceed risk of purpose of medicinal combinations. Addition of fibrat or Niacinum to therapy simvastatiny, as a rule, provides small additional decrease in concentration of LPNP, however additional decrease in the TG level and increase in concentration of LPVP can be also reached.

3. Doses of a simvastatin for the patients receiving Amiodaronum or verapamil should not exceed 20 mg. Use of a simvastatin in doses more than 20 mg a day together with Amiodaronum or verapamil is not recommended if only advantages of use of such combination do not exceed potential risk of development of a myopathy.

4. The patients accepting fuzidinovy acid together with simvastatiny have to be under careful observation. It must be kept in mind a possibility of the termination of treatment simvastatiny at reception of fuzidinovy acid.

5. All patients beginning therapy simvastatiny, and also patients who need to increase a drug dose need to be preduprezhdit about possibility of a myopathy and need of the immediate address to the doctor in case of developing of any pains of not clear character, morbidity in muscles or muscular weakness. Therapy simvastatiny should be stopped immediately if the myopathy is diagnosed or it is supposed. Existence of above-mentioned symptoms and/or increase in level of a kreatinfosfokinaza, more than 10-fold in comparison with the upper bound of norm, indicate existence of a myopathy. In most cases after the immediate termination of reception of a simvastatin symptoms of a myopathy disappear, and the level of a kreatinfosfokinaza decreases. At the beginning of therapy simvastatiny or at increase in doses of drug it is reasonable to carry out periodic determination of level of a kreatinfosfokinaza, however there are no reliable data that such monitoring is capable to prevent development of a myopathy.

6. Many patients at whom developed рабдомиолиз during therapy simvastatiny had the complicated anamnesis, including had a renal failure, as a rule, owing to a long-term diabetes mellitus. Such patients demand as much as possible careful observation. Therapy simvastatiny has to be suspended at patients some days before performance of big operative measures, and also in the postoperative period.

Influence on a liver

In clinical trials at some adult patients receiving симвастатин steady increase in level of liver enzymes was noted (more than 3 times above the upper bound of norm). At drug withdrawal activity of transaminases usually gradually is returned to initial level. Increase in level of transaminases was not followed by jaundice or other clinical symptomatology. These reactions are not connected with hypersensitivity. Some of patients had deviations of indicators of function of a liver prior to therapy simvastatiny and/or consumed excess amount of alcohol.

Before an initiation of treatment, and then according to clinical indications, all patients are recommended to carry out functional hepatic trials. Patients at whom it is planned to raise a dose of a simvastatin to 80 mg a day should carry out functional hepatic trials prior to the beginning of a titration, then in 3 months after achievement of a dose of 80 mg a day then periodically to repeat (for example, 1 time in half a year) during the whole first year of treatment. Special attention should be paid to patients at whom the level of serumal transaminases is increased. To these patients control of function of a liver has to be carried out timely in an initiation of treatment and a thicket further. When the level of transaminases increases, especially at steady exceeding by 3 times of the upper bound of norm, drug it is necessary to cancel.

At treatment simvastatiny, as well as other hypolipidemic means, observed moderated (less than 3 times higher than the upper bound of norm) increase in activity of serumal transaminases. These changes appeared soon after an initiation of treatment, often had passing character, were not followed by any symptoms and did not demand therapy cancellation.

Ophthalmologic inspection.

In the absence of any drug treatment increase in the area of a phacoscotasmus is considered a consequence of process of aging. Data of long-term clinical tests known for today do not indicate existence of an adverse effect of a simvastatin on lens of the person.

Use for elderly people.

Efficiency of use of a simvastatin for treatment of patients is more senior than 65 years receiving it during controlled clinical trials which was estimated concerning decrease in levels of the general cholesterol and LPNP cholesterol, it turned out same, as well as for population in general. Increase in frequency of side effects which would come to light clinically or laboratory indicators, is noted.

As drug contains lactose, it needs to be considered at use by the patient with a hereditary lactose intolerance.

Grapefruit juice in large numbers increases Cmax and AUC of a simvastatin and risk of a myopathy (their simultaneous use is not recommended).

Ability to influence speed of response at control of motor transport or work with other mechanisms.

There are no data.

Side effects:

From the alimentary system: dyspepsia (nausea, vomiting, gastralgia, abdominal pain, lock or diarrhea, meteorism), hepatitis, cholestatic jaundice, increase in activity of "hepatic" transaminases and alkaline phosphatase, kreatinfosfokinaza; very seldom – acute pancreatitis, a liver failure.

From a nervous system and sense bodys: adynamy, dizziness, headache; deterioration, memory loss, a sleep disorder, including sleeplessness, nightmares; depression, spasms, paresthesias, peripheral neuropathy, illegibility of visual perception, disturbance of flavoring feelings.

From a musculoskeletal system: myopathy, mialgiya, myasthenia; seldom – рабдомиолиз.

Allergic and immunopathological reactions: skin rash, a small tortoiseshell, an itch, an alopecia, a Quincke's disease, a volchanochnopodobny syndrome, a rheumatic polimialgiya, a vasculitis, thrombocytopenia, an eosinophilia, increase SOE, arthritis, an arthralgia, a photosensitization, fever, a dermahemia, "inflows" of blood to the person, an asthma, a dermatomyositis, heat.

Others: anemia, heartbeat, an acute renal failure (owing to a rabdomioliz), an intersticial disease of lungs, sexual dysfunction, decrease in a potentiality, weakness, an indisposition.

Interaction with other medicines:

Simvastatin is metabolized by CYP3A4, however has no the inhibiting activity concerning this coenzyme. Therefore influence of a simvastatin on concentration in a blood plasma of the medicines which are metabolized under the influence of CYP3A4 is not expected. Powerful CYP3A4 inhibitors increase risk of a myopathy due to reduction in the rate of removal of a simvastatin. Treat such means: итраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, HIV protease inhibitors, нефазодон (see the section "Features of Use").

Cyclosporine or даназол. The risk of development of a myopathy / рабдомиолиза increases at the combined purpose of cyclosporine or даназол with high doses of a 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 drugs which are not powerful CYP3A4 inhibitors, but are capable to cause a myopathy in the conditions of monotherapy. Such drugs are:

Gemfibrozil and other fibrata (except a fenofibrat at whose combined reception with simvastatiny the risk of emergence of a myopathy does not exceed that at monotherapy by each of drugs separately), especially with high doses of a simvastatin, and also Niacinum (niacin) in a dose ≥ 1 g a day (see the section "Features of Use").

Amiodaronum and verapamil: the risk of development of a myopathy increases at joint reception of Amiodaronum or verapamil with high doses of a simvastatin (see the section "Features of Use").

Diltiazem: the risk of development of a myopathy slightly increases at the patients receiving diltiazem along with simvastatiny in a dose of 80 mg (see the section "Features of Use").

Fuzidinovy acid: the patients receiving fuzidinovy acid along with simvastatiny can have the increased risk of development of a myopathy (see the section "Features of Use").

Other medicinal interactions.

Coumarin derivatives.

Simvastatin in a dose of 20-40 mg a day slightly exponentiates effect of coumarinic anticoagulants: the prothrombin time (the International Normalized Relation – MNO) increases at healthy volunteers from 1,7 to 1,8 and at patients with a hypercholesterolemia from 2,6 to 3,4. At the patients accepting coumarinic anticoagulants, the prothrombin time or MNO have to be defined prior to therapy simvastatiny, and also is rather frequent in an initiation of treatment. As soon as the stable level of an indicator of a prothrombin time or MNO 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 a simvastatin it is also necessary to carry out control of a prothrombin time or MNO according to the above scheme. Therapy simvastatiny does not cause changes of a prothrombin time and risk of bleedings in the patients who were not accepting anticoagulants.

Other types of interaction.

Juice of grapefruit contains one or more components which inhibit CYP3A4 and can increase concentration in a blood plasma of the drugs which are metabolized CYP3A4. Increase in activity of inhibitors of GMG-KOA-reduktazy after the use of 250 ml of juice a day is maximum, makes 13% and has no clinical value. However consumption of a large amount of juice (more than 1 liter a day) at reception of a simvastatin considerably increase the level of the inhibiting activity concerning GMG-KOA-reduktazy in a blood plasma. Therefore it is necessary to avoid consumption of a large amount of juice of grapefruit (see the section "Features of Use").

Contraindications:

• Hypersensitivity to any component of drug.
• Liver diseases in an acute stage or unclear and permanent increase in levels of transaminases of serum.
• A myasthenia and/or the expressed increase in activity of a kreatinfosfokinaza (exceeds the upper bound of norm by 10 times).
• Need of simultaneous treatment by strong inhibitors of CYP3A4 cytochrome, such, as итраконазол, кетоконазол, флуконазол, позаконазол, HIV protease inhibitors (for example, нелфинавир), erythromycin, кларитромицин, телитромицин and нефазодон.
• Pregnancy or the period of feeding by a breast (see also "Features of use").

Overdose:

Several cases of overdose of a simvastatin, at the same time are known at one of patients specific symptoms and his effects are noted. The maximum accepted dose made 3,6 g.

Treatment: symptomatic, it is necessary to cause vomiting, to wash out a stomach, purpose of absorbent carbon, control of vital signs, functions of a liver and activity of KFK is necessary; the specific antidote does not exist, the hemodialysis is inefficient.

Storage conditions:

Term godnosti.1,5 years. To store in the place, unavailable to children, in original packaging at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in a blister strip packaging; on the 2nd blister strip packagings in a pack.