Allesta

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALLESTA® (ALLESTA®)

Composition:

Active substance: simvastatin;

One film-coated tablet contains simvastatin 10 mg or 20 mg or 40 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; citric acid, monohydrate; ascorbic acid; magnesium stearate; butylhydroxytoluene (E 321); pregelatinized starch; povidone; Opadry II pink.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, pink-red tablets with a score line on one side.

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

Pharmacological properties

Pharmacodynamics

Following oral administration, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to form the corresponding beta-hydroxyacid derivative, a potent inhibitor of HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase), the enzyme that catalyzes the conversion of HMG-CoA to mevalonate—the initial and rate-limiting step in cholesterol biosynthesis. Simvast inflamm has been shown to reduce both normal and elevated levels of low-density lipoprotein cholesterol (LDL-C). Low-density lipoproteins (LDL) are derived from very low-density lipoproteins (VLDL) and are primarily catabolized by high-affinity LDL receptors. The LDL-lowering effect of simvastatin may involve both a reduction in LDL-C precursor concentration and upregulation of LDL receptors, resulting in decreased production and increased catabolism of LDL cholesterol. Apolipoprotein B levels are also significantly reduced during treatment with simvastatin. In addition, simvastatin markedly increases high-density lipoprotein cholesterol (HDL-C) and reduces plasma triglyceride levels. As a result of these changes, the ratios of total cholesterol to HDL-C and LDL-C to HDL-C are reduced.

Pharmacokinetics

Simvastatin is an inactive lactone that is readily hydrolyzed, converting in vivo into 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 have been evaluated in adults. Pharmacokinetic data in children and adolescents are lacking.

Absorption. In humans, simvastatin is well absorbed and undergoes extensive first-pass metabolism in the liver. 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-hydroxyacid following an oral dose of simvastatin is less than 5% of the administered dose. Peak concentrations of active inhibitors in plasma are reached approximately 1 to 2 hours after administration of simvastatin. Concomitant food intake does not affect absorption. Pharmacokinetics following single and multiple doses of simvastatin demonstrated no accumulation of the drug after repeated dosing.

Distribution. The plasma protein binding of simvastatin and its active metabolite is >95%.

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

SLCO1B1 polymorphism

Reduced OATP1B1 transporter activity is observed in carriers of the c.521T>C allele of the SLCO1B1 gene. The mean area under the plasma concentration-time curve (AUC) of the major active metabolite—simvastatin acid—is 120% in heterozygous carriers (CT) and 221% in homozygous carriers (CC), compared to patients with the most common genotype (TT). The C allele occurs with a frequency of 18% in the European population, 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 may increase the risk of developing rhabdomyolysis (see section "Special warnings and precautions for use").

Clinical Characteristics.

Indications.

Hypercholesterolemia

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

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

Cardiovascular prevention

Reduction of risk of mortality in patients with cardiovascular disease and reduction of 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 in conjunction with other cardioprotective therapies.

Contraindications.

• Hypersensitivity to simvastatin or to any component of this medicinal product.
• Active liver disease or unexplained persistent elevations in serum transaminases.
• Pregnancy and breastfeeding (see section "Use in Pregnancy or Breastfeeding").
• Concomitant use of strong CYP3A4 inhibitors (medicinal products that increase AUC approximately 5-fold or more), such as itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone, and medicinal products containing cobicistat (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").
• Concomitant use of gemfibrozil, cyclosporine, or danazol.
• In patients with homozygous familial hypercholesterolemia receiving lomitapide, concomitant use of simvastatin in doses exceeding 40 mg is contraindicated (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use", and "Dosage and Administration").

Interaction with Other Medicinal Products and Other Forms of Interaction.

Several mechanisms of action of medicinal products may contribute to potential interactions with HMG-CoA reductase inhibitors. Medicinal products and herbal preparations that inhibit certain enzyme activities (e.g., CYP3A4) and/or transporter activity (e.g., OATP1B1) may increase plasma concentrations of simvastatin and simvastatin acid, thereby increasing the risk of myopathy/rhabdomyolysis.

It is necessary to consult the instructions for use of all concomitantly administered medicinal products for additional information on their potential interactions with simvastatin and/or on possible changes in enzymes or transporters, and for possible dose adjustments and management.

Interaction studies have been conducted only in adults.

Pharmacodynamic Interaction

Interaction with lipid-lowering medicinal products which, when used alone, may cause myopathy

The risk of developing myopathy, including rhabdomyolysis, is increased when simvastatin is used concomitantly with fibrates. In addition, there is a pharmacokinetic interaction with gemfibrozil, which leads to increased plasma levels of simvastatin (see subsection "Pharmacokinetic Interaction" below and sections "Contraindications" and "Special Warnings and Precautions for Use"). When simvastatin is used concomitantly with fenofibrate, there is no evidence that the risk of myopathy exceeds the sum of the 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 daily) of niacin (see section "Special Warnings and Precautions for Use").

Pharmacokinetic Interaction

The table below summarizes recommendations for co-administration of interacting medicinal products (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Dosage and Administration").

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

Effect of other medicinal products on simvastatin

Interaction with CYP3A4 inhibitors

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the plasma concentration of the HMG-CoA reductase inhibitory activity during treatment with simvastatin. 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 results in more than a 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin causes 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, as well as with medicinal products containing cobicistat, is contraindicated, as is combination with gemfibrozil, cyclosporine, and danazol (see section "Contraindications"). If therapy with potent CYP3A4 inhibitors (agents increasing AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be suspended for the duration of treatment with these agents, and consideration should be given to using an alternative statin. Simvastatin should be used with caution in combination with other, less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections "Special precautions for use" and "Dosage and administration").

Fluconazole

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

Cyclosporine

The risk of myopathy/rhabdomyolysis increases when cyclosporine is used concomitantly with simvastatin; therefore, the use of the medicinal product with cyclosporine is contraindicated (see sections "Contraindications" and "Special precautions for use"). 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 AUC for simvastatin occurs primarily due to inhibition of CYP3A4 and/or the OATP1B1 transporter protein.

Danazol

The risk of developing myopathy and rhabdomyolysis increases with concomitant use of danazol and simvastatin; therefore, the use of the medicinal product with danazol is contraindicated (see sections "Contraindications" and "Special precautions for use").

Gemfibrozil

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

Fusidic acid

The risk of myopathy, including rhabdomyolysis, may be increased during concomitant use of systemic fusidic acid and statins. Concomitant use of this combination may lead to increased plasma concentrations of both agents. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) is not fully known. Cases of rhabdomyolysis (including fatal cases) have been reported in patients taking this combination. If the use of fusidic acid is considered necessary, treatment with simvastatin should be discontinued for the duration of fusidic acid therapy (see sections "Contraindications" and "Special precautions for use").

Amiodarone

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

Calcium channel blockers

• Verapamil

The risk of developing myopathy and rhabdomyolysis increases during concomitant use of verapamil with simvastatin at doses of 40 mg or 80 mg (see sections "Contraindications" and "Special precautions for use"). In a pharmacokinetic study, concomitant use with verapamil led to a 2.3-fold increase in exposure to simvastatin acid, primarily due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily for patients taking this drug concomitantly with verapamil.

• Diltiazem

The risk of developing myopathy and rhabdomyolysis increases during concomitant use of diltiazem with simvastatin at a dose of 80 mg (see sections "Contraindications" and "Special precautions for use"). In a pharmacokinetic study, concomitant use of the medicinal product with diltiazem led to a 2.7-fold increase in exposure to simvastatin acid, primarily due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily for patients taking this drug concomitantly with diltiazem.

• Amlodipine

Patients taking amlodipine concomitantly with simvastatin have an increased risk of developing myopathy. In a pharmacokinetic study, concomitant use with amlodipine led to a 1.6-fold increase in exposure to simvastatin acid. Therefore, the dose of simvastatin should not exceed 20 mg daily for patients taking this drug concomitantly with amlodipine.

Lomitapide. The risk of myopathy and rhabdomyolysis increases with concomitant use of lomitapide and simvastatin (see sections "Contraindications", "Special precautions for use", and "Dosage and administration"). Therefore, for 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, may have an increased risk of developing myopathy (see sections "Contraindications" and "Special 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 be inhibitors of the OATP1B1 transporter protein may lead to increased plasma concentrations of simvastatin acid and an increased risk of developing myopathy.

Inhibitors of breast cancer resistance protein (BCRP)

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

Niacin (nicotinic acid)

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

Daptomycin

Cases of myopathy and/or rhabdomyolysis have been observed with concomitant use of HMG-CoA reductase inhibitors and daptomycin. Caution should be exercised when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent may cause myopathy and/or rhabdomyolysis when used alone. Patients receiving daptomycin should temporarily discontinue the use of simvastatin.

Grapefruit juice

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

Colchicine

Cases of myopathy and rhabdomyolysis have been reported in patients with renal insufficiency who concomitantly used colchicine and simvastatin. Frequent and careful clinical monitoring of patients taking 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 therapy with rifampicin (e.g., for treatment of tuberculosis). In a pharmacokinetic study in healthy volunteers, 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 daily 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 taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin therapy and frequently during the initial phase of treatment to ensure that no significant effect on prothrombin time has occurred. Once prothrombin time reaches a stable level, it should be monitored at intervals normally recommended for patients taking coumarin anticoagulants.

Prothrombin time should also be monitored when changing the dosage 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 more than 10 times above the upper limit of normal (ULN). Myopathy sometimes progresses to rhabdomyolysis, with or without acute renal failure due to myoglobinuria; fatal cases have been reported very rarely. The risk of developing myopathy increases due to high inhibitory activity against HMG-CoA reductase in blood plasma (increased plasma levels of simvastatin and simvastatin acid), which may partially be 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 depends on the dose of the drug. In the database of clinical trials involving 41,413 patients taking 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 daily, respectively. During these trials, patients were closely monitored, and certain concomitant medications with potential interactions were excluded.

In a clinical trial in which patients with a history of myocardial infarction received simvastatin 80 mg daily (mean observation period 6.7 years), the incidence of myopathy was approximately 1.0% compared to 0.02% in patients receiving simvastatin 20 mg daily. 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 sections "Pharmacological properties" and "Adverse reactions").

In patients taking simvastatin 80 mg, the risk of developing myopathy is higher than with other statins with similar efficacy in lowering LDL-C. Therefore, simvastatin 80 mg should be used only in patients with severe hypercholesterolemia and an increased risk of cardiovascular complications, in whom therapeutic effect has not been achieved with lower doses, and when the expected benefit outweighs the potential risk. For patients taking simvastatin 80 mg who require concomitant administration of an interacting drug, a lower dose of simvastatin should be used or an alternative statin with lower interaction potential should be considered (see below "Measures to reduce the risk of myopathy caused by interaction with other medicinal products", as well as sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Method of administration and dosage").

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

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 developing 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 doses (80 mg) of simvastatin is approximately 1% overall.

Results from the SEARCH study indicate that in homozygous carriers of the C allele (designated CC) taking simvastatin 80 mg, the risk of developing myopathy within one year is 15%, whereas the risk in heterozygous carriers of the C allele (CT) is 1.5%.

The corresponding risk in patients with the most common genotype is 0.3% (see section "Pharmacokinetics"). 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 to assess the benefit-risk ratio and to avoid high doses in 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 intense physical exertion or in the presence of any probable alternative causes for elevated creatine kinase, as this complicates interpretation of the results. In case of significant elevation of creatine kinase at baseline (more than 5 times ULN), repeat testing should be performed after 5-7 days to confirm the results.

Prior to initiating therapy

All patients starting simvastatin therapy, as well as patients whose simvastatin dose has been increased, should be warned about the risk of developing myopathy and the need to seek immediate medical attention if unexplained muscle pain, tenderness, or muscle weakness occurs.

Caution should be exercised in patients with predisposing factors for rhabdomyolysis. To establish an appropriate baseline value, creatine kinase levels should be measured before starting therapy in the following situations:

• advanced age (age ≥ 65 years);
• female gender;
• impaired renal function;
• uncontrolled hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of muscle toxicity with statins or fibrates;
• alcohol abuse.

In such situations, the risk during treatment should be weighed against the potential benefit, and clinical monitoring is also recommended. If muscle disorders were previously observed in a patient during treatment with fibrates or statins, initiation of therapy with other drugs of this class should be done cautiously.

Treatment should not be initiated if there is a significant baseline elevation of creatine kinase (more than 5 times ULN).

During treatment

If a patient experiences pain, weakness, or cramps during statin therapy, creatine kinase levels should be checked. If significantly elevated levels (more than 5 times ULN) are detected in the absence of intense physical exertion, treatment should be discontinued. If symptoms are severe and cause daily discomfort, even if creatine kinase levels are less than 5 times ULN, discontinuation of treatment should be considered. If myopathy is suspected for any other reason, treatment should be discontinued. Very rarely, immune-mediated necrotizing myopathy (IMNM) associated with statin use has 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 after discontinuation of statins (see section "Adverse reactions").

If symptoms resolve and creatine kinase levels return to normal, resumption of the same statin or an alternative statin at the lowest dose under close monitoring may be considered.

Myopathy occurs more frequently 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, such monitoring does not always prevent the development of myopathy.

Simvastatin therapy should be temporarily discontinued a few days before planned major surgery, as well as after medical or surgical procedures.

Measures to reduce the risk of developing myopathy caused by interaction with other medicinal products (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 sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage"). The risk of developing myopathy, including rhabdomyolysis, may increase when fusidic acid is used concomitantly with statins (see section "Interaction with other medicinal products and other forms of interaction"). In patients with HoFH, this risk increases when lomitapide and simvastatin are used concomitantly.

Accordingly, the use of simvastatin with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). If therapy with potent CYP3A4 inhibitors (drugs that increase AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be discontinued for the duration of treatment with these drugs (or an alternative statin should be considered). Simvastatin should also be used cautiously in combination with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section "Interaction with other medicinal products and other forms of interaction"). Concurrent 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 daily in patients taking simvastatin with other fibrates, except fenofibrate (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage"). Fenofibrate should be used cautiously with simvastatin, as each of these drugs alone may cause myopathy.

Simvastatin should not be taken concomitantly with fusidic acid or within 7 days after discontinuation of fusidic acid. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients taking this combination (see section "Interaction with other medicinal products and other forms of interaction"). In patients for whom systemic fusidic acid therapy is essential, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases, when prolonged systemic therapy 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 an individual basis and under close medical supervision.

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

Patients taking other medicinal products that exhibit moderate inhibitory effects on CYP3A4 concomitantly with simvastatin, especially with high doses of simvastatin, may have an increased risk of developing myopathy. When simvastatin is taken concomitantly with a moderate CYP3A4 inhibitor (drugs that increase AUC approximately 2-5 times), dose adjustment of simvastatin may be required. For some moderate CYP3A4 inhibitors, such as diltiazem, the maximum recommended dose of simvastatin is 20 mg (see section "Method of administration and dosage").

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

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant use of HMG-CoA reductase inhibitors and niacin (nicotinic acid) at lipid-modifying doses (≥1 g daily); monotherapy with either of these drugs 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 daily with or without ezetimibe, no additional cardiovascular benefit was observed with the addition of lipid-modifying doses (≥1 g daily) of niacin (nicotinic acid). Physicians considering combination therapy of simvastatin with niacin (nicotinic acid) at lipid-modifying doses (≥1 g daily) or with other niacin-containing products should carefully evaluate the potential benefits and risks and closely monitor patients for symptoms such as muscle pain, tenderness, or weakness, especially during the first months of therapy and when increasing the dose of either drug.

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 1.24% among Chinese patients receiving simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg together with a combination drug of modified-release nicotinic acid/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 in Chinese patients than in non-Chinese patients, concomitant use of simvastatin and lipid-modifying doses (≥1 g daily) of niacin (nicotinic acid) is not recommended in patients of Asian origin. Acipimox is structurally similar to niacin. Although acipimox has not been studied, the risk of muscle toxicity may be similar to that with niacin.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors and daptomycin (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic effects

Persistent elevations in serum transaminase levels (more than 3 times ULN) have been observed in several adult patients receiving simvastatin. Transaminase levels usually returned slowly to baseline after temporary discontinuation or withdrawal of simvastatin.

Liver function tests are recommended before starting therapy and, if clinically indicated, during treatment. Patients in whom the simvastatin dose is to be increased to 80 mg daily should have additional testing before dose escalation, then 3 months after dose increase to 80 mg daily, 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 transaminases. In such patients, liver function tests should be repeated immediately and performed more frequently thereafter.

If transaminase levels continue to rise, particularly if they are more than 3 times ULN and persistent, simvastatin should be discontinued. It should be noted that alanine aminotransferase levels may vary depending on muscle status; therefore, elevations in both alanine aminotransferase and creatine kinase may indicate myopathy (see above "Myopathy/Rhabdomyolysis").

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 simvastatin, therapy should be discontinued immediately. If an alternative etiology is not identified, reinitiation of the drug should not be considered.

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

With simvastatin therapy, as with other lipid-lowering agents, mild (less than 3 times ULN) increases in serum transaminase activity have been reported. These changes occurred soon after starting therapy, were often transient, were not associated with 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 elevated blood glucose levels requiring treatment for diabetes. However, the benefit of statins in reducing the risk of cardiovascular disease outweighs this risk; therefore, this should not be a reason for discontinuing statin therapy. There is a basis for periodic clinical and biochemical monitoring of glycemia in patients at risk (fasting glucose 5.6-6.9 mmol/L, body mass index >30 kg/m², elevated triglycerides, hypertension) according to current recommendations.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including simvastatin, particularly during long-term therapy (see section "Adverse reactions"). Relevant manifestations may include dyspnea, non-productive cough, and worsening general condition (increased 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, lens opacification is considered a consequence of the aging process. Available data do not indicate a harmful effect of simvastatin on the human eye lens.

Myasthenia

In isolated cases, statins have been reported to induce "de novo" or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of symptom exacerbation, the drug ALLESTA® should be discontinued.

Recurrences have been reported upon re-administration of the same or another statin.

Use in elderly patients

The efficacy of simvastatin in patients aged 65 years and older, as evaluated in controlled clinical trials, regarding reduction of total cholesterol and LDL-C levels, 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; therefore, it should not be taken by patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

Simvastatin is contraindicated during pregnancy (see section "Contraindications").

The safety of the drug in pregnant women has not been established. No controlled clinical trials have been conducted in pregnant women. Rare cases of congenital anomalies have been reported after in utero exposure to HMG-CoA reductase inhibitors. However, analysis of data from follow-up of approximately 200 pregnant women who used simvastatin or other similar HMG-CoA reductase inhibitors during the first trimester of pregnancy showed that the incidence of congenital abnormalities was comparable to that in the general population. Observation of this number of pregnancies was statistically sufficient to exclude an increase in the frequency of congenital anomalies by 2.5 times or more compared to the baseline frequency in the general population. Although there is no evidence that the frequency of congenital anomalies in children of patients who took simvastatin or other similar HMG-CoA reductase inhibitors differs from that in the general population, maternal treatment with simvastatin may reduce fetal levels of mevalonate, a precursor in cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering agents during pregnancy usually has minimal impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, simvastatin should not be prescribed to pregnant women, women attempting to become pregnant, or women suspected of being pregnant. Simvastatin therapy should be suspended for the entire duration of pregnancy or until pregnancy is ruled out (see section "Contraindications").

Period of 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 in women taking simvastatin, breastfeeding should be discontinued (see section "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.

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

Dosage and Administration

The dosage range of the drug is from 5 to 80 mg orally once daily in the evening. Dose titration, if necessary, should be performed at intervals of at least 4 weeks until the maximum daily dose of 80 mg is reached, which should be taken once daily in the evening. The 80 mg dose is recommended only for patients with severe hypercholesterolemia and high risk of cardiovascular complications in whom desired results have not been achieved with lower doses, and when the expected benefit outweighs potential risks (see sections "Pharmacological Properties" and "Special Warnings").

Hypercholesterolemia

Patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout the treatment with simvastatin. The usual initial dose is 10–20 mg once daily in the evening. For patients requiring a significant (more than 45%) reduction in LDL-C levels, the initial dose may be 20–40 mg once daily in the evening. Dose titration, if necessary, should be performed as described above.

Homozigous Familial Hypercholesterolemia

The recommended initial dose of simvastatin is 40 mg once daily in the evening. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are unavailable.

For patients concurrently taking lomitapide, the simvastatin dose must not exceed 40 mg daily (see sections "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Special Warnings").

Cardiovascular Prevention

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

Concomitant Therapy

Simvastatin is effective as monotherapy and in combination with bile acid sequestrants. The drug should be taken no later than 2 hours before or no earlier than 4 hours after bile acid sequestrants.

For patients taking simvastatin concomitantly with fibrates other than gemfibrozil (see section "Contraindications") or fenofibrate, the simvastatin dose must not exceed 10 mg daily. For patients concurrently taking amiodarone, amlodipine, verapamil, diltiazem, or medicinal products containing elbasvir or grazoprevir, the daily dose of simvastatin must not exceed 20 mg (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings").

Dosage in Renal Impairment

No dosage adjustment is required in patients with moderate renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 mL/min), the appropriateness of prescribing a dose of 10 mg daily should be carefully considered, and if such dosing is deemed necessary, the drug should be administered with caution.

Use in Elderly Patients

No dose adjustment is required.

Use in Children (10–17 years)

For children (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, the recommended usual initial dose is 10 mg once daily in the evening. Prior to initiating simvastatin therapy, children should be placed on a standard cholesterol-lowering diet, which should be maintained during treatment.

The 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 "Pharmacodynamics" and "Special Warnings"). Dose titration should be performed at intervals of 4 weeks or longer.

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

Experience with simvastatin in prepubertal children is limited.

Children.

The safety and efficacy of simvastatin in children 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 with at least one year of established menstrual cycles. The adverse reaction profile in patients receiving simvastatin was generally similar to that in patients receiving placebo. Doses exceeding 40 mg were not studied in this patient group. In this study, no effects of simvastatin on growth, sexual development, or menstrual cycle duration in girls were observed (see sections "Pharmacodynamics", "Dosage and Administration", and "Adverse Reactions").

Girls should be counseled regarding available contraceptive methods when using simvastatin (see sections "Contraindications" and "Use in Pregnancy or 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 menstruation.

Overdose.

Several cases of overdose are known to date. The maximum ingested dose 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.

Side effects

The frequency of adverse reactions is defined as follows: very common (>1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Rare: Anaemia.

Immune system disorders

Very rare: Anaphylaxis.

Psychiatric disorders

Very rare: Insomnia.

Frequency not known: Depression.

Nervous system disorders

Rare: Headache, paraesthesia, dizziness, peripheral neuropathy.

Very rare: Memory impairment.

Frequency not known: Myasthenia gravis.

Eye disorders

Rare: Blurred vision, visual disturbance.

Frequency not known: Ocular myasthenia.

Respiratory, thoracic and mediastinal disorders

Frequency not known: Interstitial lung disease (see section "Special precautions").

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 skin reactions.

Musculoskeletal and connective tissue disorders

Rare: Myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section "Special precautions"), myalgia, muscle spasms.

*In clinical trials, myopathy occurred more frequently in patients receiving simvastatin 80 mg daily compared to those receiving 20 mg daily (1.0% vs. 0.02%, respectively).

Very rare: Muscle rupture.

Frequency not known: Tendonopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy**.

Reproductive system and breast disorders

Very rare: Gynaecomastia.

Frequency not known: Erectile dysfunction.

General disorders and administration site conditions

Rare: Asthenia.

Rare cases of hypersensitivity reactions have been reported, including some of the following manifestations: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, elevated ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea, and weakness.

Investigations

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

With statin use, including simvastatin, increases in HbA1c and fasting plasma glucose levels have been reported.

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.

**Immune-mediated necrotizing myopathy (IMNM), a rare autoimmune myopathy associated with statin use, has been very rarely observed. IMNM is characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that do not resolve after discontinuation of the statin; histopathological features of necrotizing myopathy on muscle biopsy with minimal inflammatory infiltrate; and improvement with immunosuppressive therapy (see section "Special precautions. Myopathy/Rhabdomyolysis").

Additional adverse effects reported with some statins include:

• Sleep disorders, including nightmares;
• Sexual dysfunction;
• Diabetes mellitus: incidence depends on the presence or absence of risk factors (fasting plasma glucose ≥5.6 mmol/L, BMI >30 kg/m², elevated triglycerides, history of hypertension).

Children and adolescents (aged 10–17 years)

In a 48-week study in 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. The 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 precautions").

Shelf life.

2 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

Tablets, film-coated, 10 mg

10 tablets in a blister; 3 blisters in a cardboard box.

Tablets, film-coated, 20 mg

10 or 14 tablets in a blister; 3 blisters (10 tablets per blister) or 2 blisters (14 tablets per blister) in a cardboard box.

Tablets, film-coated, 40 mg

15 or 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.