Simvasterol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIMVASTEROL (SIMVASTEROL)

Composition:

Active substance: simvastatin;

One film-coated tablet contains 20 mg or 40 mg of simvastatin;

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, butylhydroxyanisole (E 320), ascorbic acid, citric acid, colloidal anhydrous silicon dioxide, talc, magnesium stearate;

Tablet coating: hypromellose (Pharmacoat® 606), iron oxide red (E 172), hypromellose (Methocel® E15 LV Premium), talc, iron oxide yellow (E 172), triethyl citrate, titanium dioxide (E 171), talc, povidone K-30.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

20 mg tablets: oval, biconvex, film-coated, orange-colored;

40 mg tablets: oval, biconvex, film-coated, pink-colored.

Pharmacotherapeutic group. Hypolipidemic agents, single-component. HMG-CoA reductase inhibitors. ATC code C10AA01.

Pharmacological Properties

Pharmacodynamics. After oral administration, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding beta-hydroxyacid derivative, a potent inhibitor of 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. It has been demonstrated that Simvasterol reduces 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 mechanism of LDL-lowering effect of Simvasterol may involve both a reduction in VLDL-C concentration and stimulation of LDL receptors, thereby decreasing LDL-C production and increasing its catabolism. Apolipoprotein B levels also decrease significantly during treatment with Simvasterol. In addition, Simvasterol 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. Hepatic uptake is dependent on hepatic blood flow. The liver is the primary site of action of the active form. Systemic bioavailability of the beta-hydroxyacid following an oral dose of simvastatin has been found to be less than 5% of the administered dose. Peak concentrations of active inhibitors in plasma are reached approximately 1–2 hours after administration of simvastatin. 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. Plasma protein binding of simvastatin and its active metabolite is > 95%.

Elimination. Simvastatin is a substrate of CYP3A4 (see section "Contraindications", "Interaction with other medicinal products and other forms of interaction"). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. After oral administration of radiolabeled simvastatin to humans, 60% of the administered radioactivity was recovered in feces and 13% in urine within 96 hours. The amount recovered in feces represents both absorbed drug excreted in bile and unabsorbed drug. After intravenous administration of the beta-hydroxyacid metabolite, its mean elimination half-life is 1.9 hours. On average, only 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).

SLCO1B1 Polymorphism

In carriers of the SLCO1B1 c.521T > C allele, reduced OATP1B1 transporter activity is observed. The mean exposure (AUC) of the major active metabolite—simvastatin acid—is 120% higher in heterozygous carriers (CT) and 221% higher in homozygous carriers (CC), compared to patients with the most common genotype (TT). The C allele occurs in the European population with a frequency of 18%, while the homozygous CC genotype is found with a frequency of 1.5%. Patients with the SLCO1B1 polymorphism are at risk of increased exposure to simvastatin acid, which increases the risk of developing rhabdomyolysis (see section "Special Warnings and Precautions for Use").

Clinical characteristics.

Indications.

Hypercholesterolemia

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

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

Cardiovascular prevention

Use to reduce cardiovascular mortality and morbidity in patients with established atherosclerotic cardiovascular disease or diabetes, with normal or elevated cholesterol levels, as an adjunctive therapy to correction of other risk factors and 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.
• Pregnancy and breastfeeding (see section "Use in pregnancy or lactation").
• Concomitant use of strong CYP3A4 inhibitors (agents 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 "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of gemfibrozil, cyclosporine, or danazol (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Homozygous familial hypercholesterolemia in patients receiving lomitapide and Simvastaterol at doses exceeding 40 mg (see sections "Dosage and administration", "Special warnings and precautions for use", and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Several mechanisms may contribute to interactions with HMG-CoA reductase inhibitors. Medicinal products or herbal preparations that inhibit certain enzyme pathways (e.g., CYP3A4) and/or transporters (e.g., OATP1B1) may increase plasma concentrations of simvastatin and simvastatin acid and lead to myopathy/rhabdomyolysis.

Refer to the prescribing information of concurrently administered medicinal products for additional information on their potential interaction with simvastatin, on possible effects on enzymes or transporters, and on potential dose adjustments and administration regimens.

Interaction studies have been conducted only in adults.

Pharmacodynamic interaction

Interactions with lipid-lowering medicinal products that may cause myopathy. A pharmacokinetic interaction has been observed with gemfibrozil, 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 risks when each drug is used alone. Adequate data from pharmacovigilance and pharmacokinetic studies are lacking for other fibrates.

The risk of myopathy, including rhabdomyolysis, increases when administered concomitantly with fibrates. Cases of myopathy/rhabdomyolysis have occasionally been associated with concomitant use of simvastatin with lipid-modifying doses (≥ 1 g/day) of niacin (see section "Special warnings and precautions for use").

Pharmacokinetic interaction

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

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

Effects 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 by increasing plasma concentrations of the HMG-CoA reductase inhibitory activity 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, 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 given to using an alternative statin) during such treatment. Caution should be exercised when combining simvastatin with other less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see section "Dosage and administration", "Special precautions").

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

Cyclosporine. The risk of developing myopathy/rhabdomyolysis increases when cyclosporine is co-administered with simvastatin; therefore, concomitant use with cyclosporine is contraindicated (see sections "Contraindications" and "Special precautions"). Although the mechanism of action 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, in part, 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, concomitant use with danazol is contraindicated (see sections "Contraindications" and "Special precautions").

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"). Concomitant use with gemfibrozil is contraindicated.

Fusidic acid. The risk of myopathy, including rhabdomyolysis, is increased during concomitant use of systemic fusidic acid and statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients taking this combination. If systemic treatment with fusidic acid is required, simvastatin therapy should be discontinued for the duration of treatment (see section "Special precautions"). 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 with amiodarone (see section "Special precautions"). In a clinical study, 6% of patients taking simvastatin 80 mg and amiodarone reported myopathy. 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"). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure to simvastatin acid, primarily due to partial 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"). In a pharmacokinetic study, concomitant administration with diltiazem resulted in a 2.7-fold increase in exposure to simvastatin acid, primarily due to partial 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 administration with amlodipine resulted in a 1.6-fold increase in exposure to 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 when lomitapide is used concomitantly with simvastatin. 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 effect on CYP3A4 concomitantly with simvastatin, especially at higher simvastatin doses, have an increased risk of developing myopathy (see section "Special precautions").

Inhibitors of the OATP1B1 transporter protein. Simvastatin acid is a substrate of the OATP1B1 transporter protein. Concomitant administration of medicinal products that are inhibitors of the OATP1B1 transporter protein may lead to increased plasma concentrations of simvastatin acid and development of myopathy (see sections "Contraindications" and "Special precautions").

Inhibitors of the 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 development of myopathy (see sections "Dosage and administration", "Special precautions").

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 simvastatin 20 mg resulted in a moderate increase in AUC of simvastatin and simvastatin acid, and in Cmax concentrations of simvastatin acid in plasma.

Daptomycin. Cases of myopathy and/or rhabdomyolysis have been observed during concomitant use of HMG-CoA reductase inhibitors with daptomycin. Caution should be exercised when prescribing HMG-CoA reductase inhibitors with daptomycin, as each of these agents may cause myopathy and/or rhabdomyolysis. Patients receiving daptomycin should temporarily discontinue use of the medicinal product Symvastorol.

Grapefruit juice. Grapefruit juice inhibits the activity of cytochrome P450 3A4. Simultaneous 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 simvastatin therapy.

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

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 area under the concentration-time curve (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. In very rare cases, elevated INR values were observed. In patients treated with coumarin anticoagulants, prothrombin time should be measured before starting simvastatin therapy and frequently monitored at the beginning of therapy to ensure no significant change in this parameter. After stabilization of prothrombin time, monitoring can be performed at intervals typically recommended for patients on coumarin anticoagulants. This procedure should be repeated when changing or discontinuing simvastatin. During simvastatin therapy in patients not taking anticoagulants, no bleeding or changes in prothrombin time were observed.

Special precautions for use.

Myopathy/Rhabdomyolysis. Simvastatin, like other HMG-CoA reductase inhibitors, may cause myopathy, which presents as muscle pain, tenderness or weakness and is associated with an increase in creatine kinase activity to more than ten times 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 due to high plasma levels of inhibitory activity against HMG-CoA reductase (elevated plasma levels of simvastatin and simvastatin acid), which may be partially related to interactions with medicinal products that interfere 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, where 41,413 patients received Simvasterol, of whom 24,747 (approximately 60%) were enrolled in studies with a mean observation 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 interacting medicinal products were excluded. In a clinical trial where patients with a history of myocardial infarction received Simvasterol 80 mg/day (mean observation 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 within the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1% (see section "Adverse reactions", "Pharmacological properties"). The risk of myopathy is higher in patients receiving 80 mg of simvastatin compared to patients receiving other statins with similar efficacy in lowering LDL-C. Therefore, the 80 mg dose of Simvasterol should be used only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications who have not achieved treatment goals with lower doses, and when the expected benefit outweighs the potential risks. For patients receiving 80 mg of simvastatin who require concomitant therapy with interacting medicinal products, a lower dose of simvastatin or an alternative statin with a lower potential for interaction with other medicinal products should be used (see below "Measures to reduce the risk of myopathy caused by interaction with other medicinal products", "Contraindications", "Dosage and administration", and "Interaction with other medicinal products and other forms of interaction").

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

Cases of de novo occurrence or exacerbation of pre-existing myasthenia gravis or ocular myasthenia have been reported after statin use (see section "Adverse reactions"). Treatment with Simvasterol should be discontinued if symptoms worsen. Recurrences have been reported after re-administration of the same or another statin.

Reduced function of transporter proteins

Reduced function of hepatic transporter proteins from the OATP family may increase systemic exposure to simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function 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 carry the SLCO1B1 (c.521T > C) allele, encoding a less active OATP1B1 protein, have increased systemic exposure to simvastatin acid and an increased risk of myopathy. Regardless of genetic testing, the risk of developing myopathy associated with high doses (80 mg) of simvastatin is approximately 1% overall. Results from the SEARCH study show that homozygous carriers of the C allele (designated CC) taking 80 mg of simvastatin have a 15% risk of developing myopathy within one year, while the risk in heterozygous carriers of the C allele (CT) is 1.5%. The corresponding risk in patients with the most common genotype (TT) is 0.3%. Whenever possible, genotyping for the presence of the C allele should be performed before prescribing 80 mg of simvastatin to individual patients as part of a benefit-risk assessment, and high doses should be avoided in those identified as CC genotype carriers. However, the absence of this gene based on genotyping does not exclude the possibility of developing 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 probable alternative cause of elevated creatine kinase, as this complicates the interpretation of existing values. If significantly elevated creatine kinase levels are observed at baseline (more than 5 times ULN), levels should be re-measured after 5–7 days to confirm the results.

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

• advanced age (age ≥ 65 years);
• female sex;
• renal impairment;
• uncontrolled hypothyroidism;
• personal or family history of inherited muscle disorders;
• history of muscle toxicity due to statins or fibrates;
• alcohol abuse.

In such situations, the risk of treatment should be considered relative to the potential benefit, and clinical monitoring is also recommended. If a patient previously experienced muscle-related adverse effects with a fibrate or statin, treatment with another agent in this class should be initiated with caution. 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 use, creatine kinase levels should be measured. If these levels are significantly elevated (> 5 × 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 × ULN, discontinuation of treatment should be considered. Treatment should be discontinued if myopathy is suspected for any other reason. Very rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy occurring during or after statin treatment, have been observed. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that do not resolve despite discontinuation of statin use (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 percentage of myopathy was observed in patients whose dose was increased to 80 mg. Periodic measurement of creatine kinase levels is recommended, as this may help detect subclinical cases of myopathy. However, there are no reliable data indicating that such monitoring can prevent the development of myopathy. Simvastatin therapy should be temporarily discontinued in patients several days before major surgical procedures, as well as after medical or surgical interventions.

Measures to reduce the risk of myopathy caused by interaction with other medicinal products (also see section "Interaction with other medicinal products and other forms of interaction"). The risk of developing myopathy and rhabdomyolysis is significantly increased when simvastatin is used concomitantly with potent 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. The use of these medicinal products is contraindicated (see section "Contraindications"). The risk of developing myopathy and rhabdomyolysis is also increased when amiodarone, amlodipine, verapamil, or diltiazem are used concomitantly with certain doses of simvastatin (see section "Dosage and administration", "Interaction with other medicinal products and other forms of interaction"). The risk of developing myopathy, including rhabdomyolysis, increases when fusidic acid is used concomitantly with statins. In patients with HoFH, this risk increases when lomitapide and simvastatin are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, the 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", "Interaction with other medicinal products and other forms of interaction"). If therapy with potent CYP3A4 inhibitors (agents increasing AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be discontinued for the duration of treatment with these agents (and consideration should be given to using an alternative statin). Additionally, simvastatin should be used cautiously when used concomitantly with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of grapefruit juice and simvastatin should be avoided. The use of simvastatin with gemfibrozil is contraindicated (see section "Contraindications"). Due to the increased risk of developing myopathy and rhabdomyolysis, the dose of simvastatin should not exceed 10 mg/day for patients taking simvastatin with other fibrates, except fenofibrate (see section "Dosage and administration", "Interaction with other medicinal products and other forms of interaction"). Fenofibrate should be prescribed with caution concomitantly with simvastatin, as each of these agents may cause myopathy. Simvastatin should not be taken concomitantly with systemic medicinal products containing fusidic acid or within 7 days after discontinuation of fusidic acid. If fusidic acid use is necessary, 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 taking a combination of 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 long-term systemic treatment with fusidic acid is necessary, e.g., in severe infections, the need for concomitant use of simvastatin and fusidic acid should be evaluated on a case-by-case basis and treatment should be conducted under close medical supervision. Concomitant use of simvastatin at doses exceeding 20 mg/day with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. In patients with HoFH, the risk of myopathy increases when lomitapide and simvastatin are used concomitantly (see section "Dosage and administration", "Interaction with other medicinal products and other forms of interaction"). Patients taking other medicinal products with a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, especially with high doses of simvastatin, have an increased risk of developing myopathy. When simvastatin is used concomitantly with a moderate CYP3A4 inhibitor (agents increasing AUC approximately 2–5-fold), dose adjustment of simvastatin may be required. With concomitant use of certain moderate CYP3A4 inhibitors, such as diltiazem, a maximum dose of 20 mg simvastatin is recommended (see section "Dosage and administration").

Simvastatin is a substrate of the efflux transporter breast cancer resistance protein (BCRP). Concomitant use with BCRP inhibitors (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and the development of myopathy; depending on the dose of BCRP inhibitors, dose adjustment of simvastatin should be considered. Concomitant use of elbasvir and grazoprevir with simvastatin has not been studied; however, the daily dose of simvastatin should not exceed 20 mg for 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 observation period 3.9 years) involving patients at high risk of cardiovascular disease with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, no additional cardiovascular benefit was observed with the addition of lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid). Physicians considering combined therapy of simvastatin with 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 the development of muscle pain, tenderness, or weakness, especially during the first months of therapy and when increasing the dose of either of these medicinal products.

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

Acipimox is structurally similar to niacin. Although acipimox has not been studied, the risk of developing muscle toxicity with this agent cannot be excluded.

An interim analysis by the independent clinical outcomes monitoring committee of an ongoing study identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and niacin/laropiprant 2000 mg/40 mg. Therefore, Chinese patients should be treated with simvastatin (particularly doses of 40 mg or higher) concomitantly with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or niacin-containing products with caution. Since the risk of myopathy with statin use is dose-dependent, Chinese patients should not be prescribed simvastatin 80 mg with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or niacin-containing products. It is unknown whether there is an increased risk of myopathy in other Asian patients taking simvastatin concomitantly with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or niacin-containing products.

Liver effects. In clinical trials, persistent increases in serum transaminase levels (> 3 × ULN) were observed in several adult patients receiving simvastatin. In these patients, transaminase activity usually gradually returned to baseline levels after interruption or discontinuation of simvastatin. Before starting treatment, and subsequently as clinically indicated, all patients should be recommended to undergo liver function tests. For patients for whom the simvastatin dose is planned to be increased to 80 mg/day, additional liver function tests should be performed before starting titration, then 3 months after reaching the dose of 80 mg/day, followed by periodic repeat testing (e.g., once every 6 months) during the first year of treatment. Particular attention should be paid to patients with elevated serum transaminase levels. Liver function monitoring in these patients should be repeated immediately and more frequently thereafter. If transaminase levels increase, especially with persistent elevation exceeding 3 times ULN, the medicinal product should be discontinued. Alanine aminotransferase may be released from muscle tissue; therefore, increased levels of alanine aminotransferase and creatine kinase may indicate myopathy (see above "Myopathy/Rhabdomyolysis"). In the post-marketing period, rare cases of fatal and non-fatal liver failure have been reported in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Simvasterol, therapy should be immediately discontinued. If no alternative etiology is found, re-initiation of Simvasterol should not be considered. The medicinal product should be used with caution in patients who abuse alcohol. With simvastatin treatment, as with other lipid-lowering agents, mild (< 3 ULN) increases in serum transaminase activity have been reported. These changes occurred soon after starting treatment, were often transient, were not associated with any symptoms, and did not require discontinuation of therapy.

Diabetes mellitus. Some evidence suggests that statins as a class increase plasma glucose levels and may cause hyperglycemia in some patients at high risk of developing diabetes in the future, at levels where treatment for diabetes may be recommended. However, the benefit of statins in reducing vascular risk outweighs this risk, and therefore it should not be a reason for discontinuing statin therapy. Patients at risk of developing diabetes (fasting glucose 5.6–6.9 mmol/L, body mass index > 30 kg/m², elevated triglyceride levels, arterial hypertension) should be monitored both clinically and biochemically according to national guidelines.

Interstitial lung disease. Cases of interstitial lung disease have been reported with the use of some statins, including simvastatin, particularly during long-term therapy (see section "Adverse reactions"). Relevant manifestations may include dyspnea, non-productive cough, and worsening general health (fatigue, weight loss, and fever). If there is suspicion that a patient has developed interstitial lung disease, statin therapy should be discontinued.

Ophthalmological examination. In the absence of any medicinal treatment, an increase in lens opacity is considered a consequence 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 treating patients over 65 years of age, who received it during controlled clinical trials, was evaluated in terms of lowering total and LDL-C cholesterol levels and was found to be similar to that in the general population. No increase in the frequency of adverse effects, either clinically or laboratory-confirmed, was observed.

The medicinal product contains lactose. Patients with rare hereditary intolerance to galactose, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Simvasterol is contraindicated during pregnancy (see section "Contraindications"). The safety of using the medicinal product during pregnancy has not been established. No controlled clinical trials of simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies have been received after in utero exposure to HMG-CoA reductase inhibitors. However, according to observational data from approximately 200 pregnant women who took Simvasterol or another similar HMG-CoA reductase inhibitor during the first trimester, the incidence of congenital anomalies was comparable to that in the general population. This number of pregnancy cases was statistically sufficient to exclude an increase in the number of congenital anomalies by 2.5 times or more compared to the frequency in the general population. There is no evidence that the incidence of congenital anomalies in offspring of patients who took Simvasterol or another similar HMG-CoA reductase inhibitor differs from that observed in the general population; however, treatment of the mother with Simvasterol may reduce fetal mevalonate levels, a precursor in cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering agents during pregnancy usually has little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, Simvasterol should not be prescribed to pregnant women or to women attempting to become pregnant or suspected of being pregnant. Use of Simvasterol should be suspended for the entire duration of pregnancy or until it is confirmed that the woman is not pregnant (see section "Contraindications").

Breastfeeding. It is unknown whether simvastatin or its metabolites are excreted in human milk. Due to the significant number of drugs excreted in breast milk and the high risk of serious adverse reactions in women taking Simvasterol, breastfeeding should be avoided (see "Contraindications").

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.

Simvasterol has no effect or a negligible effect on the ability to drive or operate machinery. However, when driving vehicles or operating machinery, it should be considered that during the post-marketing period, rare reports of dizziness have been received.

Method of Administration and Dosage

The dosage range for Simvastorol is 5 to 80 mg orally once daily in the evening. Dose titration of Simvastorol, if necessary, should be performed 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 potential risks (see sections "Special Warnings and Precautions for Use," "Pharmacological Properties").

Hypercholesterolemia. The patient should be placed on a standard cholesterol-lowering diet, which must be maintained throughout the entire course of treatment with Simvastorol.

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

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

For patients taking Simvastorol concomitantly with lomitapide, the dose of Simvastorol must not exceed 40 mg/day.

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

Concomitant therapy

Simvastorol 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 taking simvastatin concomitantly with fibrates other than gemfibrozil (see section "Contraindications") or with fenofibrate, the simvastatin dose must not exceed 10 mg/day. For patients taking Simvastorol concomitantly with amiodarone, amlodipine, verapamil, or diltiazem, the daily dose of Simvastorol must not exceed 20 mg (see sections "Special Warnings and Precautions for Use," "Interaction with Other Medicinal Products and Other Forms of Interaction").

Renal impairment. No dosage adjustment is required for patients with mild renal impairment. For patients with severe renal impairment (creatinine clearance <30 mL/min), careful consideration should be given to initiating a dose of 10 mg daily, and if such dosing is considered necessary, the drug should be administered with caution.

Use in elderly patients. No dosage adjustment is required.

Use in children and adolescents (10–17 years). For children and adolescents (boys at Tanner stage II or above and girls who have had at least one year of menstrual cycles) aged 10–17 years with heterozygous familial hypercholesterolemia, the recommended usual starting dose is 10 mg once daily in the evening. Prior to 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 "Special Warnings and Precautions for Use," "Pharmacodynamics"). Dose titration should be performed at intervals of 4 weeks or longer. Experience with use of Simvastorol in prepubertal children is limited.

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 above and girls who had had at least one year of menstrual cycles. The adverse effect profile in patients taking simvastatin was generally similar to that in patients receiving placebo. Doses exceeding 40 mg have not been studied in this patient group. In this study, no effect of simvastatin on growth, sexual development, or menstrual cycle duration in girls was observed (see sections "Method of Administration and Dosage," "Undesirable Effects"). Girls should be counseled regarding available contraceptive methods when using simvastatin (see sections "Contraindications," "Use in Pregnancy and Lactation"). For patients under 18 years of age, efficacy and safety have not been studied beyond 48 weeks of treatment; long-term effects on physical, cognitive, and sexual development are 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. The highest dose ingested was 3.6 g. All patients recovered without sequelae. There is no specific antidote for overdose. In case of overdose, symptomatic and supportive measures should be applied.

Adverse Reactions

The frequency of the adverse events listed below, reported during clinical trials and/or the post-marketing period, has been 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 events, as well as myalgia, elevated serum transaminases, and creatine kinase, were recorded. In 4S, all the adverse events listed below were documented. If the incidence of an adverse event during these studies was lower or similar with simvastatin compared to placebo, and spontaneous reports indicated a reasonable causal relationship, such events were classified as rare. In the HPS study involving 20,536 patients receiving 40 mg/day of the medicinal product Symvasterol (n = 10,269) or placebo (n = 10,267), safety profiles were comparable between patients receiving Symvasterol 40 mg and those receiving placebo over a mean study duration of 5 years. Rates of discontinuation due to adverse effects were similar (4.8% in patients receiving Symvasterol 40 mg vs. 5.1% in those receiving placebo). The incidence of myopathy was < 0.1% in patients receiving Symvasterol 40 mg. Elevated transaminases (> 3 × ULN, confirmed by repeat testing) occurred in 0.21% (n = 21) of patients receiving Symvasterol 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), not known (cannot be estimated from available data).

Blood and lymphatic system disorders.
Rare: anaemia.

Psychiatric disorders.
Very rare: insomnia.
Not known: depression.

Nervous system disorders.
Rare: headache, paraesthesia, dizziness, peripheral neuropathy.
Very rare: memory impairment.

Respiratory, thoracic and mediastinal disorders.
Not known: interstitial lung disease (see section "Special warnings and precautions for use").

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

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

Skin and subcutaneous tissue disorders.
Rare: rash, pruritus, alopecia.
Very rare: lichenoid drug eruption.

Musculoskeletal and connective tissue disorders.
Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section "Special warnings and precautions for use"), myalgia, muscle spasms.
Very rare: muscle rupture.

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

Not known: tendinopathy, sometimes complicated by rupture; immune-mediated necrotizing myopathy**; myasthenia gravis.

** Very rare cases of immune-mediated necrotizing myopathy (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, which 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 warnings and precautions for use. Myopathy/Rhabdomyolysis").

Reproductive system and breast disorders.
Very rare: gynaecomastia.
Not known: erectile dysfunction.

General disorders and administration site conditions.
Rare: asthenia. Hypersensitivity reactions have rarely been reported, including some of the following manifestations: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis and arthralgia, urticaria, photosensitivity, fever, hot flushes, dyspnoea, and weakness.

Eye disorders.
Rare: blurred vision, visual disturbances.
Frequency not known: ocular myasthenia.

Laboratory findings.
Rare: increased serum transaminase levels (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) (see section "Special warnings and precautions for use. Effect on liver"); increased alkaline phosphatase levels; increased serum creatine kinase levels (see section "Special warnings and precautions for use"). With statin use, including Symvasterol, increases in HbA1c and fasting serum glucose levels have been reported. During the post-marketing period, rare cases of cognitive disorders (e.g., memory loss, forgetfulness, memory impairment, confusion) associated with statin use, including simvastatin, have been reported. Overall, these cases were non-serious and reversible upon discontinuation of the statin; the time to onset of symptoms (from 1 day to years) and symptom resolution (average 3 weeks) varied.

Additional adverse reactions reported with certain statins include: sleep disorders, including nightmares; sexual dysfunction; diabetes mellitus: the incidence of new-onset diabetes depends on the presence or absence of risk factors (fasting plasma glucose ≥ 5.6 mmol/L, body mass index > 30 kg/m², elevated triglycerides, history of hypertension).

Children and adolescents (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 menstrual cycles) aged 10–17 years with heterozygous familial hypercholesterolemia (n = 175), the safety and tolerability profile in patients receiving Symvasterol was generally similar to that in patients receiving placebo. Long-term effects on physical, intellectual, and sexual development are unknown. There is insufficient data beyond one year of treatment (see sections "Dosage and administration" and "Special warnings and precautions for use").

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Packaging.
20 mg strength: 14 tablets in a blister; 2 blisters in a cardboard carton.
40 mg strength: 7 or 14 tablets in a blister; 2 or 4 blisters in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.
Pharmaceutical Works «Polpharma» S.A., Poland.

Manufacturer's address and place of business.
19 Pelplinska Street, 83-200 Starogard Gdanski, Poland.