Simgal (Tablets) Instructions for Use

ATC Code

C10AA01 (Simvastatin)

Active Substance

Simvastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

A hypolipidemic drug, an inhibitor of HMG-CoA reductase, obtained synthetically from a fermentation product of Aspergillus terreus. It is an inactive lactone that undergoes hydrolysis in the body to form a hydroxy acid derivative. The active metabolite inhibits HMG-CoA reductase, the enzyme that catalyzes the initial reaction of mevalonate formation from HMG-CoA.

Since the conversion of HMG-CoA to mevalonate is an early stage of 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.

It causes a decrease in the plasma levels of TG, LDL, VLDL, and total cholesterol (in cases of heterozygous familial and non-familial forms of hypercholesterolemia, in mixed hyperlipidemia, when elevated cholesterol is a risk factor).

It increases HDL levels and reduces the LDL/HDL and total cholesterol/HDL ratios.

The onset of the effect is within 2 weeks from the start of administration, the maximum therapeutic effect is achieved after 4-6 weeks. The effect persists with continued treatment; upon discontinuation of therapy, cholesterol levels gradually return to the initial level.

Pharmacokinetics

Absorption

The absorption of simvastatin is high. C_max is reached 1.3-2.4 hours after oral administration and decreases by 90% after 12 hours. It undergoes a significant first-pass effect through the liver.

Distribution and Metabolism

Binding to plasma proteins is about 95%.

Simvastatin is metabolized in the liver by hydrolysis to form pharmacologically active beta-hydroxy metabolites. Other active and inactive metabolites are also formed.

Excretion

The T_1/2 of active metabolites is 1.9 hours. It is excreted mainly with feces (about 60%), about 10-15% is excreted by the kidneys as inactive metabolites.

Indications

Hypercholesterolemia

• Primary hypercholesterolemia (type IIa and IIb) when diet therapy with low cholesterol content and other non-drug measures (physical activity and weight reduction) are ineffective in patients with an increased risk of coronary atherosclerosis;
• Combined hypercholesterolemia and hypertriglyceridemia, not corrected by special diet and physical activity.

Coronary Heart Disease (CHD)

• Prevention of myocardial infarction;
• Reduction of the risk of death;
• Slowing the progression of atherosclerosis;
• Reduction of the risk of revascularization procedures.

Cerebrovascular Disease

• Stroke or transient ischemic attacks.

ICD codes

Dosage Regimen

Tablets

Before starting treatment with Simgal, the patient should be prescribed a standard hypocholesterolemic diet, which must be followed throughout the entire course of treatment.

Simgal should be taken orally once a day in the evening, with a sufficient amount of water.

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

The recommended dose of Simgal for the treatment of hypercholesterolemia ranges from 10 to 80 mg once a day in the evening. The recommended initial dose of the drug for patients with hypercholesterolemia is 10 mg. The maximum daily dose is 80 mg. Dose changes (titration) should be made at intervals of 4 weeks. In most patients, the optimal effect is achieved when taking the drug in doses up to 20 mg/day.

For homozygous familial hypercholesterolemia, the recommended daily dose of Simgal is 40 mg once a day in the evening or 80 mg in 3 doses (20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening).

When treating patients with CHD or high risk of developing CHD, effective doses of Simgal are 20-40 mg/day. Therefore, the recommended initial dose in such patients is 20 mg/day. Dose changes (titration) should be made at intervals of 4 weeks; if necessary, the dose can be increased to 40 mg/day. If the LDL content is less than 75 mg/dL (1.94 mmol/L), the total cholesterol content is less than 140 mg/dL (3.6 mmol/L), the dose of the drug must be reduced.

In elderly patients and patients with mild or moderate renal impairment, no dose adjustment of the drug is required.

In patients with chronic renal failure (CrCl < 30 ml/min) or those taking 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 Simgal should not exceed 10 mg/day.

For patients taking amiodarone or verapamil simultaneously with Simgal, the daily dose of Simgal should not exceed 20 mg.

Adverse Reactions

When using therapeutic recommended doses, Simgal is generally well tolerated.

From the digestive system nausea, vomiting, abdominal pain, constipation, diarrhea, pancreatitis, flatulence, hepatitis, increased activity of liver transaminases, alkaline phosphatase, CPK are possible.

From the central and peripheral nervous system asthenic syndrome, headache, dizziness, insomnia, convulsions, paresthesia, peripheral neuropathy, blurred vision, taste disturbance.

From the musculoskeletal system myopathy, muscle cramps, myalgia, weakness; rarely – rhabdomyolysis.

From the urinary system acute renal failure (due to rhabdomyolysis).

From the hematopoietic system thrombocytopenia, anemia.

Allergic reactions angioedema, rheumatic polymyalgia, vasculitis, arthritis, urticaria, skin hyperemia, lupus-like syndrome, fever, increased ESR, eosinophilia.

Dermatological reactions photosensitivity, skin rash, itching, alopecia, dermatomyositis.

Other hot flashes, shortness of breath, palpitations, decreased potency.

Contraindications

• Active liver disease, persistent increase in liver enzyme activity of unknown etiology;
• Skeletal muscle diseases (myopathy);
• Pregnancy;
• Lactation period (breastfeeding);
• Children and adolescents under 18 years of age (efficacy and safety have not been established);
• Hypersensitivity to simvastatin and other components of the drug (including hereditary lactose intolerance), as well as to other drugs of the statin class (HMG-CoA reductase inhibitors) in the anamnesis.

With caution the drug should be prescribed to patients who abuse alcohol, patients after organ transplantation who are undergoing therapy with immunosuppressants (due to an increased risk of rhabdomyolysis and renal failure); in conditions that can lead to the development of severe renal failure, such as arterial hypotension, acute severe infectious diseases, severe metabolic and endocrine disorders, water-electrolyte balance disorders, surgical interventions (including dental) or trauma; patients with decreased or increased skeletal muscle tone of unknown etiology; epilepsy.

Use in Pregnancy and Lactation

Simgal is contraindicated in pregnant women. There are several reports of the development of abnormalities in newborns whose mothers took Simvastatin.

Women of childbearing age taking Simvastatin should avoid conception.

Data on the excretion of simvastatin in breast milk are not available. If it is necessary to prescribe Simgal during lactation, it should be taken into account that many drugs are excreted in breast milk, and there is a threat of developing severe reactions, therefore breastfeeding during drug administration is not recommended.

Use in Hepatic Impairment

Contraindicated in active liver disease, persistent increase in liver enzyme activity of unknown etiology.

Use in Renal Impairment

In patients with chronic renal failure (CrCl less than 30 ml/min) or those taking cyclosporine, fibrates, nicotinamide, the initial dose of Simgal is 5 mg, the maximum daily dose is 10 mg.

Pediatric Use

Contraindicated: children and adolescents under 18 years of age (efficacy and safety have not been established).

Geriatric Use

In elderly patients, no dose adjustment of the drug is required.

Special Precautions

At the beginning of therapy with Simgal, a transient increase in the level of liver enzymes is possible. Therefore, before starting therapy and then regularly, liver function tests should be performed (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 6 months), and also when increasing doses, a liver function test should be performed. When increasing the dose to 80 mg, the test should be performed every 3 months. With a persistent increase in transaminase activity (more than 3 times compared to the initial level), the administration of Simgal should be discontinued.

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

Discontinuation of hypolipidemic agents during pregnancy does not significantly affect the results of long-term treatment of primary hypercholesterolemia.

Since HMG-CoA reductase inhibitors inhibit cholesterol synthesis, and cholesterol and other products of its synthesis play a significant role in fetal development, including the synthesis of steroids and cell membranes, Simvastatin may have an adverse effect on the fetus when prescribed to pregnant women (women of reproductive age should avoid conception). If pregnancy occurs during treatment, the drug should be discontinued, and the woman should be warned about the possible danger to the fetus.

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

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

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

Before starting and during treatment, the patient must be on a hypocholesterolemic diet.

Simultaneous intake of grapefruit juice may increase the severity of side effects associated with taking Simgal, so their simultaneous intake should be avoided.

Simgal is not indicated in cases where there is hypertriglyceridemia of types I, IV and V.

Treatment with Simgal 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 Simgal: fibrates (gemfibrozil, fenofibrate), cyclosporine, nefazodone, macrolides (erythromycin, clarithromycin), antifungal agents from the azole group (ketoconazole, itraconazole) and HIV protease inhibitors (ritonavir). The risk of developing myopathy is also increased in patients with severe renal failure.

All patients starting therapy with Simgal, 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. Therapy with the drug should be stopped immediately if myopathy is diagnosed or suspected.

To diagnose the development of myopathy, it is recommended to regularly measure CPK levels.

During treatment with Simgal, an increase in serum CPK content is possible, which should be taken into account in the differential diagnosis of chest pain. The criterion for drug withdrawal is an increase in serum CPK content by more than 10 times relative to the upper limit of normal. In patients with myalgia, myasthenia and/or a pronounced increase in CPK activity, treatment with the drug is stopped.

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

In case of missing a current dose, the drug should be taken as soon as possible. If it is time to take the next dose, the dose should not be doubled.

Patients with severe renal failure should be treated under the control of renal function.

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

Effect on the ability to drive vehicles and mechanisms

No adverse effects of Simgal on the ability to drive a car and work with mechanisms have been reported.

Overdose

In none of the few known cases of overdose (maximum dose taken 450 mg) were specific symptoms identified.

Treatment induce vomiting, prescribe activated charcoal; if necessary, symptomatic therapy is carried out. Liver and kidney functions, serum CPK levels should be monitored.

If myopathy with rhabdomyolysis and acute renal failure develops (a rare but severe side effect), the drug should be discontinued immediately and the patient should be given a diuretic and sodium bicarbonate (IV infusion). Hemodialysis is indicated if necessary.

Rhabdomyolysis can cause hyperkalemia, which can be eliminated by IV administration of calcium chloride or calcium gluconate, infusion of glucose with insulin, the use of potassium ion exchangers or, in severe cases, with the help of hemodialysis.

Drug Interactions

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

The risk of developing myopathy/rhabdomyolysis increases with the combined administration of cyclosporine or danazol with high doses of simvastatin.

The risk of developing myopathy increases with the combined administration of other hypolipidemic agents (gemfibrozil and other fibrates /except fenofibrate/, as well as nicotinic acid in a dose of ≥1 g/day), which are not potent inhibitors of CYP3A4, but can cause myopathy during monotherapy.

The risk of developing myopathy increases with the combined use of amiodarone or verapamil with high doses of simvastatin.

The risk of developing myopathy slightly increases in patients receiving diltiazem simultaneously with simvastatin at a dose of 80 mg.

Simvastatin potentiates the effect of oral anticoagulants (phenprocoumon, warfarin) and increases the risk of bleeding, which requires monitoring of blood coagulation parameters before starting treatment, and also quite often in the initial period of therapy. Once a stable level of prothrombin time or INR is reached, its further monitoring should be carried out at intervals recommended for patients receiving anticoagulant therapy. When changing the dosage or discontinuing simvastatin, prothrombin time or INR should also be monitored according to the above scheme.

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

Simvastatin increases the level of digoxin in blood plasma.

Cholestyramine and colestipol reduce bioavailability (simvastatin can be used 4 hours after taking these drugs, while an additive effect is noted).

Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme and can increase the plasma concentration of drugs metabolized by the CYP3A4 isoenzyme. 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, consumption of large volumes 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.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature from 10°C (50°F) to 25°C (77°F).

Shelf Life

Shelf life – 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.