Simvastatin-ALSI, 10 mg 30 pcs

Hypolipidemic agent obtained synthetically from Aspergillus terreus fermentation product is an inactive lactone, it undergoes hydrolysis in the body to form a hydroxy acid derivative. The active metabolite inhibits 3-hydroxy-3-methylglutaryl-CoA reductase ‑(HMG-CoA reductase), the enzyme that catalyzes the initial reaction of mevalonate formation from HMG-CoA. Since the conversion of HMG-CoA to mevalonate represents an early step in cholesterol synthesis, Simvastatin administration does not cause 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 decreases plasma levels of triglycerides (TG), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL) and total cholesterol (in cases of heterozygous familial and non-familial forms of hypercholesterolemia, mixed hyperlipidemia, when elevated cholesterol is a risk factor).

Enhances high-density lipoprotein (HDL) and decreases the ratio of LDL/HDL and total cholesterol/HDL.

The onset of the effect is 2 weeks after the start of administration, the maximum therapeutic effect is achieved after 4-6 weeks. The effect is maintained during continuation of treatment, when therapy is discontinued cholesterol content gradually returns to baseline levels.

Indications

Hypercholesterolemia:

Ischemic heart disease:

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

Active ingredient

Composition

One film-coated tablet contains:

the active ingredient:

simvastatin – 10 mg;

excipients:

Microcrystalline cellulose – 70.00 mg,

lactose monohydrate (milk sugar) – 21.00 mg,

pregelatinized starch (starch 1500) – 33.73 mg,

colloidal silica (aerosil) – 0.75 mg,

ascorbic acid – 2.50 mg,

butyl hydroxyanisole – 0.02 mg,

stearic acid – 1.25 mg,

magnesium stearate – 0.75 mg,

polyvinyl alcohol – 2.33 mg,

macrogol (polyethylene glycol) – 1.18 mg,

Magnesium dye black iron oxide – 0.02 mg,

dermal taccharide – 2.33 mg./p>

talcum powder – 0.86 mg,

iron oxide yellow dye – 0.28 mg,

Red iron oxide dye – 0.19 mg,

Titanium dioxide – 0.97 mg.

Interaction

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

Cyclosporine or danazole: the risk of myopathy/rhabdomyolysis is increased when cyclosporine or danazole are coadministered with high doses of Simvastatin.

Other hypolipidemic agents that may cause myopathy: the risk of myopathy is increased by co-administration of other hypolipidemic agents that are not potent CYP3A4 inhibitors but that may cause myopathy with monotherapy. Such as gemfibrozil and other fibrates (except fenofibrate), as well as nicotinic acid at a dose ≥ 1 g per day.

Amiodarone and verapamil: the risk of myopathy increases when coadministering amiodarone or verapamil with high doses of Simvastatin.

Diltiazem: the risk of myopathy is slightly increased in patients receiving diltiazem concomitantly with Simvastatin at a dose of 80 mg.

Simvastatin potentiates the effect of oral anticoagulants (e.g., phenprocoumon, warfarin) and increases the risk of bleeding, which requires monitoring of blood clotting prior to treatment, and often enough during the initial period of therapy. Once a stable level of prothrombin time or International Normalized Ratio (INR) is achieved, it should be further monitored at intervals recommended for patients receiving anticoagulant therapy. If the dosage is changed or Simvastatin is discontinued, prothrombin time or INR should also be monitored according to the above scheme.

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

Elevates plasma levels of digoxin.

Colestyramine and colestipol reduce bioavailability (Simvastatin can be used 4 hours after taking these drugs, with an additive effect).

Grapefruit juice contains one or more components that inhibit CYP3A4 and may increase the plasma concentration of drugs metabolized by CYP3A4. The increase in HMG-CoA reductase inhibitor activity after consuming 250 ml of juice per day is minimal and of no clinical significance. However, consumption of a large volume of juice (more than 1 liter per day) while taking Simvastatin significantly increases the level of inhibitory activity against HMG-CoA reductase in plasma. In this regard, consumption of grapefruit juice in large quantities should be avoided.

Directions for use

Prior to treatment with Simvastatin, the patient should be prescribed a standard hypocholesterolemic diet, which should be followed during the entire course of treatment.

Simvastatin should be taken orally once a day in the evening with plenty of water.

The timing of the drug should not be associated with food intake.

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

Changing (adjusting) the dose should be done at 4 week intervals. In most patients the optimal effect is achieved with doses of up to 20 mg daily.

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

When treating patients with coronary heart disease (CHD) or high risk of CHD, effective doses of Simvastatin are 20-40 mg daily. Therefore, the recommended starting dose in such patients is 20 mg per day. The dose should be changed (adjusted) at intervals of 4 weeks, if necessary, the dose can be increased to 40 mg per day. If LDL content is less than 75 mg/dl (1.94 mmol/l), total cholesterol – less than 140 mg/dl (3.6 mmol/l), the drug dose should be reduced.

In elderly patients and in patients with mild to moderately severe renal failure no changes in the dosage of the drug are required.

In patients with chronic renal insufficiency (creatinine clearance less than 30 ml/min) or those receiving cyclosporine, 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 daily.

For patients taking amiodarone or verapamil concomitantly with Simvastatin, the daily dose should not exceed 20 mg.

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Special Instructions

In the beginning of Simvastatin therapy a transient increase in the level of “hepatic” enzymes is possible.

Liver function tests should be performed regularly before initiating therapy and thereafter (monitor the activity of “liver” enzymes every 6 weeks for the first 3 months, then every 8 weeks for the remaining first year, and then once every six months), and a liver function test should be performed when increasing doses. If the dose is increased to 80 mg, a test should be performed every 3 months. If there is a persistent increase in transaminase activity (3 times the baseline level), Simvastatin should be discontinued.

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

The withdrawal of hypolipidemic agents during pregnancy has no significant effect on the results of long-term treatment of primary hypercholesterolemia.

In patients with reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephrotic syndrome) when cholesterol levels increase, therapy of the underlying disease should be given first.

Simvastatin is prescribed with caution in people who abuse alcohol and/or have a history of liver disease.

The patient should be on a hypocholesterolemic diet before and during treatment.

The concomitant administration of grapefruit juice may increase the severity of side effects associated with Simvastatin administration, so concomitant administration should be avoided.

Simvastatin is not indicated in cases with hypertriglyceridemia types I, IV and V.

The treatment with Simvastatin may cause myopathy leading to rhabdomyolysis and renal failure. The risk of this pathology increases in patients receiving one or more of the following drugs simultaneously with Simvastatin: fibrates (gemfibrozil, fenofibrate), cyclosporine, nefazadone, macrolides (erythromycin, clarithromycin), antifungal agents of azole group (ketoconazole, itraconazole) and HIV protease inhibitors (ritonavir). The risk of myopathy also increases in patients with severe renal insufficiency.

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 seek immediate medical attention in case of unexplained pain, muscle soreness, lethargy or muscle weakness, especially if accompanied by malaise or fever. Therapy with the drug should be stopped immediately if myopathy is diagnosed or suspected.

In order to diagnose the development of myopathy, regular measurements of CPK are recommended.

The treatment with Simvastatin may increase serum CPK, which should be considered in differential diagnosis of chest pain. The criterion for discontinuation of the drug is an increase in serum CPK more than 10 times the upper limit of normal. In patients with myalgia, myasthenia and/or marked increase of CPK activity, the drug shall be discontinued.

The drug is effective both as monotherapy and in combination with bile acid sequestrants.

If the current dose is missed, the drug should be taken as soon as possible. If it is time for the next dose, the dose should not be doubled.

Patients with severe renal insufficiency should be treated under monitoring of renal function.

The duration of use of the drug is determined by the attending physician individually.

Influence on driving and operating machinery

No adverse effects of the drug on driving and operating machinery have been reported.

Synopsis

Features

The absorption of Simvastatin is high. After oral administration the maximum concentration in blood plasma is reached after about 1.3-2.4 hours and decreases by 90% after 12 hours. The binding to plasma proteins is about 95%.

It is metabolized in the liver, has a “first pass” effect through the liver (it is hydrolyzed with the formation of the active derivative: beta-hydroxy acid, other active and inactive metabolites have also been found). The elimination half-life of active metabolites is 1.9 hours.

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

Contraindications

Side effects

Digestive system disorders: abdominal pain, constipation, flatulence, nausea, diarrhea, pancreatitis, vomiting, hepatitis, increased activity of “liver” enzymes, alkaline phosphokinase and creatine phosphokinase (CPK).

Nervous system and sensory system disorders: asthenic syndrome, headache, dizziness, insomnia, muscle cramps, paresthesias, peripheral neuropathy, blurred vision, taste disorders.

Musculoskeletal system: myopathy, myalgia, muscle cramps, weakness; rhabdomyolysis is rare.

Allergic and immunopathological reactions: angioneurotic edema, rheumatic polymyalgia, vasculitis, thrombocytopenia, increased sed rate, fever, arthritis, urticaria, photosensitization, skin flushing, hot flashes, shortness of breath, lupus-like syndrome, eosinophilia.

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

Others: anemia, palpitation, acute renal failure (due to rhabdomyolysis), decreased potency.

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Overdose

None of the known few cases of overdose (maximum dose taken 450 mg) have shown specific symptoms.

Treatment: induce vomiting, take activated charcoal, conduct symptomatic therapy. Liver and renal functions and serum CPK levels should be monitored.

In case of myopathy with rhabdomyolysis and acute renal failure (a rare but severe side effect) the drug should be stopped immediately and the patient should be given a diuretic and sodium bicarbonate (intravenous infusion). Hemodialysis is indicated if necessary.

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

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