Simlo - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 75,500 mg, starch corn 10,180 mg, pregelatinized starch 1,250 mg, sodium carboxymethyl starch (type A) 7,500 mg, silicon dioxide colloid 1,200 mg, butyl hydroxytoluene 0.020 mg, citric acid monohydrate 1,250 mg, ascorbic acid 2,500 mg, cellulose microcrystalline 9,400 mg, magnesium stearate 1,200 mg.

- Sheath: hypromellose 1,200 mg, talc 0,520 mg, titanium dioxide 0,520 mg, iron dye yellow oxide 0,002 mg, iron dye oxide red 0,038 mg, macrogol-400 0,120 mg ..

Each tablet coated with a film coating of 20 mg contains: -

Active substance: simvastatin 20,000 mg '

Excipients: lactose monohydrate 151,000 mg, corn starch 20,360 mg, pregelatinized starch 2,500 mg, sodium carboxymethyl starch (type A) 15,000 mg, silicon dioxide colloid 2,400 mg, butyl hydroxy toluene 0.040 mg, citric acid monohydrate. 2,500 mg, ascorbic acid 5,000 mg, microcrystalline cellulose 18,800 mg, magnesium stearate 2,400 mg.

Sheath: hypromellose 2,400 mg, talc 1,040 mg, titanium dioxide 1,040 mg, iron dye oxide yellow 0.044 mg, iron dye oxide red 0.036 mg, macrogol-400 0.240 mg.

Description:

Dosage of 10 mg: Oval biconvex tablets covered with a film shell of light pink color, engraved "BL" on one side and "10" on the other. On a cross-section: the nucleus is from white to almost white with a yellowish hue of color.

Dosage of 20 mg: Oval biconvex tablets covered with a filmy coating of light pink with a weak yellowish hue of color, engraved "BL" on one side and "20" on the other. On a cross-section: the nucleus is from white to almost white with a yellowish hue of 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:

The active substance of Simlo® is simvastatin, the main effect of which is the reduction of total cholesterol and low-density lipoprotein (LDL) cholesterol in the blood plasma. It is an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid (early stage of cholesterol synthesis). Simvastatin reduces the concentration of total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides. The concentration of very low density lipoprotein cholesterol (VLDL) also decreases, while the concentration of high-density lipoprotein (HDL) moderately increases. Reduces the concentration of total cholesterol and LDL in cases of heterozygous family and non-family forms of cholesterolemia, with mixed hyperlipidemia, when elevated cholesterol concentration is a risk factor. Simvastatin helps reduce the concentration of total cholesterol and LDL cholesterol in patients with coronary heart disease, thereby reducing the risk of myocardial infarction and death for these patients.

Simvastatin also significantly reduces the concentration of apolipoprotein B, moderately increases HDL cholesterol concentrations and lowers plasma concentrations of triglycerides (TG). As a result of these effects, simvastatin decreases the ratio of total cholesterol (OX) to HDL cholesterol (OX/ HDL) and LDL cholesterol to HDL cholesterol (LDL / HDL).

The antiatherosclerotic effect of simvastatin is a consequence of exposure simvastatin on the walls of blood vessels and components. Simvastatin changes the metabolism of macrophages, inhibiting the activation of macrophages and the destruction of atherosclerotic plaques. Simvastatin 'suppresses the synthesis of isoprenoids, which are growth factors in the proliferation of smooth muscle. cells of the inner shell of the vessels. Under the action of simvastatin, endothelium-dependent enlargement is improved. blood vessels. The therapeutic effect develops in 2 weeks, the maximum effect is observed after 4-6 weeks of treatment.

Pharmacokinetics:

Simvastatin is presented in an inactive lactone form, which is relatively well absorbed (from 61% to 85%) from the gastrointestinal tract. Bioavailability is less than 5%.After oral administration, the maximum therapeutic concentration in the blood plasma (FROM_max)achieved in 1-2 hours and reduced by 90 % after 12 hours. Simultaneous food intake does not affect the absorption of simvastatin. With prolonged administration of cumulation, simvastatin does not occur in the body.

Communication with blood plasma proteins is 98%.

Simvastatin is a substrate of isoenzyme CYP3A4. It is metabolized in the blood, has the effect of "primary passage" through the liver (basically hydrolyzed in its active form, beta hydroxy acid). The possibility of the penetration of simvastatin through the blood-brain barrier and the hematoplacental barrier has not been studied. It is mainly excreted through the intestine (60%) in the form of metabolites. About 13% is excreted by the kidneys in an inactive form. The half-life of active metabolites (T1/2) is 1.9 hours.

Indications:

Hyperlipidemia (type Pa and Pb according to Fredrickson) 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; hyperlipoproteinemia that can not be corrected by special diet and exercise;

- / homozygous hereditary hypercholesterolemia (as an adjunct to hypolipidemic therapy);

ischemic heart disease (secondary prevention):

the drug is indicated to patients to reduce overall mortality; with the aim of reducing the risk of coronary mortality and preventing myocardial infarction; with the aim of reducing the risk of stroke and transient cerebral circulatory disorders; with the aim of slowing progressing coronary atherosclerosis

Contraindications:

- hypersensitivity to simvastatin or to others components of the drug, as well as to other drugs statin series (inhibitors GMK-CoA- reductase) in the anamnesis;

- lactase deficiency, intolerance lactose, glucose-galactose malabsorption;

- liver disease in the active phase or persistent increase activity "hepatic" transaminases of unclear etiology;

- Skeletal Muscle Disease (myopathy);

- simultaneous reception strong inhibitors of isoenzymes cytochrome P450 (isoenzyme CYP3A4) (eg, itraconazole, ketoconazole, posaconazole, voriconazole,

bocetrevir,telaprevir, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone, preparations containing kobitsystat), concomitant treatment with gemfibrozil, cyclosporin, danazol (cm. sections "Interaction with other medicines", "Special instructions"),

pregnancy and period breastfeeding;
age under 18 years (efficacy and safety of use not studied)

Carefully:

Patients, patients with alcoholism, patients after organ transplantation, who undergo immunosuppressant therapy (due to an increased risk of rhabdomyolysis and renal insufficiency); at conditions that can lead to the development of a pronounced deficiency of kidney function, such as arterial hypotension, acute infectious diseases of severe course, pronounced metabolic and endocrine disorders, disturbances of water electrolyte balance, surgical interventions (including dental) or trauma; patients with decreased or increased tone of skeletal muscles of unknown etiology; from epilepsy, uncontrollable convulsions; at simultaneous admission with fibrates (except gemfibrozil - see section Contraindications"), nicotinic acid in lipid-lowering doses (more than 1 g / day), amiodarone, verapamil, diltiazem, Amlodipine, ranolazine, dronedarone, colchicine, fusidic acid (due to increased risk of myopathy and rhabdomyolysis), grapefruit juice; at severe renal failure (clearance creatinine less than 30 ml / min), (see the sections "Method of administration and dose", "Interaction with other drugs", "Special instructions").

Dosing and Administration:

Inside, once in the evening. The time of reception should not be associated with food intake. Before starting treatment with the drug Simlo The patient should be assigned a standard hypocholesterol diet, which must be observed throughout the course of treatment. Recommended doses for the treatment of hypercholesterolemia are from 5 to 80 mg per day.

HMost often the initial dose of Simlo is 10 mg. Changes (selection) of the dose should be carried out at intervals of not less than 4 weeks.

The maximum daily dose is 80 mg. A dose of 80 mg should be given only to patients who did not achieve the desired LDL result with a dose of 40 mg.In most patients, the optimal effect is achieved when taking the drug at a dose of 20 mg per day. The maximum daily dose is recommended only for patients with severe hypercholesterolemia or a high risk of cardiovascular complications and in the event that the intended benefit of treatment exceeds the potential risk. The duration of the drug is determined by the doctor individually. In elderly patients and in patients with moderate renal insufficiency changes in the dosage of the drug do not tRequired.

With renal insufficiency

Simvastatin is excreted by the kidneys in an insignificant amount, therefore, when used in patients with moderate renal impairment (creatinine clearance more than 30 ml / min), there is no need for correction of doses. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the recommended dose of simvastatin should not exceed 10 mg / day.

Hypercholesterolemia The recommended initial dose of the drug for patients with hypercholesterolemia is 10 mg. With a view to a more pronounced decrease in the concentration of LDL cholesterol (more than 45%), treatment can be started from 20-40 mg per day (once in the evening).

In patients with hereditary hypercholesterolemia (type Pa), the recommended daily dose of the drug Simlo is 40 mg inin the evening or 80 mg in 3 doses (20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening); to these patients recommended in combination with another lipid-lowering therapy (eg, apheresis of LDL). A dose of 80 mg is recommended to be prescribed only if the expected benefit of therapy exceeds the possible risk.

Cardiovascular prevention

In the treatment patients with ischemic heart disease (CHD) or with a high risk of CHD development is prescribed in an initial dose of 20 mg per day in the evening; if necessary, the dose is gradually increased every 4 weeks to 40 mg. If the LDL content is less than 75 mg / dL (1.94 mmol / L), the total cholesterol concentration is less than 140 mg / dL (3.6 mmol / L), the dose of the drug should be reduced. In patients with ischemic heart disease (CHD) and having additional risk factors for complications withabout the cardiovascular system, such as diabetes mellitus, peripheral vascular disease, cerebral vascular lesions or a history of stroke, the recommended initial daily dose of simvastatin is 40 mg per day.

Concomitant therapy

Simlo® is effective as at monotherapy, and in combination with bile acid sequestrants (eg, colestramine and Colestipol). Have patients, receiving treatment with fibrates (except gemfibrozil - see the section "Contraindications" or fenofibrate), and nicotinic acid in lipid-lowering doses (more than 1 g / day), the recommended initial dose of the Simlo drug is 5 mg, the maximum daily dose is 10 mg. Further increase in dose in such situations is not recommended. In patients simultaneously receiving verapamil, diltiazem, dronedaron daily doses of the drug imlo should not exceed 10 mg. For patients who simultaneously take amlodipine, amiodarone, ranolazine The daily dose of the Simlo® preparation should not exceed 20 mg.

If a patient taking Simlo's preparation at a dose of 80 mg per day needs treatment with another drug that can interact with simvastatin, then it is necessary to lower the dose of the drug Simlo or prescribe another drug statin series that has less potential for possible drug interaction (see section "Interaction with other drugs").

Side effects:

Classification of incidence of adverse events (according to the World Organization

Health - WHO):

Very often> 1/10

Frequently from> 1/100 to <1/10

Infrequently from> 1/1000 to <1/100

Rfrom> 1/10000 to <1/1000

Very rarely from <1/10000, including individual messages

Frequency is not known - can not be calculated by available data.

From the digestive side

system: rarely - constipation, abdominal pain, flatulence, dyspepsia, nausea, vomiting, diarrhea, acute pancreatitis, hepatitis, cholestatic jaundice, increase activity "hepatic" transaminase, alkaline phosphatase, creatine phosphokinase (CK);

highly rare - fatal and non-fatal liver failure.

From the nervous system and sense organs: rarely - head pain, paresthesia, dizziness, peripheral neuropathy, asthenia, blurred vision taste sensations; insomnia, cramps, memory impairment, depression, nightmares.

From the side of the locomotor system apparatus: rarely - myopathy, rhabdomyolysis, myalgia, muscle

convulsions; frequency unknown -

tendonopathy, possibly with a rupture

tendons.

Allergic and

immunopathological reactions:

rarely - developed syndrome

hypersensitivity:

angioedema,

lupus-like syndrome,

rheumatic polymyalgia,

dermatomyositis, vasculitis,

thrombocytopenia, eosinophilia,

increase in settling velocity

erythrocytes, arthritis, arthralgia,

urticaria, photosensitivity, fever, "hot flushes" of blood to the face, shortness of breath and severe weakness; very rarely - immunosupplemented necrotizing myopathy (autoimmune myopathy). From the skin: rarely - skin rash, itching, alopecia. On the part of the respiratory system: frequency unknown - interstitial lung disease.

FROMabout the sides of the hematopoiesis: rarely anemia

Other: rarely - sensation heart beat, acute renal failure (due to rhabdomyolysis), decreased potency. When some statins were used, gynecomastia was observed,increase of glycosylated hemoglobin, activity of gamma-glutamyltranspeptidase.

Overdose:

In none of the known few cases of overdose (the maximum dose of 3.6 g) specific symptoms were identified.

Treatment: in case of an overdose, symptomatic treatment is performed; it is necessary to carry out general measures: monitoring and maintaining vital functions, preventing further absorption of the drug (gastric lavage, intake of activated charcoal or laxatives). It is recommended to monitor the liver function and the activity of CK in the blood serum. There is no specific antidote.

In the development of myopathy with rhabdomyolysis and acute renal failure (a rare but severe side effect), stop taking the medication immediately, administer the patient diuretic and sodium hydrogen carbonate (intravenous infusion). Rhabdomyolysis can cause hyperkalemia, which can be eliminated by intravenous administration of calcium chloride and calcium gluconate, infusion of 5 % solution of dextrose (glucose) with insulin of short action, using potassium ion exchangers or, in severe cases, by hemodialysis.

Interaction:ABOUTsimultaneous application simvastatin with fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day) increases the risk of myopathy, including rhabdomyolysis (with simultaneous use with fenofibrate - no evidence of an increaserisk of development of myopathy in comparison with monotherapy with each drug alone). Also, the risk of developing myopathy increases with the simultaneous use of simvastatin with fusidic acid, colchicine.

Pharmacokinetic interactions

Strong inhibitors of isoenzyme cytochrome CYP3A4 (itraconazole, ketoconazole, posaconazole, bocetrevir, telaprevir, erythromycin, clarithromycin, telithromycin, voriconazole, HIV protease inhibitors and nefazodone, preparations containing kobitsystat), participating in metabolic transformation simvastatin in the liver, increase risk of myopathy and rhabdomyolysis with therapy simvastatin. Simultaneous use with these drugs it is contraindicated. It is necessary with caution at the same time assign simvastatin with less strong inhibitors isoenzyme CYP3A4: verapamil, diltiazem, dronedarone.

The daily dose of simvastatin on the background ofsimultaneous reception of verapamil, diltiazem, dronedarone and fibrates (except fenofibrate) should not exceed 10 mg, and on the background of simultaneous reception amiodarone and ranolazine - 20 mg, if only the expected benefit clearly does not exceed the potential risk development of myopathy and rhabdomyolysis. The maximum daily dose simvastatin should not exceed 20 mg with its joint with amlodipine.

In patients taking fusidic acid or colchicine at the same time with simvastatin, may increase the risk of developing myopathy, so their simultaneous application is not

recommended. In exceptional cases with combined treatment with these drugs therapy should be conducted under a thorough medical observation.

Simvastatin in a dose of 20-40 mg / day in volunteers and patients with gand cholesterolemia potentiates Effects coumarin anticoagulants (eg,

warfarin), in particular an increase prothrombin time,

International normalized relationship (INR). Therefore y patients, host coumarin anticoagulants,

prothrombin time and MNO must be determined before

initiation of therapy simvastatin, in initial period of treatment, with change in dose simvastatin or cancellation of the drug. When stable indicator prothrombin time and INR, further control is necessary carry out with intervals, recommended for patients, receiving therapy anticoagulants.

Therapy simvastatin does not cause changes prothrombin time and risk bleeding in patients not host anticoagulants.

DRheypfruit juice suppresses the activity of the isoenzyme CYP3A4. Simultaneous reception of a large amount of grapefruit juice (more than 1 liter per day) and simvastatin leads to a significant increase concentration in the blood plasma of simvastatin acid. Therefore, during the treatment with simvastatin, grapefruit juice should be avoided.

Special instructions:Have patients with reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephrotic syndrome) with increasing concentration

Cholesterol should be first conduct therapy underlying the disease.

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

During the treatment with the drug Simlo Women of reproductive age should applyAdequate means of contraception.Treatment with simvastatin, like other inhibitors of HMG-CoA reductase, can cause

myopathy, sometimes resulting in rhabdomyolysis with or without renal insufficiency,

as a consequence of myoglobinuria. The risk of myopathy increases with an increase in the dose of the drug "Simlo" and patients with severe renal failure. Among

predisposing factors for the development of myopathy are isolated

elderly age (over 65 years), belonging to the female sex, uncontrolled hypothyroidism and impaired renal function.

When treating with the drug Simlo "possible increase activity serum creatine phosphokinase (CK), which should be taken into account in the differential diagnosis of chest pain and after intensive physical exertion.

Before starting therapy with Simlo® or increasing its dose Patients should be informed about risk of myopathy and need immediately seek medical advice if the appearance of unexplained pain, tension or weakness in the muscles, especially if it is accompanied by malaise or fever.

Initial activity of CKB before initiation of therapy is necessary

determine in the following situations:

- in elderly patients;

- with kidney damage;

- with uncontrolled hypothyroidism;

- with a burdened family a history of hereditary muscle diseases;

- if there is an anamnesis toxic effects on muscles of statins or fibrates;

- at patients, patients alcoholism.

It is necessary to assess the possible risk and the expected benefit and during therapy is recommended clinical monitoring on the background of therapy. Ifsimilar activity of CKF

significantly increased (more than 5 times the upper limit of the norm), the measurement should be repeated after 5-7 days to confirm the results. With a significant initial increase in the activity of CK (more than 5 times the upper limit of the norm), the drug should not be prescribed.

Before and during the course of treatment, the patient should be on a hypocholesterol diet.

During treatment with the drug Simlo® when muscle pain, weakness or cramps occur, it is necessary to determine activity CKF. The criterion for the discontinuation of the drug is an increase activity CK in the serum more than 5 times higher than the normal limit. If the muscle symptoms are severe and cause discomfort, even with the activity of CK less than 5 times the upper limit of the norm, should stop treatment. When suspected myopathy therapy it is necessary to stop, outside dependence on the cause of myopathy.

If the symptoms disappear, and activity KFK returned to normal level, possibly re-administration of a statin or alternative preparation of the same class in the minimum clinically effective dose and under careful medical supervision. Therapy with the preparation of Simlo is necessary temporarily stop for a few days before extensive surgical interventions, as well as in postoperative period.

Patients with severe renal disease Insufficiency treatment is carried out under the control of kidney function.

Measures to reduce the risk myopathy caused by medicinal interactions

Risk of myopathy and rhabdomyolysis significantly increases with simultaneous application of Simlo and strong inhibitors of CYP3A4 (eg: itraconazole, ketonosol, pozanosol, HIV protease inhibitors, bocetrevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, voriconazole, drugs containing the co-cystatite), gemfibrozil, cyclosporine or danazol (see " Contraindications "," Interactions with other drugs ").Risk development of Myopathy and rhabdomyolysis also increases when combined simvastatin with fusidic acid, colchicine, fibrates (except fenofibrate), high doses of nicotinic acid (at lipid-lowering doses - more than 1 g / day) or with combined therapy drugs amiodarone, amlodipine, ranolazine, verapamil, dronedaron with high doses of the drug Simlo (see "Interaction with other medicinal products. means ", "Method of administration and dose"). The risk also increases somewhat with the simultaneous administration of diltiazem and high doses of the drug Simlo (80 mg). Consequently, the application of preparation of Simlo concomitantly with itraconazole, ketoconazole, posaconazole, boceprevirov, telaprevir, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone and voriconazole, drugs containing cobicystate contraindicated (see section "Contraindications"). If you can not abandon the therapy listed strong inhibitors of isoenzyme CYP3A4, should refrain from prescribing Simlo. Simlo It is also necessary to combine with caution with some others, less strong inhibitors of isoenzyme CYP3A4: ineparamil, diltiazem and dronedarone (see section "Interaction with other drugs", "Method of administration and dose"). Simultaneous administration of Simlo should be avoided and

grapefruit juice.

Combined treatment simvastatin and fusidic acid is also not recommended.

In patients taking high doses of nicotinic acid in lipid-lowering doses (more than 1 g / day), other fibrates (except fenofibrate), and verapamil, diltiazem, dronedaron daily dose of the drug Simlo should not exceed 10 mg. Benefits their combined use from with the preparation of Simlo in a dose higher 10 mg per day should be carefully weighed taking into account the potential risk of such combinations.

There is a risk of development of myopathy in the appointment of fenofibrate separately and Simlo therefore Care must be taken when taking this combination at the same time.

When you receive Simlo in doses exceeding 20 mg per day, simultaneous administration of amiodarone, amlodipine, and ranolazine should be avoided.

The data of modern long-term studies do not contain information on the adverse effects of simvastatin on the lens of the human eye.

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

During the treatment period, care must be taken when driving a vehicle and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets film-coated 10 mg, 20 mg.

Packaging:

10 or 14 tablets in an aluminum foil blister and PVC / PVDC film.

2 blisters for 14 tablets or 3 blisters for 10 tablets in a cardboard box, along with instructions for use.

When, the destruction of unused packages of the drug, special precautions are not required.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013619 / 01-2002

Date of registration:05.10.2011

The owner of the registration certificate:Ipka Laboratories Ltd.Ipka Laboratories Ltd. India

Manufacturer: & nbsp

IPCA LABORATORIES, Ltd. India

Information update date: & nbsp31/07/2015

Illustrated instructions

Instructions

Simlo® (Simlo® )