Simvastatin pills 10mg, 30pcs

Composition

One film coated tablet contains: Active ingredient: simvastatin — 10 mg; excipients: cellulose microcrystalline — 70,00 mg, lactose monohydrate (milk sugar) — 21,00 mg, pregelatinized starch (starch 1500) from 33.73 mg, silicon dioxide colloid (Aerosil) — 0.75 mg, ascorbic acid — 2,50 mg, butylhydroxyanisole — 0.02 mg, stearic acid — 1.25 mg, magnesium stearate — 0.75 mg, polyvinyl alcohol — 2,33 mg, macrogol (polyethylene glycol) — 1,18 mg, dye iron oxide black — 0.02 mg, talc — 0.86 mg, dye iron oxide yellow — 0,28 mg, dye iron oxide red — 0.19 mg, titanium dioxide — 0,97 mg.

Pharmacological properties

Pharmacotherapeutic group:  hypolipidemic agent, HMG-CoA reductase inhibitor.

ATX Code: C 10 AA 01

PHARMACOLOGICAL PROPERTIES

Simvastatin is a hypolipidemic drug obtained synthetically from the fermentation product of Aspergillus terreus.

Pharmacodynamics :

After oral use, simvastatin, which is an inactive lactone, undergoes hydrolysis in the liver to form the corresponding form of beta-hydroxy acid simvastatin, which is the main metabolite and has a high inhibitory activity against HMG-CoA (3-hydroxy-3-methylglutaryl – coenzyme A) reductase, an enzyme that catalyzes the initial and most significant stage of cholesterol biosynthesis.

Clinical studies have shown the effectiveness of simvastatin in reducing the concentration of total cholesterol (TC) in blood plasma, low-density lipoprotein cholesterol( LDL), triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL), as well as increasing the concentration of high-density lipoprotein cholesterol (HDL) in patients with heterozygous familial and nonfamilial hypercholesterolemia or mixed hyperlipidemia in cases where high cholesterol is a risk factor and the appointment of a single diet is not enough. A noticeable therapeutic effect is observed within 2 weeks of taking the drug, the maximum therapeutic effect is observed within 4-6 weeks after the start of treatment. The effect persists with continued therapy. When simvastatin is discontinued, the cholesterol concentration returns to the initial value observed before the start of treatment.

The active metabolite of simvastatin is a specific inhibitor of HMG-CoA reductase, an enzyme that catalyzes the formation of mevalonate from HMG-CoA. Despite this, taking simvastatin in therapeutic doses does not lead to complete inhibition of HMG-CoA reductase, which allows maintaining the production of biologically necessary amounts of mevalonate. Since the conversion of HMG-CoA to mevalonate is an early step in cholesterol biosynthesis, it is believed that the use of simvastatin should not cause accumulation of potentially toxic sterols in the body. In addition, HMG-CoA is rapidly metabolized back to acetyl-CoA, which is involved in many biosynthetic processes in the body.

Although cholesterol is a precursor to all steroid hormones, no clinical effect of simvastatin on steroidogenesis has been observed. Since simvastatin did not cause an increase in bile lithogenicity, its effect on the increase in the incidence of cholelithiasis is unlikely.

Simvastatin reduces both elevated and normal LDL cholesterol levels. LDL is formed from very low-density lipoproteins (VLDL). LDL catabolism is mainly carried out by the high-affinity LDL receptor. The mechanism of lowering the LDL-C concentration after taking simvastatin may be due to both a decrease in the concentration of VLDL-C and activation of LDL receptors, which leads to a decrease in the formation and increased catabolism of LDL-C. Simvastatin therapy also significantly reduces the concentration of apolipoprotein B (apo B). Since each LDL particle contains one molecule of apo B. And other lipoproteins contain small amounts of apo B, it can be assumed that simvastatin not only causes cholesterol loss in LDL particles. but it also reduces the concentration of circulating LDL particles. In addition, simvastatin increases the concentration of HDL cholesterol and reduces the concentration of TG in blood plasma. As a result of these changes, the ratio of TC/HDL and LDL / HDL decreases.

In a multicenter, randomized, double-blind, placebo-controlled trial, simvastatin reduced the risk of overall mortality by 30%, CHD mortality by 42%, and the incidence of nonfatal confirmed myocardial infarction by 37%. Simvastatin also reduced the risk of requiring surgery to restore coronary blood flow (such as coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes mellitus, the risk of major coronary complications was reduced by 55%. Moreover, simvastatin significantly (by 28%) reduced the risk of fatal and non-fatal cerebral circulatory disorders (strokes and transient cerebral circulatory disorders).

In a multicenter, randomized, double-blind, placebo-controlled study of heart protection (HPS), the efficacy of simvastatin therapy was demonstrated in patients with or without hyperlipidemia, who are at high risk of developing CHD due to concomitant diabetes mellitus, a history of stroke, and other vascular diseases. Before starting therapy,33% of patients had LDL concentrations below 116 mg / dl,25% of patients had LDL concentrations between 116 mg / dl and 135 mg / dl, and 42% of patients had LDL concentrations above 135 mg / dl.

In this study, simvastatin 40 mg / day compared with placebo reduced overall mortality by 13%, the risk of CHD — related death by 18%, the risk of major coronary complications (including non — fatal myocardial infarction or CHD — related death) by 27%, the need for surgical interventions to restore coronary blood flow (including coronary artery bypass grafting and percutaneous transluminal angioplasty), as well as peripheral blood flow and other The risk of non — coronary revaecularization increased by 30% and 16%, respectively, and the risk of stroke increased by 25%. The rate of hospitalization for heart failure (HF) decreased by 17%. The risk of major coronary and vascular complications was reduced by 25% in patients with or without CHD, including patients with diabetes mellitus, peripheral vascular diseases, or cerebrovascular pathology. In patients with diabetes mellitus, simvastatin reduced the risk of serious vascular complications by 21%, including the need for surgical interventions to restore peripheral blood flow, amputation of the lower extremities, and the occurrence of trophic ulcers.

In another multicenter placebo-controlled study using quantitative assessment of coronary blood flow, simvastatin (according to coronary angiography) slowed the progression of coronary atherosclerosis and the appearance of both new areas of atherosclerosis and new total occlusions, while patients receiving standard therapy showed a steady progression of atherosclerotic damage to the coronary arteries.

Analysis of subgroups from two studies that included patients with hypertriglyceridemia (type IV hyperlipidemia according to the Fredrickson classification) showed that simvastatin at a dose of 20 to 80 mg per day reduced the concentration of TG by 21-39% (in the placebo group by 11-13%), LDL cholesterol — by 23-35% (in the placebo group by 1-3%), non — high-density lipoprotein cholesterol (non — HDL, calculated as the difference between the concentration of TC and the concentration of HDL-C) – by 26-43%) (in the placebo group by 1-3%) and increases HDL-C by 9-14% (in the placebo group by 3%).

In 7 patients with dysbetalipoproteinemia (Fredrickson type III hyperlipidemia), simvastatin 80 mg per day reduced the concentration of LDL cholesterol, including intermediate density lipoproteins (HDL) by 51% (in the placebo group by 8%), and the concentration of VLDL and HDL cholesterol by 60% (in the placebo group by 4%).

Pharmacokinetics:

Metabolism

Simvastatin is an inactive lactone that is rapidly hydrolyzed. converting to the beta-hydroxy acid simvastatin (L-654,969), a strong inhibitor of HMG-CoA reductase. The main metabolites of simvastatin in blood plasma are the beta-hydroxy acid simvastatin (L-654,969) and its b’ – hydroxy, b’-hydroxymethyl and 6′-exomethylene derivatives. Inhibition of HMG-CoA reductase is a criterion for quantifying all pharmacokinetic studies of beta-hydroxyacid metabolites (active inhibitors), as well as active and latent inhibitors (all inhibitors) formed as a result of hydrolysis. Both types of metabolites are detected in blood plasma when simvastatin is taken orally.

Hydrolysis of simvastatin mainly occurs during the” primary passage ” through the liver, so the concentration of unchanged simvastatin in human blood plasma is low (less than 5% of the dose taken). The maximum plasma concentration (Cmax) of simvastatin metabolites is reached 1.3-2.4 hours after a single oral dose. In a study using 14C labeled simvastatin, the plasma concentration of total radioactivity (14C labeled simvastatin + 14C labeled simvastatin metabolites) peaked after 4 hours and rapidly decreased to about 10% of the maximum value within 12 hours after a single oral dose. Although the recommended therapeutic dose range for simvastatin is between 5 and 80 mg per day, the linear nature of the AUC profile (area under the concentration – time curve)is not consistent. active metabolites in the general bloodstream are preserved when the dose is increased to 120 mg.

Suction

Approximately 85% of the oral dose of simvastatin is absorbed. Food intake (within the framework of a standard hypocholesterol diet) immediately after taking simvastatin does not affect the pharmacokinetic profile of the drug.

Distribution

After oral use, higher concentrations of simvastatin are detected in the liver than in other tissues. The concentration of the active metabolite of simvastatin L-654.969 in the systemic circulation is less than 5% of the oral dose; 95% of this amount is in the protein-bound state.

The result of active metabolism of simvastatin in the liver (more than 60% in men) is its low concentration in the general bloodstream. The possibility of penetration of simvastatin through the blood-brain barrier and the blood-placental barrier has not been studied.

Deduction

During the” primary passage ” through the liver, simvastatin is metabolized, followed by the elimination of simvastatin and its metabolites in the bile. In the study, when taking 100 mg of the drug (5 capsules of 20 mg),14 S labeled simvastatin accumulated in the blood, urine and feces. About 60% of the administered dose of labeled simvastatin was detected in the feces and about 13% in the urine. Labeled simvastatin in feces was represented by both bile-excreted products of simvastatin metabolism and unabsorbed labeled simvastatin. Less than 0.5% of the administered dose of labeled simvastatin was detected in the urine as active metabolites of simvastatin. In blood plasma,14% of the AUC was due to active inhibitors and 28% – to all HMG-CoA reductase inhibitors.

The latter indicates that. that the main part of the metabolic products of simvastatin are inactive or weak HMG-CoA reductase inhibitors. In the dose proportionality study of simvastatin 5,10,20,60,90, and 120 mg, there was no significant deviation from the linearity of AUC in total blood flow with increasing dose. Pharmacokinetic parameters for single and multiple oral use of simvastatin showed that simvastatin does not accumulate in tissues with repeated oral use.

In a study in patients with severe renal insufficiency (creatinine clearance < 30 ml/min), the total concentration of HMG-CoA reductase inhibitors in blood plasma after oral use of a single dose of the corresponding HMG-CoA reductase inhibitor (statin) was approximately 2 times higher than in healthy volunteers. In a study involving healthy volunteers, the use of simvastatin at a maximum dose of 80 mg did not affect the metabolism of midazolam and erythromycin, which are substrates of the CYP3A4 isoenzyme. This means that simvastatin is not an inhibitor of the CYP3A4 isoenzyme and suggests that oral use of simvastatin does not affect the plasma concentration of drugs metabolized by the CYP3A4 isoenzyme.

Cyclosporine is known to increase the AUC of HCC-CoA reductase inhibitors, although the mechanism of drug interaction is not fully understood. The increase in simvastatin AUC is suspected to be associated, in particular, with inhibition of the CYP3A4 isoenzyme and/or the 1-In-1 OATP transport protein (see CONTRAINDICATIONS). In a pharmacokinetic study, when used concomitantly with diltiazem, an increase in the AUC of beta-hydroxy acid simvastatin was observed by 2.7 times, presumably due to inhibition of the CYP3A4 isoenzyme (see SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

In a pharmacokinetic study, when co-administered with amlodipine, an increase in the AUC of beta-hydroxy acid simvastatin by 1.6 times was observed (see SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

In a pharmacokinetic study, when a single dose of 2 g of delayed-release nicotinic acid and simvastatin 20 mg was administered simultaneously, a slight increase in the AUC of simvastatin and simvastatin beta-hydroxy acid and Cmax of simvastatin beta-hydroxy acid in blood plasma was observed (see SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

The specific pathways of fusidic acid metabolism in the liver are unknown, but it can be assumed that there is an interaction between fusidic acid and statins that are metabolized by the CYP3A4 isoenzyme (see SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

The risk of developing myopathy increases with an increase in the concentration of HMG – CoA reductase inhibitors in blood plasma. Strong inhibitors of the CYP3A4 isoenzyme can increase the concentration of HMG-CoA reductase inhibitors and lead to an increased risk of developing myopathy (see INTERACTION WITH OTHER DRUGS; SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

Contraindications

• Hypersensitivity to any component of the drug.
• Liver disease in the active phase or persistent increase in the activity of “hepatic” transaminases in blood plasma of unclear etiology.
• Pregnancy or breast-feeding period.
• Age up to 18 years (except for children aged 10-17 years with heterozygous familial hypercholesterolemia) (see INDICATIONS FOR USE).
• Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
• Concomitant treatment with strong inhibitors of the CYP3A4 isoenzyme (itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and preparations containing cobicistat) (see INTERACTION WITH OTHER DRUGS; SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).
• Concomitant treatment with gemfibrozil, cyclosporine or danazol (see INTERACTIONS WITH OTHER DRUGS; SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

WITH CAUTION

Patients who have undergone rhabdomyolysis during simvastatin therapy, with a complicated medical history (impaired renal function, usually due to diabetes mellitus) require more careful monitoring, and simvastatin therapy should be temporarily discontinued in such patients a few days before major surgical interventions, as well as in the postoperative period;

In patients with sustained elevated activity of serum transaminases (greater than 3 times upper limit of normal), the drug should be discontinued; in severe renal failure (CC < 30 ml/min) should carefully weigh the advisability of the appointment of the drug in doses > 10 mg / day and, if necessary, assign them with care;

In case of alcohol abuse before starting treatment.

Side effects

Simvastatin is generally well tolerated, and most of the side effects are mild and transient. Less than 2% of patients who participated in clinical trials discontinued treatment due to the development of adverse events associated with Simvastatin.

In pre-marketing clinical trials, adverse events that occurred with a frequency of at least 1%, which were evaluated by researchers as possible, probable or definitely associated with taking the drug, were abdominal pain, constipation and flatulence. Other adverse events that occurred in 0.5 – 0.9% of patients were asthenia and headache.

There have been rare reports of myopathy (see SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

In a clinical trial (HPS) in which patients took simvastatin 40 mg / day or placebo for an average of 5 years, the pattern of adverse events was similar in the simvastatin and placebo groups. The frequency of discontinuation due to adverse events was also comparable in the two groups (4.8% in the simvastatin group and 5.1% in the placebo group). The incidence of myopathy in patients taking simvastatin was less than 0.1%. An increase in the activity of “hepatic” transaminases (more than 3 times higher than the upper limit of normal (ULN), confirmed in a second study) was observed in 0.21% of patients in the simvastatin group and 0.09% of patients in the placebo group.

There are reports of the possibility of developing the following adverse events (rare: >0.01%) and ><0.1%, very rare: :

Hematopoietic disorders: Rare: anemia.

Skin disorders: Rare: skin rash, pruritus, alopecia.

From the digestive system: Rare: dyspepsia, nausea, vomiting, diarrhea, pancreatitis, hepatitis / jaundice. Very rare: fatal and non-fatal liver failure.

From the central nervous system and sensory organs: Rare: dizziness, peripheral neuropathy. paresthesia. Very rare: insomnia. Frequency not established: depression.

Musculoskeletal disorders: Rare: myalgia, muscle cramps, rhabdomyolysis. Frequency not established: tendinopathy. possibly with a torn tendon.

Respiratory disorders: Frequency not established: interstitial lung disease.

From the reproductive system: Frequency not established: erectile dysfunction.

Allergic and immunopathological reactions: rarely developed hypersensitivity syndrome. This was manifested by angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, “flushes” of blood to the skin of the face, shortness of breath and general weakness.

There have been very rare reports of the development of immune-mediated necrotizing myopathy (autoimmune myopathy) due to statin use. Immune-mediated myopathy is characterized by weakness of the proximal muscles and increased serum creatine phosphokinase (CPK) activity, which persist despite discontinuation of statin treatment. A muscle biopsy shows necrotizing myopathy without significant inflammation. Improvement is observed in the treatment with immunosuppressive drugs (seeSPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

There were also rare post-marketing reports of cognitive impairments (e. g., various memory disorders — forgetfulness, memory loss, amnesia, confusion) associated with statin use. These cognitive impairments were reported when taking all statins. Overall, the reports were classified as non-serious, with varying duration to onset of symptoms (from 1 day to several years) and time to resolution (median 3 weeks). Symptoms were reversible and resolved after discontinuation of statin therapy.

The following adverse events have been reported with certain statins::

• sleep disorders, including nightmares;
• sexual dysfunction, gynecomastia.

Laboratory parameters

There are rare reports of the development of a pronounced and persistent increase in the activity of” hepatic ” transaminases. Increased activity of alkaline phosphatase and gamma-glutamyltranspeptidase has also been reported. Deviations in the parameters of functional liver tests are usually mild and transient. There are reports of increased CPK activity (see SPECIAL INSTRUCTIONS). Increased levels of glycosylated hemoglobin (HbAlc) and fasting serum glucose have been reported with statins, including simvastatin.

Children (10-17 years old)

In a clinical trial involving patients aged 10-17 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of treatment in the simvastatin group was comparable to that of the placebo group (see SPECIAL INSTRUCTIONS for use in children aged 10-17 years).

Interaction

Contraindicated drug combinations

Concomitant therapy with the following medications is contraindicated.

Strong 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 concentration of drugs metabolized by the CYP3A4 isoenzyme. Strong inhibitors of the CYP3A4 isoenzyme increase the risk of developing myopathy by reducing the rate of elimination of simvastatin. Concomitant use of strong inhibitors of the CYP3A4 isoenzyme (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, botenrevir, gelaprevir, nefazodone, drugs containing cobicistat) and simvastatin is contraindicated (see CONTRAINDICATIONS; SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

Gemfibrozil, cyclosporine or danazol. See CONTRAINDICATIONS; SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis.

Interaction with other medicinal products

Other fibrates. The risk of developing myopathy increases when simvastatin is co-administered with gemfibrozil (see CONTRAINDICATIONS) and other fibrags (except fenofibrate). These lipid-lowering agents can cause myopathy in monotherapy. When simvastatin was co-administered with fenofibrate, the risk of developing myopathy did not exceed the sum of the risks associated with monotherapy with each drug (see CONTRAINDICATIONS; SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

Amiodarone. The risk of developing myopathy/rhabdomyolysis increases with concomitant use of amiodarone with simvastatin. In a clinical study, the incidence of myopathy in patients taking simvastatin 80 mg and amiodarone concomitantly was 6% (see DOSAGE AND use; SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

Slow calcium channel blockers. The risk of developing myopathy/rhabdomyolysis increases with simultaneous use of verapamil. diltiazem or amlodipine with simvastatin (see DOSAGE AND use; SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Myopathy/Rhabdomyolysis).

Lomitapid. The risk of developing myopathy/rhabdomyolysis may increase with concomitant use of lomitapid with simvastatin (see DOSAGE AND use; SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis).

Moderate inhibitors of the CYP3A4 isoenzyme (for example, dronedarone). Concomitant use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially at higher doses, may increase the risk of developing myopathy (see SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis). When Simvastatin is co-administered with moderate inhibitors of CYP3A4 isoenzymes, it may be necessary to reduce the dose of Simvastatin.

Ranolazine (moderate inhibitor of the CYP3A4 isoenzyme). Concomitant use of ranolazine and simvastatin may increase the risk of developing myopathy (see SPECIAL INSTRUCTIONS, Myopathy/Rhabdomyolysis). When Simvastatin and ranolazine are co-administered, it may be necessary to reduce the dose of Simvastatin.

Inhibitors of the transport protein OATP 1 In 1. Simvastatin hydroxyacid is a substrate of the transport protein OATP 1 in 1. Simultaneous use of inhibitors of the transport protein OATP 1 In 1 and simvastatin may lead to an increase in the plasma concentration of simvastatin hydroxyacid and an increased risk of myopathy (see CONTRAINDICATIONS; SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

Fusidic acid. Concomitant use of fusidic acid and simvastatin may increase the risk of developing myopathy (see SPECIAL WARNINGS and PRECAUTIONS for USE). Myopathy/Rhabdomyolysis).

Nicotinic acid (at least 1 g / day). When simvastatin and nicotinic acid are used simultaneously in lipid-lowering doses (at least 1 g/day), cases of myopathy/rhabdomyolysis have been described (see SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

Colchicine. Concomitant use of colchicine and simvastatin in patients with renal insufficiency has been reported in cases of myopathy and rhabdomyolysis. 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, as well as often enough during the initial treatment period to exclude significant changes in this indicator. As soon as a stable MHO indicator is reached. its further determination should be carried out at the intervals recommended for monitoring patients receiving anticoagulant therapy. Regular measurement of prothrombin time is also recommended when changing the dose of simvastatin or after its withdrawal. In patients who did not take anticoagulants, simvastatin therapy was not associated with the occurrence of bleeding or changes in prothrombin time.

Other types of interaction

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. When drinking juice in the usual amount (1 glass 250 ml per day), this effect is minimal (there is an increase in the activity of HMG-CoA reductase inhibitors by 13% when estimated by AUC) and has no clinical significance. However, the consumption of grapefruit juice in large volumes significantly increases the activity of HMG-CoA reductase inhibitors in blood plasma. In this regard, it is necessary to avoid the use of grapefruit juice during simvastatin therapy (see SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

How to take, course of use and dosage

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 is 5 to 80 mg per day. The drug should be taken once a day in the evening. If necessary, the dose is increased at intervals of at least 4 weeks to a maximum of 80 mg once a day in the evening. The dose of 80 mg per day is recommended only for patients with a high risk of cardiovascular complications, if treatment with the drug at lower doses did not achieve the target lipid levels. and the intended benefit of therapy exceeds the possible risk (see SPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis).

Patients with coronary heart disease or a high risk of CHD

The standard initial dose of Simvastatin for patients with a high risk of developing CHD in combination with or without hyperlipidemia (in the presence of diabetes mellitus, stroke or other cerebrovascular diseases in the anamnesis, peripheral vascular diseases), as well as for patients with CHD is 40 mg once a day in the evening. Drug therapy should be administered simultaneously with diet and physical therapy.

Patients with hyperlipidemia who do not have the above risk factors

The standard initial dose of Simvastatin is 20 mg once a day in the evening. For patients who need a significant (more than 45%) reduction in the concentration of LDL cholesterol, the initial dose may be 40 mg once a day in the evening. In patients with mild or moderate hypercholesterolemia, simvastatin therapy can be prescribed at an initial dose of 10 mg once a day. If necessary, the selection of doses should be carried out in accordance with the above scheme (see DOSAGE AND use).

Patients with homozygous familial hypercholesterolemia

The drug Simvastatin is recommended at a dose of 40 mg per day, taken once in the evening. A dose of 80 mg is recommended only if the intended benefit of therapy exceeds the possible risk (seeSPECIAL INSTRUCTIONS. Myopathy/Rhabdomyolysis). In such patients, the drug is used in combination with other methods of lipid-lowering treatment (for example, LDL apheresis) or without such treatment, if it is not available.

For patients taking lomitapid concomitantly with simvastatin, the daily dose of simvastatin should not exceed 40 mg

Concomitant therapy

Simvastatin can be used either as monotherapy or in combination with bile acid sequestrants.

In patients taking simvastatin concomitantly with fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate, the maximum recommended dose of Simvastatin is 10 mg per day. For patients taking amiodarone, verapamil, diltiazem or amlodipine concomitantly with simvastatin, the daily dose of Simvastatin should not exceed 20 mg.

In case of kidney failure

Since simvastatin is excreted by the kidneys in small amounts, there is no need to change the dose in patients with moderate renal impairment. In patients with severe renal insufficiency (CC If such dosages are considered necessary, they should be administered with caution.

Use in children aged 10-17 years with heterozygous familial hypercholesterolemia

The recommended starting dose is 10 mg per day in the evening. The recommended dosage regimen is 10-40 mg per day, the maximum recommended dose of Simvastatin is 40 mg per day. The selection of doses is carried out individually in accordance with the goals of therapy.

Overdose

Several cases of overdose were reported, with the maximum dose taken being 3.6 g. No overdose effects were detected in any patient. General measures are used to treat overdose, including maintenance and symptomatic therapy.

Special instructions

Myopathy/Rhabdomyolysis

Simvastatin, like other statins, can cause myopathy, which manifests itself in the form of muscle pain, soreness or weakness and is accompanied by an increase in CPK activity (more than 10 times higher than the ULN). Myopathy can manifest in the form of rhabdomyolysis, sometimes accompanied by secondary acute renal failure due to myoglobinuria. In rare cases, a fatal outcome was observed. 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 advanced age (65 years and older), female gender, uncontrolled hypothyroidism, and impaired renal function.

As with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis depends on the dose. In clinical trials, the incidence of myopathy at doses of 20,40, 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 took Simvastatin at a dose of 80 mg per day, the incidence of myopathy was approximately 1.0%, and in patients taking the drug at a dose of 20 mg per 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%.

Patients taking simvastatin 80 mg / day have a higher risk of developing myopathy than those taking other statins that cause a comparable decrease in LDL cholesterol. Therefore, this drug at a dose of 80 mg per day should be prescribed only to patients with a high risk of cardiovascular complications, in which therapy with the drug at lower doses did not achieve the desired therapeutic effect, and the intended benefit of treatment exceeds the possible risk. If a patient taking Simvastatin 80 mg requires treatment with another drug that may interact with simvastatin, then it is necessary to reduce the dose of simvastatin or prescribe another statin that has less potential for possible drug interaction (see CONTRAINDICATIONS: METHOD OF use AND DOSES).

All patients who start therapy with Simvastatin, as well as patients who need to increase the dose, should be warned about the possibility of myopathy and informed about the need to immediately consult a doctor in case of any unexplained muscle pain, soreness in the muscles or muscle weakness. Therapy with the drug should be stopped 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 indicate the presence of myopathy. In most cases, after immediate discontinuation of Simvastatin, the symptoms of myopathy resolve and CPK activity decreases. In patients who start taking simvastatin or switch to increased doses of the drug, it is advisable to periodically determine the activity of CPK, but there is no guarantee that such monitoring can prevent the development of myopathy.

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

In a clinical study in which patients with a high risk of developing cardiovascular diseases took simvastatin at a dose of 40 mg once a day, the incidence of myopathy was approximately 0.24% among patients of Chinese nationality and 0.05% among patients of other nationality. Despite the fact that in this clinical study, the only representatives of the Mongolian race were patients of Chinese nationality, caution should be exercised when prescribing simvastatin to patients of the Mongolian race, in particular when prescribing it in low doses.

The risk of developing myonopathy/rhabdomyolysis increases when Simvastatin is co-administered with the following medications.

Contraindicated drug combinations

• Strong inhibitors of the CYP3A4 isoenzyme. Concomitant therapy with strong inhibitors of the CYP3A4 isoenzyme in therapeutic doses (for example, itraconazole, ketoconazole, nosaconazole, voriconazole, erythromycin, clarithromycin, telitrominin, HIV protease inhibitors, botenrevir, telaprevir, nefazodone or drugs containing cobicistat) is contraindicated. If short-term treatment with strong inhibitors of the CYP3A4 isoenzyme cannot be avoided, therapy with Simvastatin should be interrupted for the duration of their use (see CONTRAINDICATIONS; INTERACTION WITH OTHER DRUGS).
• Gemfibrozil, cyclosporine, or danazol. Concomitant use of these drugs with Simvastatin is contraindicated (see CONTRAINDICATIONS; INTERACTION WITH OTHER DRUGS).

Other medicinal products

• Other fibrates. In patients taking fibrates other than gemfibrozil (see CONTRAINDICATIONS) or fenofibrate, the dose of simvastatin should not exceed 10 mg per day. When simvastatin and fenofibrate are co-administered, the risk of developing myopathy does not exceed the sum of the risks associated with treatment with each drug separately. Prescribe fenofibrate in combination with simvastatin should be careful, as both drugs can cause the development of myopathy. The addition of fibragam therapy to simvastatin therapy usually leads to a small additional decrease in LDL-C concentration, but allows you to achieve a more pronounced decrease in TG concentration and an increase in HDL-C concentration. In small, short clinical trials in which both drugs were used under close supervision, the combination therapy of fibrates with simvastatin was not accompanied by the development of myopathy (see INTERACTION WITH OTHER DRUGS).
• Amiodarone. In patients taking amiodarone, the dose of simvastatin should not exceed 20 mg per day (see INTERACTION WITH OTHER DRUGS).
• Slow calcium channel blockers. In patients taking veraiamil, diltnazem or amlodipine, the dose of simvastatin should not exceed 20 mg per day (see INTERACTION WITH OTHER DRUGS).
• Lomitanide. In patients with homozygous familial hypercholesterolemia taking lomitapid, the dose of simvastatin should not exceed 40 mg per day (see INTERACTION WITH OTHER DRUGS).
• Moderate inhibitors of the CYP3A4 isoenzyme. Concomitant use of drugs with moderate inhibitory activity against the CYP3A4 isoenzyme and simvastatin, especially at higher doses, may increase the risk of developing myopathy. When simvastatin is co-administered with moderate inhibitors of the CYP3A4 isoenzyme, it may be necessary to adjust the dose of simvastatin.
• Fusidic acid. Concomitant use of fusidic acid and simvastatin may increase the risk of developing myopathy (see INTERACTIONS WITH OTHER MEDICATIONS). Concomitant use of simvastatin and fusidic acid is not recommended. If the use of systemic fusidic acid preparations is considered necessary, Simvastatin should be discontinued for the duration of this therapy.In exceptional cases where long-term therapy with systemic fusidic acid is necessary, for example, for the treatment of severe infections, the possibility of simultaneous use of Simvastatin and fusidic acid should be considered individually on a case-by-case basis, and combination therapy should be carried out under close medical supervision.
• Nicotinic acid (in lipid-lowering doses of at least 1 g / day). When Simvastatin and nicotinic acid are used simultaneously in lipid-lowering doses (at least 1 g/day), cases of myopathy/rhabdomyolysis have been described. In a clinical study involving patients with a high risk of cardiovascular disease and a well-controlled LDL-C concentration, simvastatin 40 mg / day with or without ezetimibe 10 mg / day was shown to have no additional positive effect on the outcome of cardiovascular diseases with concomitant use of nicotinic acid in lipid-lowering doses (at least 1 g / day). Therefore, the benefit of concomitant 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. In addition, in this study, the incidence of myopathy was approximately 0.24% among Chinese-born patients treated with simvastatin 40 mg or simvastatin/ezetimibe 40/10 mg, compared to 1.24% among Chinese-born patients treated with simvastatin 40 mg or simvastatin/ezetimibe 40/10 mg concomitantly with laropiprant/delayed-release nicotinic acid 40 mg/2 g. In a clinical study, the only representatives of the Mongoloid race were patients of Chinese nationality; concomitant use of simvastatin with nicotinic acid in lipid-lowering doses (at least 1 g/day) in patients of the Mongolian race is not recommended, since the incidence of myopathy is higher in patients of Chinese nationality than in patients of other nationalities (see INTERACTION WITH OTHER DRUGS).

Effects on the liver

In some adult patients taking Simvastatin, there was a steady increase in the activity of” liver ” enzymes (more than 3 times higher than the ULN). When stopping or interrupting therapy with the drug, the activity of” hepatic ” transaminases usually gradually returned to the initial level.

Increased activity of “hepatic” transaminases was not associated with jaundice or other clinical symptoms. No hypersensitivity reactions were detected. Some of the above patients had abnormalities in the results of functional liver tests before starting treatment with Simvastatin and/or were abusing alcohol.

Before starting treatment, and then in accordance with clinical indications, all patients are recommended to conduct a liver function study. Patients who plan to increase the dose of simvastatin to 80 mg per day should conduct additional liver function tests before starting the indicated 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.

Special attention should be paid to patients with increased activity of “hepatic” transaminases. These patients need to repeat liver function tests in the near future and then carry out regularly until the activity of “hepatic” transaminases normalizes. In cases where the activity of “hepatic” transaminases increases, especially if the ULN is consistently exceeded by 3 times, the drug should be discontinued. An increase in alanine aminotransferase (AJ1T) activity may be caused by muscle damage, so an increase in AL G and CK activity may indicate the development of myopathy.

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 simvastatin, therapy should be discontinued immediately. If no other cause of the development of this pathology has been identified, repeated use of the drug 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 “hepatic” transaminases are contraindications to the appointment of Simvastatin.

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

Ophthalmological examination

Data from current long-term clinical studies do not contain information about the adverse effects of Simvastatin on the lens of the human eye.

Use in children aged 10-17 years

The safety and efficacy of Simvastatin in children aged 10-17 years with heterozygous familial hypercholesterolemia were evaluated in controlled clinical trials involving boys aged 10-17 years and girls aged 10-17 years at least 1 year after menarche. In paediatric patients treated with Simvastatin, the adverse event profile was comparable to that of patients treated with placebo. The use of Simvastatin at a dose of more than 40 mg per day has not been studied in paediatric 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 duration of the menstrual cycle in girls. Girls should be advised about appropriate contraceptive methods during treatment with Simvastatin. The use of simvastatin has not been studied in children under 10 years of age and in girls aged 10-17 years before menarche.

Use in elderly patients

In patients over 65 years of age, the effectiveness of Simvastatin, estimated by the level of reduction in the concentration of TC and LDL cholesterol. It was similar to the efficacy 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 trial using Simvastatin 80 mg / day, patients over 65 years of age had an increased risk of developing myopathy compared to patients under 65 years of age.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

Simvastatin has no or negligible effect on the ability to drive vehicles and work with mechanisms. However, when driving vehicles or working with mechanisms, it should be taken into account that in the post-marketing period, rare cases of dizziness have been reported.

Storage conditions

Store in a dry place protected from light at a temperature not exceeding 25°C. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Simvastatin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets