Simvastatin

active substance:

simvastatin 

Simvastatin is a hypolipidemic drug obtained synthetically from the fermentation product of Aspergillus terreus, it is an inactive lactone, it undergoes hydrolysis in the body to form 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 cholesterol synthesis, 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.

Causes a decrease in plasma triglycerides (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and total cholesterol (in cases of heterozygous familial and non-familial forms of hypercholesterolemia, with mixed hyperlipidemia, when high cholesterol is a risk factor) ...

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

The beginning of the manifestation of the effect - after 2 weeks from the start of admission, the maximum therapeutic effect is achieved after 4-6 weeks. The effect persists with continued treatment, with discontinuation of therapy, the cholesterol content gradually returns to the initial level.

Pharmacokinetics

The absorption of simvastatin is high. After oral administration, Cmax in blood plasma is reached after about 1.3 - 2.4 hours and decreases by 90% after 12 hours. The connection with blood plasma proteins is about 95%.

It is metabolized in the liver, has the effect of the first passage through the liver (it is hydrolyzed to form an active derivative: beta-hydroxy acids, other active as well as inactive metabolites have been found).

T1 / 2 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.

Hypercholesterolemia in the absence of effect from diet therapy, combined hypercholesterolemia and triglyceridemia, ischemic heart disease, prevention of myocardial infarction and stroke, atherosclerosis.

• Hypersensitivity;
• acute liver dysfunction;
• severe renal failure.

From the digestive system: constipation, diarrhea, loss of appetite, flatulence, nausea, abdominal pain, pancreatitis, increased activity of ALT, AST, GGT, ALP.

From the side of the central nervous system and peripheral nervous system: headache, dizziness, muscle cramps, paresthesia, peripheral neuropathy.

From the side of the cardiovascular system: transient arterial hypotension is possible.

From the musculoskeletal system: myalgia, myopathy, rhabdomyolysis, increased CPK activity.

Allergic reactions: rarely - angioedema, lupus-like syndrome, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis, urticaria, fever, shortness of breath.

Dermatological reactions: photosensitization, skin rash, itching, skin flushing, alopecia.

Others: anemia.

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

Cyclosporine or danazol: The risk of myopathy / rhabdomyolysis is increased when cyclosporin or danazol is co-administered with high doses of simvastatin.

Other lipid-lowering drugs that can cause the development of myopathy: the risk of myopathy increases with the co-administration of other lipid-lowering drugs that are not potent inhibitors of CYP3A4, but can cause myopathy in monotherapy. Such as gemfibrozil and other fibrates (other than fenofibrate), and niacin (nicotinic acid) at a dose> 1 g / day.

Amiodarone and verapamil: The risk of myopathy is increased when amiodarone or verapamil is taken together with high doses of simvastatin.

Diltiazem: The risk of myopathy is slightly increased in patients receiving diltiazem concomitantly with simvastatin 80 mg.

Simvastatin potentiates the action of oral anticoagulants (eg, phenprocoumon, warfarin) and increases the risk of bleeding, which requires monitoring of blood clotting parameters before starting treatment, and also quite often in the initial period of therapy. Once a stable prothrombin time or International Normalized Ratio (MHO) level is reached, further monitoring should be performed at the intervals recommended for patients receiving anticoagulant therapy. If you change the dosage or stop taking simvastatin, you should also monitor the prothrombin time or MHO according to the above scheme.

Simvastatin therapy does not cause changes in prothrombin time and risk of bleeding in patients not taking anticoagulants. Increases the level of digoxin in blood plasma.

Kolestyramine and colestipol reduce bioavailability (the use of simvastatin is possible 4 hours after taking these drugs, while an additive effect is noted).

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentration of drugs metabolized by CYP3A4. The increase in the activity of HMG-CoA reductase inhibitors after drinking 250 ml of juice per day is minimal and has no clinical significance. However, the 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 blood plasma. In this regard, it is necessary to avoid consuming large quantities of grapefruit juice.

Inside, 1 time per day, in the evening, drinking plenty of water. The time of taking the drug should not be associated with food intake.

Before starting treatment with Simvastatin, the patient should be prescribed a standard hypocholesterol diet, which should be followed throughout the course of treatment.

The recommended dose of Simvastatin for the treatment of hypercholesterolemia varies from 10 to 80 mg once a day in the evening. The recommended starting dose 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. In most patients, the optimal effect is achieved when taking the drug in doses up to 20 mg / day.

In patients with homozygous hereditary hypercholesterolemia, the recommended daily dose of Simvastatin is 40 mg 1 time per day in the evening or 80 mg in 3 divided doses (20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening).

In the treatment of patients with coronary artery disease or a high risk of developing coronary artery disease, effective doses of Simvastatin are 20-40 mg / day. Therefore, the recommended starting dose in such patients is 20 mg / day. Changes (selection) of the dose should be carried out at intervals of 4 weeks, if necessary, the dose can be increased to 40 mg / day. If the content of LDL 

Elderly patients and patients with mild or moderate renal failure do not need to change the dosage of the drug.

In patients with chronic renal failure (Cl creatinine

For patients taking amiodarone or verapamil at the same time as simvastatin, the daily dose should not exceed 20 mg.

In none of the known several cases of overdose (maximum dose of 450 mg taken), specific symptoms have been identified.

Treatment: induce vomiting, take activated charcoal. Symptomatic therapy. It is necessary to monitor the functions of the liver and kidneys, the level of CPK 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 patient should be given a diuretic and sodium bicarbonate (intravenous infusion). Hemodialysis is indicated if necessary.

Rhabdomyolysis can cause hyperkalemia, which can be reversed by intravenous calcium chloride or calcium gluconate, glucose infusion with insulin, use of potassium ion exchangers, or, in severe cases, hemodialysis.

At the beginning of therapy with simvastatin, a transient increase in the level of liver enzymes is possible.

Before starting therapy, and then regularly conduct a study of liver function (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), as well as with increasing doses, a test should be performed to determine liver function. When the dose is increased to 80 mg, a test must be performed every 3 months. With a persistent increase in the activity of transaminases (3 times compared with the initial level), taking simvastatin should be discontinued.

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

Cancellation of lipid-lowering drugs during pregnancy does not significantly affect the results of long-term treatment of primary hypercholesterolemia.

Due to the fact that HMG-CoA reductase inhibitors inhibit cholesterol synthesis, and cholesterol and other products of its synthesis play an essential role in the development of the fetus, including the synthesis of steroids and cell membranes, simvastatin may have an adverse effect on the fetus when administered to pregnant women (women of reproductive age should avoid conception). If pregnancy occurs during treatment, the drug should be canceled, and the woman should be warned of the possible danger to the fetus.

The use of simvastatin is not recommended in women of childbearing age who do not use contraceptives.

In patients with an underactive thyroid gland (hypothyroidism) or some kidney disease (nephrotic syndrome), if the cholesterol level is high, the underlying disease should be treated first.

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

Before and during treatment, the patient should be on a cholesterol-free diet.

Simultaneous intake of grapefruit juice can increase the severity of side effects associated with taking simvastatin, so you should avoid taking them simultaneously.

Simvastatin is not indicated in cases where there is type I, IV and V hypertriglyceridemia.

Simvastatin treatment can 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), antifungals from the azole group (ketoconazole, intraconazole) and HIV proteases (ritonavir). The risk of developing myopathy is also increased in patients with severe renal failure.

All patients starting simvastatin therapy, 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 consult a doctor in case of unexplained pain, muscle soreness, lethargy or muscle weakness, especially if this is accompanied by malaise or fever. Drug therapy should be discontinued immediately if myopathy is diagnosed or suspected.

In order to diagnose the development of myopathy, it is recommended to regularly measure the value of CPK.

When treating with simvastatip, an increase in the content of serum CPK is possible, which should be taken into account in the differential diagnosis of chest pain. The criterion for discontinuation of the drug is an increase in the CPK content in the blood serum by more than 10 times relative to the upper limits of the norm. In patients with myalgia, myasthenia gravis and / or a pronounced increase in CPK activity, drug treatment is 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 to take the next dose, do not double the dose.

Patients with severe renal impairment are treated under the control of renal function.

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

Influence on the ability to drive vehicles and use mechanisms

The adverse effects of simvastatin on the ability to drive and operate machinery have not been reported.

Film-coated tablets