Cardac

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

Composition:

Active substance: simvastatin;

One film-coated tablet contains 10 mg, or 20 mg, or 40 mg of simvastatin;
Excipients: ascorbic acid (E 300), lactose monohydrate, microcrystalline cellulose, pregelatinized starch, citric acid monohydrate (E 330), butylated hydroxyanisole (E 320), magnesium stearate, Opadry pink (20A54239 or 20A54211 for 40 mg film-coated tablets).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: light pink, round, biconvex film-coated tablets, embossed with «SI» on one side and «10» on the other;

20 mg tablets: light pink, round, biconvex film-coated tablets, embossed with «SI» on one side and «20» on the other;

40 mg tablets: pink, round, biconvex film-coated tablets, embossed with «SI» on one side and «40» on the other.

Pharmacotherapeutic group. Hypolipidemic agents, single-component. 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-hydroxy acid derivative, which has high inhibitory activity against HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase)—the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the initial and most significant step in cholesterol biosynthesis. It has been demonstrated that Cardak 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 the LDL-lowering effect of Cardak may involve both a reduction in VLDL-C concentration and stimulation of LDL receptors, resulting in decreased production and increased catabolism of LDL cholesterol. Levels of apolipoprotein B also decrease significantly during treatment with Cardak. In addition, Cardak 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-hydroxy acid, 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 depends on hepatic blood flow. The liver is the primary site of action of the active form. The systemic bioavailability of the beta-hydroxy acid 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 administration of simvastatin. Concomitant food intake does not affect absorption. Pharmacokinetic studies of single and multiple doses of simvastatin have shown no accumulation of the drug after repeated dosing.

Distribution. The binding of simvastatin and its active metabolite to plasma proteins 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-hydroxy acid and four additional active metabolites. After oral administration of radiolabeled simvastatin to humans, 60% of the administered radioactivity was excreted in feces and 13% in urine within 96 hours. The amount recovered in feces represents both the absorbed drug excreted via bile and the unabsorbed drug. After intravenous administration of the beta-hydroxy acid metabolite, its mean elimination half-life is 1.9 hours. On average, only 0.3% of the dose is excreted in urine in the form of inhibitors.

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

SLCO1B1 Polymorphism

In carriers of the SLCO1B1 gene allele c.521T > C, reduced activity of the OATP1B1 protein is observed. The mean exposure (AUC) of the main active metabolite—simvastatin acid—is 120% in heterozygous carriers (CT) of the C allele and 221% 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 gene polymorphism are at risk of increased exposure to simvastatin acid, which may increase the risk of developing rhabdomyolysis (see section «Special precautions»).

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 treatments 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 correction of other risk factors and to other cardioprotective therapies (see section "Pharmacological properties. Pharmacodynamics").

Contraindications.

• Hypersensitivity to simvastatin or any component of the medicinal product.
• Active liver disease or unexplained and persistent elevations in serum transaminase levels.
• Pregnancy and breastfeeding (see section "Special precautions").
• 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 precautions" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of gemfibrozil, cyclosporine, or danazol.
• Patients with homozygous familial hypercholesterolemia receiving lomitapide and Cardak at doses exceeding 40 mg.

Interaction with other medicinal products and other types of interaction.

Interaction studies have been conducted only in adults.

Pharmacodynamic interaction

Interactions with lipid-lowering medicinal products that may cause myopathy when used individually. The risk of myopathy, including rhabdomyolysis, is increased during concomitant use with fibrates. In addition, there is a pharmacokinetic interaction with gemfibrozil, which leads to increased plasma levels of simvastatin (see below Pharmacokinetic interaction and sections "Contraindications" and "Special precautions"). With concomitant use of simvastatin and fenofibrate, there is no evidence that the risk of myopathy exceeds the sum of individual risks of each agent. There are insufficient pharmacovigilance and pharmacokinetic data on other 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 precautions").

Pharmacokinetic interaction

The table below summarizes recommendations regarding prescribing interacting medicinal products (see sections "Dosage and administration", "Contraindications", "Special precautions"). Interaction with other medicinal products associated with 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 led to 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, and nefazodone is contraindicated, as well as with gemfibrozil, cyclosporine, and danazol (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 for the duration of treatment with these agents. Combination of simvastatin with certain less potent CYP3A4 inhibitors—fluconazole, verapamil, or diltiazem—should be undertaken with caution (see sections "Dosage and administration" and "Special warnings and precautions for use").

Fluconazole. Rare cases of rhabdomyolysis associated with concomitant use of simvastatin and fluconazole have been reported (see section "Special warnings and precautions for use"). 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 warnings and precautions for use"). Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin 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 warnings and 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 warnings and 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. Concomitant administration of this combination may lead to increased plasma concentrations of both agents. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If use of fusidic acid is considered necessary, treatment with simvastatin should be discontinued for the duration of fusidic acid therapy (see section "Special warnings and precautions for use").

Amiodarone. The risk of myopathy and rhabdomyolysis increases during concomitant use of simvastatin and amiodarone (see section "Special warnings and precautions for use"). In a clinical study, 6% of patients receiving 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 warnings and precautions for use"). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure to simvastatin acid, primarily, in part, 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 warnings and precautions for use"). In a pharmacokinetic study, concomitant administration with diltiazem resulted in a 2.7-fold increase in exposure to simvastatin acid, primarily, in part, 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 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 with concomitant use of lomitapide and 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 labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, especially with higher doses of simvastatin, have an increased risk of developing myopathy (see section "Special warnings and precautions for use").

Inhibitors of the OATP1B1 transporter protein. Simvastatin acid is a substrate of the OATP1B1 transporter protein. Concomitant administration of medicinal products known to inhibit the OATP1B1 transporter protein may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy.

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, single-dose administration of 2 g extended-release nicotinic acid with simvastatin 20 mg resulted in a moderate increase in AUC and Cmax of simvastatin and simvastatin acid in plasma.

Grapefruit juice. Grapefruit juice contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of drugs metabolized by CYP3A4. The increase in HMG-CoA reductase inhibitory activity after standard consumption of 250 ml of juice per day is minimal (approximately 13% inhibition of HMG-CoA reductase activity in plasma, measured as area under the concentration-time curve) and not clinically significant. However, consumption of large quantities of juice significantly increases the level of HMG-CoA reductase inhibitory activity in plasma; therefore, grapefruit juice should be avoided during simvastatin use (see section "Special warnings and precautions for use", Myopathy/Rhabdomyolysis). 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 in healthy volunteers, the area under the concentration-time curve (AUC) for simvastatin acid decreased by 93% with concomitant administration of rifampicin.

Effect of simvastatin on the pharmacokinetics of other medicinal products. Simvastatin does not inhibit cytochrome P450 3A4; therefore, simvastatin is not expected to affect plasma concentrations of substances metabolized by cytochrome P450 3A4.

Oral anticoagulants. In two clinical studies, one conducted in healthy volunteers and the other in patients with hypercholesterolemia, simvastatin at doses of 20–40 mg daily slightly enhanced the effect of coumarin anticoagulants: the prothrombin time, expressed as the international normalized ratio (INR), increased from a baseline of 1.7 to 1.8 in healthy volunteers and from 2.6 to 3.4 in patients with hypercholesterolemia. Very rare cases of increased INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin therapy and frequently during the initial stages of treatment to ensure no significant change in prothrombin time has occurred. Once a stable prothrombin time level is achieved, monitoring should continue at intervals normally recommended for patients receiving coumarin anticoagulant therapy. Prothrombin time should also be monitored when changing the simvastatin dose or discontinuing simvastatin. Simvastatin therapy is not associated with bleeding or changes in prothrombin time in patients not taking anticoagulants.

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 of more than 10 times the upper limit of normal. Myopathy sometimes takes the form of rhabdomyolysis, with or without acute renal failure due to myoglobinuria; fatal cases have been reported very rarely. The risk of myopathy increases with higher levels of HMG-CoA reductase inhibitory activity in plasma. As with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis depends on the dose of the drug. In the clinical trial database, where 41,413 patients received simvastatin, 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 drugs were excluded. In a clinical trial in which patients with a history of myocardial infarction received simvastatin 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 during 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 simvastatin compared to patients receiving therapy based on other statins with similar efficacy in lowering LDL cholesterol. Therefore, the 80 mg dose of simvastatin should be used only in patients with severe hypercholesterolemia and an increased risk of cardiovascular complications who have not achieved treatment goals on lower doses, and when the expected benefit outweighs the potential risks. For patients receiving simvastatin 80 mg who require concomitant therapy with interacting drugs, a lower dose of simvastatin or an alternative statin with a lower interaction potential should be used (see below "Measures to reduce the risk of drug interaction-induced myopathy"). In a clinical trial in which 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 in this clinical trial the Asian population was represented only by Chinese patients, simvastatin should be used cautiously in Asian patients and the lowest dose should be prescribed.

Reduced function of transporter proteins

Reduced function of hepatic transporter proteins of 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.

In patients carrying the SLCO1B1 (c.521T > C) allele, which encodes a less active OATP1B1 protein, increased systemic exposure to simvastatin acid and an increased risk of myopathy have been observed. Regardless of genetic testing, the risk of developing myopathy associated with high-dose (80 mg) simvastatin is approximately 1% overall. Results from the SEARCH study show that homozygous carriers of the C allele (designated CC), who take simvastatin 80 mg, 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%. Such specific genotyping is not widely available in clinical practice. Where possible, before prescribing simvastatin 80 mg to individual patients, genotyping for the presence of the C allele should be considered as part of a benefit-risk assessment, and high doses should be avoided in those found to be carriers of the CC genotype. However, the absence of this gene by 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 other likely alternative cause of elevated creatine kinase, as this complicates the interpretation of existing values. In cases of significant baseline elevation of creatine kinase levels (more than 5 times the upper limit of normal), levels should be re-measured after 5-7 days to confirm the results. Before treatment. All patients starting 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 they experience any unexplained muscle pain, muscle tenderness, or muscle weakness. Caution should be exercised in patients with predisposing factors for rhabdomyolysis. To establish an appropriate baseline value, 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 caused by a statin or fibrate;
• alcohol abuse.

In such situations, the risk of treatment should be considered relative to the potential benefit, and clinical monitoring is recommended. If a patient previously experienced muscle disorders while taking a fibrate or statin, treatment with another agent of this class should be initiated with caution. Treatment should not be initiated if baseline creatine kinase levels are significantly elevated (more than 5 times the upper limit of normal).

During treatment. If pain, weakness, or cramps occur during statin use, creatine kinase levels should be measured. If these levels, in the absence of severe physical exertion, are significantly elevated (more than 5 times the upper limit of normal), treatment should be discontinued. If muscle symptoms are severe and cause daily discomfort, even if creatine kinase levels are less than 5 times the upper limit of normal, discontinuation of treatment should be considered. If myopathy is suspected for any other reason, treatment should be discontinued. 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 helps 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 elective major surgical procedures, as well as after medical or surgical interventions.

In isolated cases, statins have been reported to induce de novo or exacerbate existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of symptom exacerbation, the drug Cardak should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

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 developing myopathy and rhabdomyolysis is significantly increased when simvastatin is co-administered 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 co-administered 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 co-administered 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"). Thus, 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 (drugs that increase AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be stopped for the duration of treatment with these drugs (and consideration should be given to using an alternative statin). Moreover, simvastatin should be used with caution when co-administered with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant intake 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 per day for patients receiving 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 together with simvastatin, as each of these drugs can cause myopathy when taken separately. Simvastatin should not be taken simultaneously with fusidic acid. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients who received this combination (see section "Interaction with other medicinal products and other forms of interaction"). For patients for whom systemic fusidic acid therapy is life-saving, statin therapy should be discontinued for the duration of fusidic acid treatment. The patient should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy can be resumed seven days after the last dose of fusidic acid. In exceptional cases, when prolonged systemic treatment with fusidic acid is necessary, e.g., for the treatment of severe infections, the need for concomitant use of simvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision. Concomitant use of simvastatin in doses exceeding 20 mg per 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 who are taking other medicinal products labeled as having a moderate inhibitory effect on CYP3A4, concomitantly with simvastatin, especially with high doses of simvastatin, may have an increased risk of developing myopathy. When simvastatin is co-administered with a moderate CYP3A4 inhibitor (drugs that increase AUC approximately 2-5 fold), dose adjustment of simvastatin may be required. When co-administering simvastatin with certain moderate CYP3A4 inhibitors, e.g., diltiazem, a maximum dose of 20 mg simvastatin is recommended (see section "Dosage and administration"). 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 drugs can cause myopathy. In a clinical trial (median observation period 3.9 years), in which patients at high risk of cardiovascular disease and with well-controlled LDL cholesterol levels on simvastatin 40 mg/day with or without ezetimibe were included, 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 drugs. 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 0.24% of Chinese patients who were prescribed simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg together with a combination modified-release product of nicotinic acid/laropiprant 2000 mg/40 mg. Although in this clinical trial the Asian population was represented only by Chinese patients, since the incidence of myopathy among Chinese patients is higher than among 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 muscle toxic effects during its use cannot be excluded.

An interim analysis by an independent safety monitoring committee of an ongoing clinical outcomes study identified a higher than expected incidence of myopathy in Chinese patients receiving simvastatin 40 mg and nicotinic acid/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 statins 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 times the upper limit of normal) were observed in several adult patients receiving simvastatin. When simvastatin was interrupted or discontinued in these patients, transaminase activity usually gradually returned to baseline levels. Before starting treatment, and subsequently according to clinical indications, liver function tests are recommended for all patients. For patients whose simvastatin dose is to be increased to 80 mg/day, additional liver function tests should be performed before starting titration, then 3 months after reaching the 80 mg/day dose, followed by periodic repeat testing (e.g., once every 6 months) during the first year of treatment. Particular attention should be paid to patients in whom serum transaminase levels have increased. Liver function monitoring in these patients should be repeated immediately and more frequently thereafter. If transaminase levels rise, especially with persistent elevations exceeding 3 times the upper limit of normal, the drug should be discontinued. It should be noted that alanine aminotransferase may be released from muscle tissue; therefore, elevated alanine aminotransferase with 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 severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Cardak, therapy should be immediately discontinued. If no alternative etiology is found, Cardak should not be restarted. The drug should be used with caution in patients who abuse alcohol. During treatment with simvastatin, as with other lipid-lowering agents, mild (less than 3 times the upper limit of normal) 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. Certain evidence indicates that statins as a class increase blood glucose levels and in some patients at high risk of developing diabetes in the future may cause hyperglycemia levels at which treatment for diabetes is 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 triglycerides, arterial hypertension) should be monitored 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 interstitial lung disease is suspected in a patient, statin therapy should be discontinued.

Ophthalmological examination. In the absence of any pharmacological treatment, an increase in lens opacity area 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, as assessed in controlled clinical trials, was evaluated in terms of lowering total and LDL 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 product contains lactose. Patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.

Use during pregnancy or breastfeeding.

Pregnancy. Cardak is contraindicated during pregnancy (see section "Contraindications"). The safety of using the drug during pregnancy has not been established. No controlled clinical trials of simvastatin in pregnant women have been conducted. Rare reports of congenital anomalies have been received after in utero exposure to HMG-CoA reductase inhibitors. However, analysis of approximately 200 pregnant women prospectively followed and exposed to simvastatin 40 mg or another similar HMG-CoA reductase inhibitor during the first trimester 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 the number of congenital anomalies compared to the frequency in the general population. Although there is no evidence that the frequency of congenital anomalies in offspring of patients who took simvastatin or another similar HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce fetal mevalonate levels, a precursor of 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, Cardak should not be prescribed to pregnant women, women trying to become pregnant, or women suspected of being pregnant. Cardak should be suspended for the entire duration of pregnancy or until pregnancy is ruled out (see section "Contraindications").

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

Ability to affect reaction speed when driving vehicles or operating machinery.

Cardak has no or negligible effect on the ability to drive vehicles 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.

Dosage and Administration

The dosing range for Cardac is 5 to 80 mg orally once daily in the evening. Dose titration, if needed, 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", "Pharmacodynamics"). Simvastatin 80 mg may be used only in patients who have been on simvastatin 80 mg for at least the previous 12 months without evidence of toxicity.

Hypercholesterolemia. Patients should be placed on a standard cholesterol-lowering diet before initiating Cardac and should remain on this diet during treatment with Cardac. The usual starting dose is 10–20 mg once daily in the evening. For patients who require a large reduction (more than 45%) in LDL-C levels, the starting dose may be 20–40 mg once daily in the evening. Dose adjustments, if necessary, should be made as described above.

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

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

Cardiovascular prevention. The usual dose of Cardac for patients at high risk of coronary heart disease (with or without hyperlipidemia) is 20–40 mg once daily in the evening. Drug therapy may be initiated simultaneously with diet and exercise. Dose adjustments, if necessary, should be made as described above.

Concomitant therapy

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

Dosage in renal insufficiency. Dose adjustment is not necessary in patients with mild renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), the initiation of therapy with a dose of 10 mg once daily should be carefully considered, and if such dosage 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 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. 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. Dose selection should be individualized according to treatment goals and in accordance with pediatric treatment guidelines (see sections "Special Warnings and Precautions", "Pharmacodynamics"). Dose titration should be performed at intervals of 4 weeks or longer. Experience with simvastatin in prepubertal children is limited.

Children.

The safety and efficacy of simvastatin in patients aged 10–17 years with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial 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 receiving simvastatin was generally similar to that in patients receiving placebo. Doses above 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 "Dosage and Administration", "Adverse Effects"). Girls should be counseled regarding available contraceptive methods when using simvastatin (see section "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 maximum dose ingested was 3.6 g. All patients recovered without sequelae. There is no specific antidote for overdose. In the event of overdose, symptomatic and supportive measures should be employed.

Adverse Reactions

The frequency of the adverse reactions listed below, reported during clinical trials and/or in 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 reactions, as well as myalgia, elevated serum transaminases, and creatine kinase were recorded. In 4S, all adverse reactions listed below were documented. If 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 infrequent, these 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), safety profiles were comparable between patients receiving simvastatin 40 mg and those receiving placebo over a mean study duration of 5 years. Discontinuation rates due to adverse effects were similar (4.8% in patients receiving simvastatin 40 mg vs. 5.1% in placebo group). 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 categories 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), unknown (cannot be estimated from available data).

Eye disorders. Unknown: ocular myasthenia.

Blood and lymphatic system disorders. Rare: anaemia.

Psychiatric disorders. Very rare: insomnia. Unknown: depression.

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

Respiratory, thoracic and mediastinal disorders. Unknown: interstitial lung disease (see section "Special 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.

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

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

Unknown: tendinopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy**

** 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 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 for use. Myopathy/Rhabdomyolysis").

Reproductive system and breast disorders. Unknown: erectile dysfunction.

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

Laboratory findings

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

With use of certain statins, additional adverse reactions reported include: sleep disorders, including nightmares; sexual dysfunction; diabetes mellitus: incidence of new-onset diabetes will depend 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 established menstruation), aged 10–17 years, with heterozygous familial hypercholesterolemia (n = 175), the safety and tolerability profile in patients treated with simvastatin 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 section "Dosage and administration", "Special precautions for use").

Shelf life.

3 years.

Storage conditions.

Keep out of reach of children. Store at temperatures not exceeding 25 °C.

Packaging.

Film-coated tablets, 10 mg, 10 tablets in a blister pack, 3 blisters in a cardboard box.

Film-coated tablets, 20 mg, 10 tablets in a blister pack, 3 blisters in a cardboard box.

Film-coated tablets, 40 mg, 10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

1. Aurobindo Pharma Limited - Unit III / Aurobindo Pharma Limited - Unit III.
2. Aurobindo Pharma Ltd, Formulation Unit XV / Aurobindo Pharma Ltd, Formulation Unit XV

Manufacturer's address and location of operations.

1. Survey No.: 313, 314 - Blocks I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India
2. Plot No 17A, E.Bonangi (Village), Parawada (Mandal), Visakhapatnam, Andhra Pradesh, 531021, India