Simvastol tablets po 20mg bl N14x2 Armedica

Pharmacodynamics and pharmacokinetics

Pharmacodynamics

The drug is an inactive lactone and belongs to the synthetic derivatives of Aspergillus terreus . During metabolism, a hydroxy acid derivative is formed, which inhibits HMG-CoA reductase , which catalyzes the reaction that initiates the formation of mevalonate , which is involved in the initial stage of cholesterol . At the same time, taking the drug is not accompanied by the accumulation of sterols . Under the influence of simvastatin, lipoproteins , triglycerides and total cholesterol in the body decreases . At the same time, the level lipoproteins . The effect in most patients appears within 10-14 days from the start of administration and reaches its peak after 1-1.5 months. After stopping taking the drug, cholesterol return to their previous levels slowly.

Pharmacokinetics

Simvastatin is well absorbed; the maximum concentration in the blood is observed on average after two hours. High binding to blood proteins - about 95%. It is transformed in the liver with the formation of beta-hydroxy acid , which has high pharmacological activity. The half-life of metabolites is about two hours. It is excreted in the form of metabolites through the intestines and, to a lesser extent, through the kidneys.

Simvastol tablets po 20mg bl N14x2 Armedica

Concomitant therapy with the following drugs is contraindicated. Potent inhibitors of the CYP3A4 isoenzyme. Simvastatin is metabolized by the CYP3A4 isoenzyme, but does not inhibit the activity of this isoenzyme. This suggests that taking simvastatin does not affect the plasma concentrations of drugs metabolized by the CYP3A4 isoenzyme. Potent inhibitors of the CYP3A4 isoenzyme increase the risk of developing myopathy by reducing the rate of elimination of simvastatin. Concomitant use of potent inhibitors of the CYP3A4 isoenzyme (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) and simvastatin is contraindicated. Other fibrates. The risk of developing myopathy increases when simvastatin is used concomitantly with gemfibrozil and other fibrates (except fenofibrate). These lipid-lowering drugs can cause myopathy in monotherapy. With simultaneous use of simvastatin with fenofibrate, the risk of developing myopathy did not exceed the sum of the risks with monotherapy with each drug. Amiodarone. The risk of developing myopathy/rhabdomyolysis increases when amiodarone is used concomitantly with simvastatin. In a clinical study, the incidence of myopathy in patients taking simvastatin 80 mg and amiodarone simultaneously was 6%. Blockers of "slow" calcium channels. The risk of developing myopathy/rhabdomyolysis increases when verapamil, diltiazem or amlodipine is used concomitantly with simvastatin. Lomitapide. The risk of developing myopathy/rhabdomyolysis may be increased when lomitapide is used concomitantly with simvastatin. Moderate inhibitors of the CYP3A4 isoenzyme (for example, dronedarone). With simultaneous use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially at higher doses, the risk of developing myopathy may increase. With simultaneous use of Simvastol and moderate inhibitors of CYP3A4 isoenzymes, a reduction in the dose of simvastatin may be required. Ranolazine (moderate CYP3A4 inhibitor). With simultaneous use of ranolazine and simvastatin, the risk of developing myopathy may increase. When simvastatin and ranolazine are used concomitantly, a dose reduction of simvastatin may be required. Inhibitors of the transport protein OATP1B1. Simvastatin hydroxy acid is a substrate of the transport protein OATP1B1. Concomitant use of OATP1B1 transport protein inhibitors and simvastatin may lead to an increase in the concentration of simvastatin hydroxy acid in the blood plasma and an increased risk of developing myopathy. Fusidic acid. With simultaneous use of fusidic acid and simvastatin, the risk of developing myopathy may increase. Nicotinic acid (at least 1 g/day). With the simultaneous use of simvastatin and nicotinic acid in lipid-lowering doses (at least 1 g/day), cases of myopathy/rhabdomyolysis have been described. Colchicine. With the simultaneous use of colchicine and simvastatin in patients with renal failure, cases of myopathy and rhabdomyolysis have been described. When combined with these drugs, such patients should be closely monitored. Indirect anticoagulants (coumarin derivatives). Simvastatin at a dose of 20-40 mg per day potentiates the effect of coumarin anticoagulants: prothrombin time, defined as the international normalized ratio (MHO), increases from the initial level of 1.7 to 1.8 in healthy volunteers and from 2.6 to 3.4 in patients with hypercholesterolemia. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin therapy, and also often enough during the initial period of treatment to exclude significant changes in this indicator. Once a stable MHO is achieved, further determinations should be made at intervals recommended for monitoring patients receiving anticoagulant therapy. When changing the dose of simvastatin or after its discontinuation, regular measurement of prothrombin time is also recommended. In patients not taking anticoagulants, simvastatin therapy was not associated with bleeding or changes in prothrombin time.

Indications for use

• Hypercholesterolemia : Types IIa and IIb of primary hypercholesterolemia in the absence of the effect of a low-cholesterol diet and non-drug measures (weight loss, physical activity) in patients at risk of developing atherosclerosis of the heart vessels; combined hypertriglyceridemia and hypercholesterolemia ;
• Coronary heart disease : to reduce the risk of death after myocardial infarction , to reduce the risk of developing disorders of the cardiovascular system ( stroke ), to slow down the development of atherosclerosis of the coronary vessels.

Simvastatin

At the beginning of simvastatin therapy, a transient increase in liver enzyme levels is possible.

Before starting therapy and then regularly conduct liver function testing (monitor liver enzyme activity every 6 weeks for the first 3 months, then every 8 weeks for the remainder of the first year, and then every six months), and when increasing doses, a test should be performed to determine liver function. When increasing the dose to 80 mg, a test must be performed every 3 months. If there is a persistent increase in transaminase activity (3 times compared to the initial 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 (due to severe acute infection, arterial hypotension, planned major surgery, trauma, severe metabolic disorders).

Cancellation of lipid-lowering drugs during pregnancy does not have a significant effect on 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 a significant role in fetal development, including the synthesis of steroids and cell membranes, simvastatin may have adverse effects on the fetus when administered to pregnant women (women reproductive age should avoid conception). If pregnancy occurs during treatment, the drug should be discontinued and the woman warned of the possible danger to the fetus.

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

In patients with low thyroid function (hypothyroidism) or certain kidney diseases (nephrotic syndrome), if cholesterol levels are elevated, the underlying disease should be treated first.

Simvastatin should be 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-lowering diet.

Concomitant use of grapefruit juice may increase the severity of side effects associated with simvastatin, so concomitant use should be avoided.

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

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), azole antifungals (ketoconazole, intraconazole) and inhibitors HIV protease (ritonavir). The risk of developing myopathy also increases in patients with severe renal failure.

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 immediately seek medical attention if unexplained pain, muscle soreness, lethargy or muscle weakness occurs, especially if 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 CPK value.

When treated with simvastatip, an increase in serum CPK levels 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 normal. In patients with myalgia, myasthenia gravis and/or a marked increase in CPK activity, treatment with the drug is discontinued.

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

If you miss the current dose, the drug must be taken as soon as possible.

If it is time to take the next dose, do not double the dose.

In patients with severe renal failure, treatment is carried out under the monitoring of renal function.

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

Impact on the ability to drive vehicles and operate machinery

No adverse effects of simvastatin on the ability to drive or use machines have been reported.

Side effects

Nausea, vomiting, abdominal pain, flatulence , diarrhea , constipation, pancreatitis , hepatitis , dizziness , headache muscle cramps asthenic syndrome , insomnia , paresthesia , neuropathy , taste disturbance, myalgia , weakness, muscle cramps, photosensitivity , eosinophilia , increased ESR , thrombocytopenia , allergic reactions, anemia , decreased potency, skin hyperemia, palpitations.

Simvastol, instructions for use (Method and dosage)

Treatment with the drug should be carried out against the background of prescribing a hypocholesterol diet . Take Simvastol tablets once a day, without food intake, preferably in the evening, with water.

Treatment of hypercholesterolemia - the initial dose is 10 mg and further dose adjustment should be carried out every 4 weeks. the optimal effect is observed in patients when prescribing a dose of up to 20 mg/day. The maximum dose of the drug per day should not exceed 80 mg.

For the treatment of patients with coronary artery disease , the effective dose of the drug is 20-40 mg/day. Dose adjustment is carried out monthly; according to indications, the dose can be increased to 40 mg per day. Elderly patients and patients with moderate renal failure

Simvastol®

Muonatia/ Rhabdomyolysis

Simvastatin, like other statins, can cause myopathy, which manifests itself as muscle pain, soreness or weakness and is accompanied by an increase in CPK activity (more than 10 times the ULN). Myopathy may manifest itself in the form of rhabdomyolysis, sometimes accompanied by secondary acute renal failure due to myoglobinuria. In rare cases, death has occurred. The risk of developing myopathy increases with increasing plasma concentrations of substances that have an inhibitory effect on HMG-CoA reductase. Risk factors for developing myopathy include older age (65 years or older), female gender, uncontrolled hypothyroidism, and impaired renal function.

As with treatment with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis is dose dependent. IN

In clinical studies of simvastatin (median follow-up duration was 4 years), the incidence of myopathy when using doses of 20 mg, 40 mg and 80 mg per day was 0.03%, 0.08% and 0.61%, respectively. In these studies, patients were closely monitored and a number of drugs that may interact with simvastatin were not used.

In a clinical study in which patients with a history of myocardial infarction were treated with simvastatin 80 mg daily (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0%, and in patients treated with simvastatin 20 mg daily day - 0.02%. Approximately half of the cases of myopathy were reported during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.

In patients taking simvastatin at a dose of 80 mg per day, the risk of developing myopathy is higher than when using other statins that cause a comparable decrease in LDL cholesterol concentrations. Therefore, the drug Simvastol® at a dose of 80 mg per day should be prescribed only

patients with a high risk of cardiovascular complications, in whom drug therapy at lower doses did not achieve the desired therapeutic effect, and the expected benefit of treatment outweighs the possible risk. If a patient taking Simvastol® at a dose of 80 mg requires treatment with another drug that may interact with simvastatin, then it is necessary to reduce the dose of Simvastol® or prescribe another statin that has less potential for possible drug interactions (see sections "Contraindications" and "Method of administration and dosage").

All patients who begin drug therapy

Simvastol®
, as well as patients who need to increase their dose, should be warned about the possibility of myopathy and informed about the need to immediately consult a doctor if any unexplained muscle pain, muscle soreness or muscle weakness occurs.
Therapy with Simvastol
should be discontinued immediately if myopathy is suspected or diagnosed.
The presence of the above symptoms and/or a more than 10-fold increase in CPK activity compared to ULN indicates the presence of myopathy. In most cases, after immediate cessation of taking Simvastol, the symptoms of myopathy resolve and CPK activity decreases. In patients starting to take Simvastol® or switching to higher doses of the drug, periodic determination of CPK activity is advisable, but there is no guarantee that such monitoring can prevent the development of myopathy.

Many patients who experienced rhabdomyolysis during simvastatin therapy had a complicated medical history, including impaired renal function, usually due to diabetes mellitus. Such patients require more careful monitoring. Therapy with Simvastol® should be temporarily discontinued several days before major surgical interventions, as well as in the postoperative period.

In a clinical study in which patients at high risk for cardiovascular disease received simvastatin 40 mg once daily (median follow-up 3.9 years), the incidence of myopathy was approximately 0.24% in Chinese patients and 0.05 % among patients of other nationalities. Although the only Mongoloid patients in this clinical study were Chinese, caution should be exercised when prescribing simvastatin to Mongoloid patients, particularly at low doses.

The risk of developing myopathy/rhabdomyolysis increases with simultaneous use of the drug

Simvastol®
with the following medications.
Contraindicated drug combinations

- Potent inhibitors of the
CYP3A4 isoenzyme 4.
CYP3A4 isoenzyme at therapeutic doses (for example,
itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telnthromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodo, or drugs containing cobici stat)
contraindicated. If short-term treatment with potent inhibitors of the CYP3A4 isoenzyme cannot be avoided, therapy with Simvastol* should be interrupted for the period of their use (see sections “Contraindications” and “Interaction with other drugs”).

— Gemfibrozil, cyclosporine or danazol.

The simultaneous use of these drugs with Simvastol® is contraindicated (see sections “Contraindications” and “Interaction with other drugs”).

Other medicines

— Other fibrates. In patients taking fibrates other than gemfibrozil

(see section "Contraindications")
or fenofibrate, the dose of simvastatin should not exceed 10 mg per day.
With simultaneous use of simvastatin and fenofibrate, the risk of developing myopathy does not exceed the sum of the risks when treating each drug separately. Fenofibrate should be used with caution in combination with simvastatin, as both drugs can cause the development of myopathy. The addition of fibrate therapy to simvastatin therapy usually leads to a small additional decrease in LDL cholesterol concentrations, but allows for a more pronounced decrease in TG concentrations and an increase in HDL cholesterol concentrations. In small short-term clinical studies in which both drugs were used under close supervision, combination therapy with fibrates and simvastatin was not associated with the development of myopathy (see section "Interactions with other drugs").

— Amiodarone. In patients taking amiodarone, the dose of simvastatin should not exceed 20 mg per day.

(see section “Interaction with other drugs”).

— Blockers of "slow" calcium channels. In patients taking verapamil, diltiazem or amlodipine, the dose of simvastatin should not exceed 20 mg per day

(see section “Interaction with other drugs”).

— Lomitapide. In patients with homozygous seminal hypercholesterolemia taking lomitapide, the dose of simvastatin should not exceed 40 mg per day

(see section “Interaction with other drugs”).

— Moderate inhibitors of the
CYP3A4 isoenzyme 4.
With simultaneous use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially in higher doses, the risk of developing myopathy may increase . When simvastatin is used concomitantly with moderate inhibitors of the CYP3A4 isoenzyme, a dose adjustment of simvastatin may be required.

— Fusidic acid.

Concomitant use of fusidic acid and simvastatin may increase the risk of developing myopathy (see section "Interaction with other drugs"). The simultaneous use of simvastatin and fusidic acid is not recommended. If the use of systemic fusidic acid preparations is considered necessary, the drug Simvastol® should be discontinued for the period of this therapy. In exceptional cases, when long-term therapy with systemic fusidic acid preparations is necessary, for example, for the treatment of severe infections, the possibility of simultaneous use of Simvastol and fusidic acid should be considered individually in each individual case and combination therapy should be carried out under close medical supervision.

— Nicotinic acid (in lipid-lowering doses of at least 1 g/day).

With the simultaneous use of the drug Simvastol* and nicotinic acid in lipid-lowering doses (at least 1 g/day), cases of the development of myopathy/rhabdomyolysis have been described.
In a clinical trial (median follow-up 3.9 years) in patients at high cardiovascular risk with well-controlled LDL-C concentrations, simvastatin 40 mg/day with or without ezetimibe 10 mg/day showed no additional positive effect on the outcomes of cardiovascular diseases with simultaneous use of nicotinic acid in lipid-lowering doses (at least 1 g/day). Thus, the benefit of simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g/day) should be carefully weighed against the potential risks of combination therapy. Additionally, in this study, the incidence of myopathy was approximately 0.24% among Chinese patients treated with simvastatin 40 mg or simvastatin/ezetimibe 40 mg/10 mg, compared with 1.24% among Chinese patients treated with simvastatin at a dose of 40 mg or simvastatin/ezetimibe at a dose of 40 mg/10 mg simultaneously with laropiprant/nicotinic acid sustained release at a dose of 40 mg/2 g . Although in this clinical study the only representatives of the Mongoloid race were Chinese patients, The simultaneous use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g/day) in patients of the Mongoloid race is not recommended, since the incidence of myopathy is higher in patients of Chinese nationality than in patients of other nationalities
(see section “Interaction with other drugs” ).

Effect on the liver

Some adult patients taking simvastatin experienced sustained increases in liver enzyme activity (more than 3 times the ULN). When simvastatin therapy was discontinued or interrupted, hepatic transaminase activity usually gradually returned to baseline levels. Increased activity of liver transaminases was not associated with jaundice or other clinical symptoms. No hypersensitivity reactions were identified. Some of the above patients had abnormal liver function tests before starting treatment with simvastatin and/or abused alcohol.

Before starting treatment, and then in accordance with clinical indications, liver function tests are recommended in all patients. Patients in whom it is planned to increase the dose of Simvastol® to 80 mg per day should undergo additional liver function tests before proceeding to the specified dosage, then 3 months after the start of its use and then repeat regularly (for example, once every six months ) during the first year of treatment. Particular attention should be paid to patients with increased activity of “liver” transaminases. These patients need to repeat liver function tests in the near future and then regularly until the activity of “liver” transaminases normalizes. In cases where the activity of “liver” transaminases increases, especially when the ULN is persistently exceeded by 3 times, the drug should be discontinued. The cause of increased alanine aminotransferase (ALT) activity may be muscle damage, so increased ALT and CPK activity may indicate the development of myopathy (see section "Special Instructions", Myopathy/Rhabdomyolysis).

There have been rare post-marketing reports of fatal and non-fatal cases of liver failure in patients taking statins, including simvastatin. If severe liver damage with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with Simvastol®, therapy should be discontinued immediately. If no other cause for the development of this pathology has been identified, re-prescribing Simvastol® is contraindicated.

In patients who abuse alcohol and/or patients with impaired liver function, the drug should be used with extreme caution. Active liver disease or an unexplained increase in the activity of liver transaminases are contraindications to the use of Simvastol®.

During treatment with Simvastol®, as with treatment with other lipid-lowering drugs, a moderate (less than 3 times the ULN) increase in the activity of “liver” transaminases was observed. These changes appeared soon after the start of treatment, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.

Ophthalmological examination

Data from modern long-term clinical studies do not contain information regarding the adverse effects of simvastatin on the human lens.

Use in children and adolescents aged 10-17 years

The safety and effectiveness of simvastatin in children and adolescents aged 10-17 years with heterozygous familial hypercholesterolemia were assessed in controlled clinical studies involving boys 10-17 years old and girls 10-17 years old at least 1 year after menarche. In pediatric patients receiving simvastatin, the adverse event profile was comparable to that of patients receiving placebo. Use of the drug

Simvastol®
at a dose of more than 40 mg per day has not been studied in pediatric and adolescent patients.
In this study, there was no significant effect of simvastatin on the growth and puberty of boys and girls or any effect on the length of the menstrual cycle in girls. Girls should be advised about proper methods of contraception during treatment with Simvastol® (see sections “Contraindications” and “Use during pregnancy and breastfeeding”). The use of simvastatin has not been studied in children under 10 years of age or in girls 10–17 years of age before menarche.

Use in elderly patients

In patients over the age of 65 years, the effectiveness of simvastatin, assessed by the level of reduction in the concentration of total cholesterol and LDL cholesterol, was similar to the effectiveness observed in the general population. There was no significant increase in the frequency of adverse events or changes in laboratory parameters. However, in a clinical study of simvastatin 80 mg daily, patients over 65 years of age had an increased risk of developing myopathy compared with patients under 65 years of age.

Interaction

Co-administration of simvastatin with cytostatics, nicotinic acid , antifungal drugs, HIV protease inhibitors, immunosuppressants, clarithromycin , telithromycin , erythromycin , amiodarone , verapamil and diltiazem increases the risk of developing myopathy. Simvastatin enhances the effect of anticoagulants, thereby increasing the risk of bleeding. Colestipol and cholestyramine reduce the bioavailability of simvastatin . Grapefruit juice consumed in quantities of more than 1 liter per day increases the inhibitory activity of HMG-CoA reductase in the blood.

Compound

Analogues of Simvastol

Level 4 ATX code matches:
Akorta

Atomax

Lipitor

Pravastatin

Owencore

Simgal

Tulip

Lovastatin

Liptonorm

Rozulip

Zokor

Rosart

Tevastor

Atorvastatin

Liprimar

Simvastatin

Atoris

Basilip

Rosecard

Roxera

Drugs with similar therapeutic effects include: Atherostat , Vasilip , Avestatin , Vero-Simvastatin , Actalipid, Zocor forte , Zovatin , Levomir , Ovencor , Zocor , Simvahexal , Zorstat , Simvacor , Simvastatin , Simvacard , Simlo , Sincard , Simvor , Simplacor , Simgal , Kholvasim and others.