Vazostat-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASOSTAT-ZDOROVYE (VASOSTAT-ZDOROVYE)

Composition:

Active substance: simvastatin;

1 tablet contains 10 mg, 20 mg, or 40 mg of simvastatin;

Excipients:

10 mg or 20 mg dosage: butylated hydroxyanisole (E 320); ascorbic acid; citric acid monohydrate; celactose (a mixture of lactose monohydrate and powdered cellulose (75:25)); colloidal anhydrous silicon dioxide; potato starch; magnesium stearate; hypromellose; candurin (silver glitter) containing potassium aluminosilicate, titanium dioxide (E 171); colouring agent "Sepispers dry yellow R" containing hypromellose, microcrystalline cellulose, riboflavin (E 101); polyethylene glycol 4000; titanium dioxide (E 171);

40 mg dosage: butylated hydroxyanisole (E 320); ascorbic acid; citric acid monohydrate; lactose monohydrate; magnesium stearate; hypromellose; microcrystalline cellulose; copovidone; sodium croscarmellose; candurin (silver glitter) containing potassium aluminosilicate, titanium dioxide (E 171); colouring agent "Sepispers dry yellow R" containing hypromellose, microcrystalline cellulose, riboflavin (E 101); polyethylene glycol 4000; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, round-shaped, biconvex, from light yellow to yellow in colour.

Pharmacotherapeutic group. HMG-CoA reductase inhibitors. ATC code C10AA01.

Pharmacological Properties

Pharmacodynamics

After oral administration, simvastatin, an inactive lactone, is hydrolyzed in the liver to form the corresponding beta-hydroxyacid derivative, which has high inhibitory activity against HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase), the enzyme catalyzing the conversion of HMG-CoA to mevalonate—the initial and most significant step in cholesterol biosynthesis. Simvastatin has been shown to reduce both normal and elevated levels of low-density lipoprotein cholesterol (LDL-C). LDL is formed from very-low-density lipoprotein (VLDL) and is primarily catabolized by high-affinity LDL receptors. The LDL-lowering effect of simvastatin may involve both a reduction in VLDL cholesterol concentration and upregulation of LDL receptors, resulting in decreased production and increased catabolism of LDL cholesterol. Apolipoprotein B levels are also significantly reduced during simvastatin therapy. In addition, simvastatin markedly increases high-density lipoprotein cholesterol (HDL-C) and reduces plasma triglyceride levels. As a result of these changes, the ratios of total cholesterol to HDL-C and LDL-C to HDL-C are reduced.

Pharmacokinetics

Simvastatin is an inactive lactone that is readily hydrolyzed, converting in vivo to the beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs primarily in the liver; the rate of hydrolysis in human plasma is very low.

Pharmacokinetic properties were evaluated in adults. Pharmacokinetic data in children and adolescents are lacking.

Absorption. In humans, simvastatin is well absorbed and undergoes extensive first-pass hepatic metabolism. Delivery to the liver depends on hepatic blood flow. The liver is the primary site of action of the active form. Systemic bioavailability of the beta-hydroxyacid after an oral dose of simvastatin is less than 5% of the administered dose. Maximum plasma concentrations of active inhibitors are reached approximately 1–2 hours after simvastatin administration. Concomitant food intake does not affect absorption. Pharmacokinetics of single and multiple doses of simvastatin demonstrated no accumulation of the drug after repeated administration.

Distribution. The binding of simvastatin and its active metabolite to plasma proteins exceeds 95%.

Elimination. Simvastatin is a substrate of CYP3A4 (see sections «Contraindications» and «Interaction with other medicinal products and other forms of interactions»). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. After oral administration of radiolabeled simvastatin in humans, 60% of the radioactive dose was recovered in feces and 13% in urine within 96 hours. The amount recovered in feces represents both the absorbed drug excreted in bile and the unabsorbed drug. After intravenous administration of the beta-hydroxyacid metabolite, its mean elimination half-life is 1.9 hours. Only about 0.3% of the dose is excreted in urine as inhibitors.

Simvastatin acid is actively taken up into hepatocytes via the OATP1B1 transporter.

Simvastatin is a substrate of the efflux transporter breast cancer resistance protein (BCRP).

Special patient groups

SLCO1B1 polymorphism

Carriers of the c.521T>C allele of the SLCO1B1 gene exhibit reduced OATP1B1 transporter activity. The mean area under the concentration-time curve (AUC) of the major active metabolite—simvastatin acid—is 120% in heterozygous carriers (CT) and 221% in homozygous carriers (CC), compared to patients with the most common genotype (TT). The C allele occurs with a frequency of 18% in patients of European descent. Patients with the SLCO1B1 polymorphism are at risk of increased exposure to simvastatin acid, which may increase the risk of developing rhabdomyolysis (see section «Special precautions for use»).

Clinical characteristics.

Indications.

Hypercholesterolemia

Treatment of primary hypercholesterolemia or mixed dyslipidemia as an adjunct to diet when response to diet and other nonpharmacological treatments (e.g., physical exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering therapies (e.g., low-density lipoprotein apheresis) or when such treatment modalities are not suitable.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with established atherosclerotic cardiovascular disease or diabetes mellitus with normal or elevated cholesterol levels, as an additional therapy to correct other risk factors and in addition to other cardioprotective therapies (see section "Pharmacological properties. Pharmacodynamics").

Contraindications.

• Hypersensitivity to simvastatin or to any component of the medicinal product.
• Active liver disease or unexplained persistent elevations in serum transaminase levels.
• Concomitant use of strong CYP3A4 inhibitors (medicinal products that increase AUC approximately 5-fold or more), such as itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone, and medicinal products containing cobicistat (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").
• Concomitant use of gemfibrozil, cyclosporine, or danazol (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").
• In patients with homozygous familial hypercholesterolemia receiving lomitapide, simvastatin doses exceeding 40 mg are contraindicated (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", and "Dosage and administration").

Interaction with other medicinal products and other forms of interaction.

Several mechanisms of action of medicinal products may contribute to potential interactions with HMG-CoA reductase inhibitors. Medicinal products and herbal preparations that inhibit certain enzyme activities (e.g., CYP3A4) and/or transporter (e.g., OATP1B) may increase plasma concentrations of simvastatin and simvastatin acid and lead to an increased risk of myopathy/rhabdomyolysis.

Refer to the prescribing information of all concomitantly used medicinal products for additional information on their potential interactions with simvastatin and/or possible effects on enzymes or transporters, and potential dose adjustments or changes in administration regimens.

Interaction data are available only in adults.

Pharmacodynamic interaction

Interactions with lipid-lowering medicinal products that may cause myopathy when used individually. The risk of myopathy, including rhabdomyolysis, increases with concomitant administration of fibrates. In addition, a pharmacokinetic interaction with gemfibrozil has been observed, resulting in increased plasma levels of simvastatin (see subsection "Pharmacokinetic interaction" below and sections "Contraindications" and "Special warnings and precautions for use"). Regarding the combination of simvastatin and fenofibrate, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each medicinal product. Adequate data from pharmacovigilance and pharmacokinetic studies on other fibrates are lacking.

Occasionally, cases of myopathy/rhabdomyolysis have been associated with concomitant use of simvastatin and lipid-modifying doses (≥ 1 g/day) of niacin (see section "Special warnings and precautions for use").

Pharmacokinetic interaction

Recommendations for concomitant use of medicinal products interacting with simvastatin are summarized in the table below (see also sections "Contraindications", "Special warnings and precautions for use", and "Dosage and administration").

Interaction with other medicinal products associated with increased risk of myopathy/rhabdomyolysis

Interacting drugs	Appropriate recommendations
Potent CYP3A4 inhibitors, e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, cobicistat, cyclosporine, danazol, gemfibrozil	Contraindicated with simvastatin
Other fibrates (except fenofibrate)	Do not exceed 10 mg simvastatin per day
Fusidic acid	Not recommended with simvastatin
Niacin (nicotinic acid) (≥ 1 g/day)	Not recommended to be co-administered with simvastatin in patients of Asian ancestry
Amiodarone, amlodipine, verapamil, diltiazem, elbasvir, grazoprevir	Do not exceed 20 mg simvastatin per day
Lomitapide	In patients with HoFH, simvastatin should be administered at doses not exceeding 40 mg per day
Grapefruit juice	Avoid consumption of grapefruit juice when taking simvastatin.

Effect of other medicinal products on simvastatin

Interaction with CYP3A4 inhibitors. Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis due to elevated plasma concentrations of HMG-CoA reductase inhibitors during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, nefazodone, and medicinal products containing cobicistat. Concomitant administration of itraconazole resulted in more than a 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid. Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat, as well as with gemfibrozil, cyclosporine, and danazol, is contraindicated (see section "Contraindications"). If therapy with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be suspended and consideration should be given to using an alternative statin. Caution is advised when combining simvastatin with other, less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections "Special precautions for use", "Dosage and administration").

Fluconazole. Rare cases of rhabdomyolysis have been reported in association with concomitant use of simvastatin and fluconazole (see section "Special precautions for use").

Cyclosporine. The risk of developing myopathy/rhabdomyolysis increases when cyclosporine is used concomitantly with simvastatin; therefore, use with cyclosporine is contraindicated (see sections "Contraindications" and "Special precautions for use"). Although the mechanism is not fully understood, it has been demonstrated that cyclosporine increases the AUC of HMG-CoA reductase inhibitors. The increase in simvastatin AUC occurs primarily due to inhibition of CYP3A4 and/or the OATP1B1 transporter protein.

Danazol. The risk of developing myopathy and rhabdomyolysis increases when danazol is co-administered with simvastatin; therefore, use with danazol is contraindicated (see sections "Contraindications" and "Special precautions for use").

Gemfibrozil. Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway and/or the OATP1B1 transporter protein (see sections "Contraindications" and "Special precautions for use"). Concomitant use with gemfibrozil is contraindicated.

Fusidic acid. The risk of myopathy, including rhabdomyolysis, may be increased during concomitant use of systemic fusidic acid and statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) is unknown. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving this combination. Concomitant use of this combination may lead to increased plasma concentrations of both drugs. If systemic treatment with fusidic acid is required, simvastatin therapy should be discontinued for the duration of treatment (see section "Special precautions for use"). Concomitant use of this combination may lead to increased plasma concentrations of both drugs.

Amiodarone. The risk of myopathy and rhabdomyolysis increases during concomitant use of simvastatin and amiodarone (see section "Special precautions for use"). In a clinical study, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients taking this drug concomitantly with amiodarone.

Calcium channel blockers.

• Verapamil. The risk of myopathy and rhabdomyolysis increases during concomitant use of verapamil with simvastatin 40 mg or 80 mg (see section "Special precautions for use"). In a pharmacokinetic study, concomitant use with verapamil led to a 2.3-fold increase in the AUC of simvastatin acid, primarily due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients taking this drug concomitantly with verapamil.
• Diltiazem. The risk of myopathy and rhabdomyolysis increases during concomitant use of diltiazem with simvastatin 80 mg (see section "Special precautions for use"). In a pharmacokinetic study, concomitant use with diltiazem resulted in a 2.7-fold increase in the AUC of simvastatin acid, primarily due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients taking this drug concomitantly with diltiazem.
• Amlodipine. Patients taking amlodipine concomitantly with simvastatin have an increased risk of developing myopathy. In a pharmacokinetic study, concomitant use with amlodipine led to a 1.6-fold increase in the AUC of simvastatin acid. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients taking this drug concomitantly with amlodipine.
• Lomitapide. The risk of myopathy and rhabdomyolysis increases with concomitant use of lomitapide and simvastatin (see sections "Special precautions for use", "Contraindications", and "Dosage and administration"). Therefore, in patients with HoFH receiving concomitant lomitapide, the dose of simvastatin should not exceed 40 mg daily.

Moderate CYP3A4 inhibitors. Patients taking other medicinal products with moderate inhibitory effects on CYP3A4 concomitantly with simvastatin, especially at higher simvastatin doses, have an increased risk of developing myopathy (see section "Special precautions for use").

Inhibitors of the OATP1B1 transporter protein. Simvastatin acid is a substrate of the OATP1B1 transporter protein. Concomitant use of medicinal products known to be inhibitors of the OATP1B1 transporter protein may lead to increased plasma concentrations of simvastatin acid and an increased risk of developing myopathy (see sections "Contraindications" and "Special precautions for use").

Inhibitors of breast cancer resistance protein (BCRP). Concomitant use with BCRP inhibitors (including medicinal products containing elbasvir or grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of developing myopathy (see sections "Special precautions for use" and "Dosage and administration").

Niacin (nicotinic acid). Rare cases of myopathy/rhabdomyolysis have been associated with concomitant use of lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid). In a pharmacokinetic study, concomitant administration of a single 2 g dose of extended-release nicotinic acid with 20 mg simvastatin resulted in a moderate increase in the AUC and maximum plasma concentration (Cmax) of simvastatin and simvastatin acid.

Grapefruit juice. Grapefruit juice inhibits the activity of cytochrome P450 3A4. Concurrent consumption of large quantities of grapefruit juice (more than 1 L per day) and simvastatin resulted in a sevenfold increase in drug activity. Consumption of 240 mL of grapefruit juice in the morning and simvastatin in the evening also led to a 1.9-fold increase in effect. Therefore, grapefruit juice should be avoided during treatment with simvastatin.

Colchicine. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine and simvastatin in patients with renal impairment. Careful clinical monitoring of patients receiving this combination is recommended.

Rifampicin. Since rifampicin is a potent inducer of CYP3A4, loss of efficacy of simvastatin may occur in patients undergoing long-term rifampicin therapy (e.g., for treatment of tuberculosis). In a pharmacokinetic study involving healthy volunteers, the AUC of simvastatin acid decreased by 93% with concomitant administration of rifampicin.

Effect of simvastatin on the pharmacokinetics of other medicinal products. Simvastatin does not have an inhibitory effect on cytochrome P450 3A4; therefore, it is not expected that simvastatin will affect plasma concentrations of substances metabolized by cytochrome P450 3A4.

Oral anticoagulants. In two clinical studies, one involving healthy volunteers and the other involving patients with hypercholesterolemia, simvastatin at doses of 20–40 mg/day moderately increased the effect of coumarin anticoagulants: prothrombin time, measured as the international normalized ratio (INR), increased from a baseline value of 1.7 to 1.8 and from 2.6 to 3.4 in healthy volunteers and patients, respectively. Slightly elevated INR values have been observed in very rare cases. In patients receiving coumarin anticoagulants, prothrombin time should be measured before initiating simvastatin therapy and frequently monitored at the beginning of therapy to ensure no clinically significant change occurs. After prothrombin time has stabilized, monitoring can be performed at intervals typically recommended for patients receiving coumarin anticoagulants. This procedure should be repeated if the dose of simvastatin is changed or if simvastatin is discontinued. During simvastatin therapy in patients not taking anticoagulants, no bleeding or changes in prothrombin time were observed.

Special precautions for use.

There have been isolated reports that statins may induce de novo myasthenia gravis or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of symptom exacerbation, the medicinal product should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Myopathy/Rhabdomyolysis. Simvastatin, like other HMG-CoA reductase inhibitors, may cause myopathy, manifested as muscle pain, tenderness or weakness, accompanied by an increase in creatine kinase activity more than ten times above the upper limit of normal (ULN). Myopathy may occasionally progress to rhabdomyolysis, with or without acute renal failure due to myoglobinuria; very rare fatal cases have been reported. The risk of myopathy increases with high inhibitory activity against HMG-CoA reductase in plasma (elevated plasma levels of simvastatin and simvastatin acid), which may be partially related to interactions with medicinal products interfering with the metabolism and/or transport of simvastatin (see section "Interaction with other medicinal products and other forms of interaction").

As with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis is dose-dependent. In the clinical trial database involving 41,413 patients treated with simvastatin, of whom 24,747 (approximately 60%) were enrolled in studies with a mean follow-up period of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08%, and 0.61% at doses of 20, 40, and 80 mg/day, respectively. During these trials, patients were closely monitored and certain concomitant medications with potential interactions were excluded.

In a clinical trial where patients with a history of myocardial infarction received simvastatin 80 mg/day (mean follow-up period 6.7 years), the incidence of myopathy was approximately 1.0%, compared to 0.02% in patients receiving 20 mg/day. Approximately half of these cases of myopathy occurred during the first year of treatment. The incidence of myopathy in each subsequent year of treatment was approximately 0.1% (see sections "Pharmacological properties" and "Adverse reactions").

The risk of myopathy is higher in patients receiving 80 mg of simvastatin compared to patients on other statins with similar LDL-cholesterol-lowering efficacy. Therefore, the 80 mg dose of simvastatin should be used only in patients with severe hypercholesterolemia and high cardiovascular risk who have not achieved treatment goals with lower doses, and when the expected benefit outweighs the potential risks. For patients taking simvastatin 80 mg who require concomitant use of a medicinal product that may potentially interact, a lower dose of simvastatin or an alternative statin with lower interaction potential should be considered (see below "Measures to reduce the risk of drug interaction-induced myopathy", "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration").

In a clinical trial involving patients at high risk of cardiovascular disease receiving simvastatin 40 mg/day (median follow-up period 3.9 years), the incidence of myopathy was approximately 0.05% in non-Chinese patients (n=7,367) compared to 0.24% in Chinese patients (n=5,468). Although the Asian population in this clinical trial was represented only by Chinese patients, simvastatin should be used with caution in patients of Asian origin, and the lowest dose should be prescribed.

Impaired transporter function. Impaired hepatic transporter protein OATP function may increase systemic exposure to simvastatin acid and elevate the risk of myopathy and rhabdomyolysis. This impairment may result from inhibition by interacting agents (e.g., cyclosporine) or in patients who are carriers of the SLCO1B1 (c.521T>C) genotype.

Patients who are carriers of the SLCO1B1 (c.521T>C) allele, encoding a less active OATP1B1 protein, exhibit increased systemic exposure to simvastatin acid and an elevated risk of myopathy. Regardless of genetic testing, the risk of developing myopathy associated with high-dose (80 mg) simvastatin is approximately 1%. SEARCH study results indicate that the risk of developing myopathy within one year is 15% in homozygous carriers of the C allele (designated CC), 1.5% in heterozygous carriers (CT), and 0.3% in patients with the most common genotype (TT). Where possible, genotyping for the C allele should be considered before initiating simvastatin 80 mg in individual patients to assess the benefit-risk ratio and to avoid high doses in CC genotype carriers. However, absence of this gene by genotyping does not exclude the possibility of myopathy in these patients.

Measurement of creatine kinase. Creatine kinase levels should not be measured after strenuous physical exercise or in the presence of any likely alternative cause of elevated creatine kinase, as this complicates interpretation of results. In case of significant elevation of creatine kinase (more than 5 times ULN), repeat measurement should be performed after 5–7 days to confirm the results.

Before treatment. All patients initiating simvastatin therapy, as well as patients whose simvastatin dose has been increased, should be informed about the possibility of developing myopathy and the need to seek immediate medical attention if unexplained muscle pain, tenderness, or muscle weakness occurs. Caution should be exercised in patients with predisposing factors for rhabdomyolysis. To establish an appropriate baseline, creatine kinase levels should be measured before starting treatment in the following situations:

• Advanced age (age ≥ 65 years);
• Female sex;
• Renal impairment;
• Uncontrolled hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• History of muscle toxicity associated with statins or fibrates;
• Alcohol abuse.

In these situations, the risk of treatment should be weighed against the potential benefit, and clinical monitoring is recommended. If a patient previously experienced muscle-related adverse events with a fibrate or statin, initiation of another agent in this class should be done cautiously. Treatment should not be initiated if baseline creatine kinase levels are significantly elevated (more than 5 times ULN).

During treatment. If pain, weakness, or cramps occur during statin therapy, creatine kinase levels should be measured. If levels are significantly elevated (>5 times ULN) in the absence of strenuous physical exertion, treatment should be discontinued. If muscle symptoms are severe and cause daily discomfort, even if creatine kinase levels are <5 times ULN, discontinuation of treatment may be considered. Treatment should be discontinued if myopathy is suspected for any other reason. Very rarely, immune-mediated necrotizing myopathy (IMNM) associated with statin use has been reported during or after statin therapy. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that do not resolve despite discontinuation of statins (see section "Adverse reactions").

If symptoms resolve and creatine kinase levels return to normal, re-initiation of the same statin or an alternative statin at a low dose under close monitoring should be considered. A higher incidence of myopathy has been observed in patients whose dose was increased to 80 mg (see section "Pharmacological properties"). Periodic measurement of creatine kinase is recommended, as it may help detect subclinical cases of myopathy. However, there is no reliable evidence that such monitoring prevents the development of myopathy.

Simvastatin therapy should be temporarily discontinued several days before major surgical procedures, as well as after medical or surgical interventions.

Measures to reduce the risk of drug interaction-induced myopathy (also see section "Interaction with other medicinal products and other forms of interaction"). The risk of myopathy and rhabdomyolysis is significantly increased when simvastatin is co-administered with strong CYP3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat, as well as with gemfibrozil, cyclosporine, and danazol. Concomitant use of these medicinal products is contraindicated (see section "Contraindications").

The risk of myopathy and rhabdomyolysis is also increased when simvastatin is co-administered with amiodarone, amlodipine, verapamil, or diltiazem at certain simvastatin doses (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration"). The risk of myopathy, including rhabdomyolysis, increases when fusidic acid is co-administered with statins (see section "Interaction with other medicinal products and other forms of interaction"). In patients with HoFH, this risk increases when lomitapide is co-administered with simvastatin.

Thus, concomitant use of simvastatin with CYP3A4 inhibitors—itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat—is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). If therapy with strong CYP3A4 inhibitors (agents increasing AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be suspended for the duration of treatment with these agents, and an alternative statin should be considered. Furthermore, caution should be exercised when co-administering simvastatin with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration"). Concomitant intake of grapefruit juice and simvastatin should be avoided.

Concomitant use of simvastatin with gemfibrozil is contraindicated (see section "Contraindications"). Due to the increased risk of myopathy and rhabdomyolysis, the simvastatin dose must not exceed 10 mg daily in patients receiving simvastatin with other fibrates except fenofibrate (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration"). Fenofibrate should be prescribed with caution together with simvastatin, as each of these agents may cause myopathy.

Simvastatin should not be taken simultaneously with systemic formulations containing fusidic acid or within 7 days after discontinuation of fusidic acid. If fusidic acid is required, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience symptoms of muscle weakness or pain, pain or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is necessary, e.g., for treating severe infections, concomitant use of simvastatin and fusidic acid should be considered only on a case-by-case basis and under close medical supervision.

Concomitant use of simvastatin in doses exceeding 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. Concomitant use of lomitapide and simvastatin in doses exceeding 40 mg daily is contraindicated in patients with HoFH (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration").

Patients receiving other medicinal products with moderate inhibitory effects on CYP3A4 concomitantly with simvastatin, especially with high simvastatin doses, may have an increased risk of developing myopathy. Dose adjustment of simvastatin may be required when co-administered with a moderate CYP3A4 inhibitor (agents increasing AUC approximately 2–5-fold). When co-administering simvastatin with certain moderate CYP3A4 inhibitors, e.g., diltiazem, the maximum recommended dose is 20 mg simvastatin (see section "Posology and method of administration").

Simvastatin is a substrate of the breast cancer resistance protein (BCRP) efflux transporter. Concomitant use with BCRP inhibitors (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy. Therefore, depending on the dose of BCRP inhibitors prescribed, simvastatin dose adjustment may be necessary. Concomitant use of elbasvir and grazoprevir with simvastatin has not been studied, but the daily dose of simvastatin must not exceed 20 mg in patients receiving concomitant therapy with medicinal products containing elbasvir or grazoprevir (see section "Interaction with other medicinal products and other forms of interaction").

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant use of HMG-CoA reductase inhibitors and lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid); each of these agents may cause myopathy.

In a clinical trial (median follow-up period 3.9 years) involving patients at high risk of cardiovascular disease with well-controlled LDL-cholesterol levels on simvastatin 40 mg/day with or without ezetimibe, no additional cardiovascular benefit was observed with the addition of lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid). Physicians considering combined therapy with simvastatin and lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or niacin-containing products should carefully weigh the potential benefits and risks. Patients should be closely monitored for muscle pain, tenderness, or weakness, particularly during the first months of therapy and when increasing the dose of either agent.

In the study, the incidence of myopathy was approximately 0.24% among Chinese patients receiving simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg, compared to 1.24% among Chinese patients receiving simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg together with a combination product of extended-release niacin/laropiprant 2000 mg/40 mg. Although the Asian population in this clinical trial was represented only by Chinese patients, because the incidence of myopathy is higher in Chinese patients than in non-Chinese patients, concomitant use of simvastatin and lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) is not recommended in patients of Asian origin.

Acipimox is structurally similar to niacin. Although acipimox has not been studied, the risk of muscle toxicity may be similar to that with niacin.

Liver effects. In clinical trials, persistent elevations in serum transaminases (>3 times ULN) were observed in several adult patients receiving simvastatin. Upon temporary interruption or discontinuation of simvastatin, transaminase activity usually returned gradually to baseline levels.

Liver function tests are recommended before starting treatment and subsequently as clinically indicated in all patients. For patients planned to increase simvastatin dose to 80 mg daily, additional liver function tests should be performed before dose titration, then 3 months after reaching 80 mg daily, followed by periodic monitoring (e.g., every 6 months) during the first year of treatment. Particular attention should be paid to patients with elevated serum transaminases. These patients should have liver function tests repeated immediately and monitored more frequently. If transaminase levels rise, especially with persistent elevations exceeding 3 times ULN, the drug should be discontinued. Note that alanine aminotransferase may be released from muscle tissue; therefore, elevated alanine aminotransferase with elevated creatine kinase may indicate myopathy (see above "Myopathy/Rhabdomyolysis").

During the post-marketing period, rare cases of liver failure (including fatal cases) have been reported in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during simvastatin therapy, treatment should be immediately discontinued. If no other cause for these symptoms is identified, re-initiation of simvastatin should not be considered.

The medicinal product should be used with caution in patients who abuse alcohol.

With simvastatin therapy, as with other lipid-lowering agents, mild (<3 times ULN) increases in serum transaminase activity have been reported. These changes typically occur soon after starting treatment, are often transient, asymptomatic, and do not require discontinuation of therapy.

Diabetes mellitus. Evidence indicates that statins as a class increase blood glucose levels and may cause hyperglycemia in some patients at high future risk of diabetes, requiring initiation of diabetes treatment. However, the benefit of statins in reducing cardiovascular risk outweighs this risk, which should not be a reason for discontinuing statin therapy. Patients at risk of developing diabetes (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

Lung interstitial disease. Cases of interstitial lung disease have been reported with some statins, including simvastatin, particularly during long-term therapy (see section "Adverse reactions"). Relevant manifestations may include dyspnea, non-productive cough, and deterioration in general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Ophthalmological examination. In the absence of any pharmacological treatment, lens opacity progression is considered part of the aging process. Available data from long-term clinical trials do not indicate a harmful effect of simvastatin on the human eye lens.

Use in elderly patients. The efficacy of simvastatin in patients aged 65 years and older treated during controlled clinical trials was evaluated in terms of reduction in total cholesterol and LDL-cholesterol levels and was found to be comparable to that in the general population. No increase in clinically or laboratory-detected adverse reactions has been observed.

Excipients. The medicinal product contains lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Patients with known sugar intolerance should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

The medicinal product is contraindicated in pregnant women.

The safety of simvastatin use during pregnancy has not been established. No controlled clinical trials of simvastatin have been conducted in pregnant women. Rare cases of congenital anomalies have been reported after intrauterine exposure to HMG-CoA reductase inhibitors. However, analysis of approximately 200 prospectively followed pregnancies with first-trimester exposure to simvastatin or another similar HMG-CoA reductase inhibitor showed a frequency of congenital anomalies comparable to that in the general population. This number of pregnancy cases was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies compared to the general population. Although there is no evidence that the frequency of congenital anomalies in offspring of patients treated with simvastatin or another similar HMG-CoA reductase inhibitor differs from that in the general population, simvastatin treatment in the mother may reduce fetal mevalonate levels, a precursor in cholesterol biosynthesis. Atherosclerosis is a chronic process. Discontinuation of lipid-lowering agents during pregnancy usually has minimal impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, simvastatin must not be prescribed to pregnant women or to women attempting to become pregnant or suspected of being pregnant. Simvastatin should be suspended for the entire duration of pregnancy or until pregnancy is ruled out.

Breastfeeding period. It is unknown whether simvastatin or its metabolites are excreted in human breast milk. Because many drugs are excreted in breast milk and due to the significant risk of serious adverse reactions in nursing women taking simvastatin, breastfeeding should be avoided.

Fertility. There are no data from clinical studies on the effect of simvastatin on human fertility. Simvastatin did not affect fertility in male and female rats.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has no effect or a negligible effect on the ability to drive cars or operate machinery. However, when driving or operating machinery, it should be noted that during the post-marketing period, rare cases of dizziness have been reported.

Method of Administration and Dosage.

The dosage range for simvastatin is 5 to 80 mg orally once daily in the evening. If needed, the simvastatin dose should be increased at intervals of at least 4 weeks up to the maximum daily dose of 80 mg, taken once daily in the evening. The 80 mg dose is recommended only for patients with severe hypercholesterolemia and high cardiovascular risk who have not achieved treatment goals with lower doses, and when the expected benefit outweighs the potential risk (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Hypercholesterolemia.

The patient should be placed on a standard cholesterol-lowering diet, which must be maintained throughout the treatment period with simvastatin.

The usual initial dose of simvastatin is 10–20 mg once daily in the evening. For patients requiring substantial (more than 45%) reduction in LDL-C levels, the initial dose may be 20–40 mg once daily in the evening. If necessary, dose titration should be performed as described above.

Homozygous familial hypercholesterolemia.

Based on results from a controlled clinical study, the recommended initial dose of simvastatin is 40 mg once daily in the evening. The drug should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatment is unavailable.

For patients receiving concomitant lomitapide, the simvastatin dose must not exceed 40 mg/day (see sections "Contraindications", "Interactions with Other Medicinal Products and Other Forms of Interactions", and "Special Warnings and Precautions for Use").

Cardiovascular prevention.

The usual dose of simvastatin for patients at high risk of ischemic heart disease (with or without hyperlipidemia) is 20–40 mg once daily in the evening. Pharmacological therapy may be initiated simultaneously with diet and exercise. If necessary, dose titration should be performed as described above.

Concomitant therapy.

The drug is effective as monotherapy and in combination with bile acid sequestrants. The dose should be taken either >2 hours before or >4 hours after administration of a bile acid sequestrant. For patients receiving simvastatin concomitantly with fibrates other than gemfibrozil (see section "Contraindications") or fenofibrate, the simvastatin dose must not exceed 10 mg/day. For patients receiving simvastatin concomitantly with amiodarone, amlodipine, verapamil, or diltiazem, the daily simvastatin dose must not exceed 20 mg (see sections "Interactions with Other Medicinal Products and Other Forms of Interactions" and "Special Warnings and Precautions for Use").

Renal impairment.

No dosage adjustment is required for patients with mild to moderate renal impairment. For patients with severe renal impairment (creatinine clearance <30 mL/min), the appropriateness of initiating treatment with a 10 mg daily dose should be carefully considered. If such dosing is deemed necessary, the drug should be administered with caution.

Use in elderly patients. No dose adjustment is required.

Use in children and adolescents (10–17 years).

For children and adolescents (boys at Tanner stage II or higher and girls who have had at least one year of menstrual cycles) with heterozygous familial hypercholesterolemia, the recommended usual initial dose is 10 mg once daily in the evening. Before initiating simvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained during treatment with simvastatin.

Recommended doses are 10–40 mg daily; the maximum recommended dose is 40 mg daily. The dose should be individually titrated according to treatment goals and in accordance with pediatric treatment guidelines (see sections "Pharmacodynamics", "Special Warnings and Precautions for Use"). Dose titration should be performed at intervals of 4 weeks or longer. Experience with simvastatin use in prepubertal children is limited.

The safety and efficacy of doses exceeding 40 mg daily in children with heterozygous familial hypercholesterolemia have not been studied. The long-term efficacy of simvastatin therapy in childhood for reducing morbidity and mortality in adulthood has not been established.

Children.

The safety and efficacy of simvastatin in patients aged 10–17 years with heterozygous familial hyperlipidemia were evaluated in a controlled clinical study involving boys at Tanner stage II or higher and girls who had at least one year of menstrual cycles. The adverse reaction profile in patients receiving simvastatin was generally similar to that in patients receiving placebo. Doses above 40 mg were not studied in this patient group. In this study, no effects of simvastatin on growth, sexual development, or menstrual cycle duration in girls were observed (see sections "Pharmacodynamics", "Method of Administration and Dosage", and "Adverse Reactions"). Girls should be counselled regarding available contraceptive methods when using simvastatin (see sections "Contraindications" and "Use in Pregnancy and Lactation"). For patients under 18 years of age, the efficacy and safety of the drug have not been studied beyond 48 weeks of treatment; the long-term impact on physical, cognitive, and sexual development is unknown. Simvastatin has not been studied in patients under 10 years of age, in prepubertal children, or in girls who have not yet started menstruating.

Overdose.

There have been a few reported cases of overdose to date. The maximum ingested dose was 3.6 g. All patients recovered without sequelae. There is no specific antidote for simvastatin overdose. In case of overdose, symptomatic and supportive measures should be undertaken.

Adverse Reactions

The frequency of the adverse reactions listed below, reported during clinical trials and/or in the post-marketing period, is classified based on their incidence rates observed in large, long-term, placebo-controlled clinical studies, including HPS and 4S, involving 20,536 and 4,444 patients, respectively. In HPS, only serious adverse reactions, myalgia, elevated serum transaminases, and creatine kinase were recorded. In 4S, all adverse reactions listed below were documented. If the incidence rates during these studies were lower or similar with simvastatin compared to placebo, and spontaneous reports of events with a reasonable causal relationship were comparable, such adverse reactions were classified as rare. In the HPS study involving 20,536 patients receiving either 40 mg/day simvastatin (n=10,269) or placebo (n=10,267), the safety profiles were comparable between simvastatin 40 mg and placebo groups over a mean study duration of 5 years. Discontinuation rates due to adverse reactions were similar (4.8% in patients receiving simvastatin 40 mg versus 5.1% in those receiving placebo). The incidence of myopathy was <0.1% in patients receiving simvastatin 40 mg. Elevated transaminases (>3 times the upper limit of normal, confirmed by repeat testing) occurred in 0.21% (n=21) of patients receiving simvastatin 40 mg, compared to 0.09% (n=9) of patients receiving placebo.

Frequency of adverse reactions: very common (>1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders. Rare: anaemia.

Immune system disorders. Very rare: anaphylaxis.

Psychiatric disorders. Very rare: insomnia. Frequency not known: depression.

Nervous system disorders. Uncommon: headache, paraesthesia, dizziness, peripheral neuropathy. Very rare: memory impairment. Frequency not known: myasthenia gravis.

Eye disorders. Frequency not known: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders. Frequency not known: interstitial lung disease (see section "Special precautions").

Gastrointestinal disorders. Uncommon: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis.

Hepatobiliary disorders. Uncommon: hepatitis/jaundice. Very rare: fatal and non-fatal hepatic failure.

Skin and subcutaneous tissue disorders. Uncommon: rash, pruritus, alopecia.

Musculoskeletal and connective tissue disorders. Uncommon: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section "Special precautions"), myalgia, muscle spasms.

* In clinical trials, myopathy occurred more frequently in patients receiving simvastatin 80 mg daily compared to those receiving 20 mg daily (0.1% vs. 0.02%, respectively).

Frequency not known: tendonopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy (IMNM)**.

** Very rare cases of IMNM, an autoimmune myopathy, have been observed during or after statin therapy. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that do not resolve despite discontinuation of statin therapy, necrotizing myopathy features on muscle biopsy without significant inflammation, and improvement with immunosuppressive therapy (see section "Special precautions. Myopathy/Rhabdomyolysis").

Reproductive system and breast disorders. Frequency not known: erectile dysfunction.

General disorders and administration site conditions. Uncommon: asthenia. Rare cases of hypersensitivity syndrome have been reported, including some of the following manifestations: angioneurotic oedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, elevated ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, hot flushes, dyspnoea, and fatigue.

Investigations. Uncommon: increased serum transaminases (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) (see sections "Special precautions", "Hepatic effects"); increased alkaline phosphatase levels; increased serum creatine kinase levels (see section "Special precautions").

Increases in HbA1c and fasting serum glucose levels have been reported during statin use, including simvastatin.

During the post-marketing period, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, memory disturbance, confusion) associated with statin use, including simvastatin, have been received. Overall, these cases were mild and reversible upon discontinuation of the statin; time to onset of symptoms (ranging from 1 day to years) and symptom resolution (on average 3 weeks) varied.

With use of certain statins, additional adverse reactions reported include: sleep disorders, including nightmares; sexual dysfunction; diabetes mellitus: incidence may depend on presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI >30 kg/m², elevated triglycerides, history of hypertension).

Paediatric population (aged 10–17 years)

In a 48-week study involving children and adolescents (boys at Tanner stage II or above and girls with at least one year of established menstruation), aged 10–17 years, with heterozygous familial hypercholesterolaemia (n=175), the safety and tolerability profile in patients receiving simvastatin was generally similar to that in patients receiving placebo. The long-term effect on physical, intellectual, and sexual development is unknown. There are insufficient data beyond one year of treatment (see sections "Dosage and administration" and "Special precautions").

Shelf life. 3 years. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging. Tablets No. 10x3 in blisters in a carton.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

LIMITED LIABILITY COMPANY "FARMEKS GROUP".

Address of manufacturer and location of business activity.
22 Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.
(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")

100 Shevchenka Street, Boryspil, Kyiv region, 08301, Ukraine.
(LIMITED LIABILITY COMPANY "FARMEKS GROUP")