Vazilip®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Vasilip® (Vasilip®)

Composition:

Active substance: simvastatin;

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

Excipients: lactose monohydrate, pregelatinized starch, butylhydroxyanisole (E 320), citric acid, ascorbic acid, corn starch, microcrystalline cellulose, magnesium stearate;

Film coating: hypromellose, talc, propylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: white, round, slightly biconvex film-coated tablets with beveled edges.

Pharmacotherapeutic group.

Lipid-lowering agents, single-component. HMG-CoA reductase inhibitors.

ATC code C10AA01.

Pharmacological properties.

Pharmacodynamics.

Following oral administration, simvastatin, an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form, which is a potent inhibitor of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, the initial and rate-limiting step in cholesterol biosynthesis.

Simvastatin has been shown to reduce both normal and elevated levels of low-density lipoprotein (LDL) cholesterol. LDL is formed from very-low-density lipoproteins (VLDL) and is primarily catabolized by high-affinity LDL receptors. The LDL-lowering effect of simvastatin may be related both to a reduction in VLDL cholesterol (VLDL-C) levels and to upregulation of LDL receptors, resulting in decreased production and increased catabolism of LDL cholesterol (LDL-C). Additionally, simvastatin significantly reduces apolipoprotein B levels. Furthermore, simvastatin moderately increases high-density lipoprotein cholesterol (HDL-C) levels 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 in vivo to form the beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs primarily in the liver; the rate of hydrolysis in human plasma is very low.

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

Absorption

Simvastatin is well absorbed and undergoes extensive first-pass extraction in the liver. Hepatic extraction depends on hepatic blood flow. The liver is the primary site of action of the active form. After oral administration of simvastatin, the presence of the beta-hydroxyacid in the systemic circulation accounts for less than 5% of the dose. Peak plasma concentrations of active inhibitors are reached approximately 1–2 hours after simvastatin administration. Concomitant food intake does not affect drug absorption.

Pharmacokinetic studies of single or multiple doses of simvastatin have shown that there is no accumulation of the drug after repeated administration.

Distribution

Plasma protein binding of simvastatin and its active metabolites is ≥ 95%.

Elimination

Simvastatin is a substrate of CYP3A4. The main metabolites of simvastatin in human plasma are the beta-hydroxyacid and four additional active metabolites. After oral administration of radiolabeled simvastatin, 13% of the dose is excreted in urine and 60% in feces within 96 hours. The material found in feces consists of both unabsorbed drug and drug absorbed and subsequently excreted in bile. After intravenous administration of the beta-hydroxyacid metabolite, its elimination half-life is 1.9 hours. On average, only 0.3% of the intravenous dose is excreted in urine as inhibitors.

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

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

Patients in special groups

SLCO1B1 polymorphism

Carriers of the SLCO1B1 c.521T>C allele exhibit reduced OATP1B1 transporter activity. The average exposure (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 SLCO1B1 polymorphism are at risk of increased exposure to simvastatin acid, which may increase the risk of developing rhabdomyolysis (see section «Special precautions for use»).

Clinical characteristics.

Indications.

Hypercholesterolemia

Treatment of primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, when response to diet and other nonpharmacological treatments (e.g., 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), when such treatment modalities are not suitable.

Cardiovascular prevention

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

Contraindications.

• Hypersensitivity to simvastatin or to any other component of the medicinal product.
• Active liver disease or persistent unexplained elevations in serum transaminases.
• 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, nefazodone, and medicinal products containing cobicistat (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").
• Concomitant use of gemfibrozil, cyclosporine, or danazol (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").
• Pregnancy or breastfeeding (see section "Use in pregnancy or breastfeeding").
• Patients with homozygous familial hypercholesterolemia (HoFH) who are concurrently receiving lomitapide and simvastatin at doses exceeding 40 mg (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 drug action 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 transporters (e.g., OATP1B1) may increase plasma concentrations of simvastatin and simvastatin acid, thereby increasing the risk of myopathy/rhabdomyolysis.

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

Interactions have been studied only in adult patients.

Pharmacodynamic interactions

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

The risk of developing myopathy, including rhabdomyolysis, is increased when simvastatin is used concomitantly with fibrates and niacin (nicotinic acid) ≥ 1 g/day. In addition, there is a pharmacokinetic interaction with gemfibrozil, leading to increased plasma levels of simvastatin. There is no evidence that the risk of myopathy is higher with concomitant use of simvastatin and fenofibrate than with either agent alone. For other fibrates, adequate pharmacovigilance and pharmacokinetic data are lacking. Cases of myopathy/rhabdomyolysis have been reported with concomitant use of simvastatin and lipid-lowering doses of niacin ≥ 1 g/day (see section "Special warnings and precautions for use").

Pharmacokinetic interactions

Recommendations for use with interacting agents are provided in the table below (see also sections "Contraindications", "Special warnings and precautions for use", and "Dosage and administration").

Interaction with other medicinal products associated with an increased risk of myopathy/rhabdomyolysis
Substances involved in interaction	Recommendations
Potent CYP3A4 inhibitors: itraconazole ketoconazole posaconazole voriconazole erythromycin clarithromycin telithromycin HIV protease inhibitors (nelfinavir) boceprevir telaprevir nefazodone cyclosporine danazol gemfibrozil	concomitant use with simvastatin is contraindicated
Other fibrates (except fenofibrate)	do not exceed a daily dose of 10 mg simvastatin
Fusidic acid	not recommended with simvastatin
Niacin (nicotinic acid) (≥ 1 g/day)	Not recommended to co-administer with simvastatin in Mongoloid race patients
Amiodarone amlodipine verapamil diltiazem elbasvir grazoprevir	do not exceed 20 mg simvastatin per day
Daptomycin	Consider temporarily discontinuing simvastatin in patients taking daptomycin if benefit does not outweigh risk (see section "Special precautions")
Lomitapide	In patients with HoFH, simvastatin should be administered at doses not exceeding 40 mg daily
Ticagrelor	Doses of simvastatin exceeding 40 mg per day are not recommended
Grapefruit juice	avoid consumption is recommended

Effect of Other Medicinal Products on Simvastatin

Interactions Involving CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis due to increased plasma concentrations of HMG-CoA reductase inhibitors during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, and nefazodone. Concomitant use of itraconazole leads to an increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite) by more than 10-fold, and telithromycin by more than 11-fold.

Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, as well as with gemfibrozil, cyclosporine, and danazol is contraindicated (see section "Contraindications"). If treatment with potent CYP3A4 inhibitors (drugs that increase AUC by 5-fold or more) cannot be avoided, simvastatin therapy should be discontinued during the course of treatment. Use of simvastatin with certain other less potent CYP3A4 inhibitors (fluconazole, verapamil, and diltiazem) should be done with caution (see sections "Special Warnings and 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 Warnings and Precautions for Use").

Cyclosporine

The risk of developing myopathy/rhabdomyolysis increases when cyclosporine is used concomitantly with simvastatin; therefore, such use is contraindicated (see sections "Contraindications" and "Special Warnings and 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 simvastatin AUC occurs primarily due to inhibition of CYP3A4 and/or OATP1B1 protein.

Danazol

Due to the increased risk of myopathy and rhabdomyolysis with concomitant use of danazol and simvastatin, such use 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 cascade and/or OATP1B1 protein (see sections "Contraindications" and "Special Warnings and Precautions"). 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 is not fully understood. Cases of rhabdomyolysis (including fatal cases) have been reported with simvastatin use. If fusidic acid treatment is considered necessary, simvastatin therapy should be discontinued for the duration of treatment (see section "Special Warnings and Precautions for Use").

Amiodarone

The risk of myopathy and rhabdomyolysis is increased 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 amiodarone concomitantly.

Calcium Channel Blockers

• Verapamil

The risk of myopathy and rhabdomyolysis increases with concomitant use of verapamil and simvastatin at doses of 40 or 80 mg (see section "Special Warnings and Precautions for Use"). Pharmacokinetic studies have shown that concomitant use of verapamil increases exposure to simvastatin acid by 2.3-fold, primarily due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients taking verapamil concomitantly.

• Diltiazem

The risk of myopathy and rhabdomyolysis increases with concomitant use of diltiazem and simvastatin at a dose of 80 mg (see section "Special Warnings and Precautions for Use"). In a pharmacokinetic study, concomitant use of diltiazem increased exposure to simvastatin acid by 2.7-fold, primarily due to inhibition of CYP3A4. Thus, for patients receiving concomitant diltiazem therapy, the dose of simvastatin should not exceed 20 mg daily.

• Amlodipine

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

Lomitapide

The risk of myopathy and rhabdomyolysis increases with concomitant use of lomitapide and simvastatin (see sections "Contraindications" and "Special Warnings and Precautions"). Therefore, in patients with HoFH receiving concomitant lomitapide, the dose of simvastatin should not exceed 40 mg daily.

Moderate CYP3A4 Inhibitors

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

Inhibitors of the OATP1B1 Transporter Protein

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

Inhibitors of Breast Cancer Resistance Protein (BCRP)

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

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 alone may cause myopathy and/or rhabdomyolysis. Patients receiving daptomycin should temporarily discontinue simvastatin.

Niacin (Nicotinic Acid)

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

Ticagrelor

Concomitant use of ticagrelor with simvastatin increases Cmax of simvastatin by 81% and AUC by 56%, and Cmax of simvastatin acid by 64% and AUC by 52%, with some individual cases showing increases of 2–3-fold. Concomitant use of ticagrelor with simvastatin doses exceeding 40 mg daily may lead to adverse reactions of simvastatin; therefore, decisions on concomitant use at these doses should be based on a risk-benefit assessment. No effect of simvastatin on plasma levels of ticagrelor was observed. Concomitant use of ticagrelor with simvastatin doses exceeding 40 mg is not recommended.

Grapefruit Juice

Grapefruit juice inhibits the activity of cytochrome P450 3A4. Consumption of large quantities (more than 1 liter per day) of grapefruit juice in combination with simvastatin may increase the effect of simvastatin acid by 7-fold. Consumption of 240 mL of grapefruit juice in the morning and simvastatin in the evening also led to a 1.9-fold increase in effect. Therefore, grapefruit juice should be avoided during simvastatin use.

Colchicine

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

Rifampicin

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

Effect of Simvastatin on the Pharmacokinetics of Other Medicinal Products

Simvastatin does not have an inhibitory effect on 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 involving healthy volunteers and the other involving patients with hypercholesterolemia, simvastatin at doses of 2–40 mg/day was shown to moderately enhance the effect of coumarin anticoagulants: 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. Very rare cases of increased INR have been reported. In patients starting simvastatin therapy who are also taking coumarin anticoagulants, prothrombin time should be determined before initiating treatment and monitored during the initial treatment period to detect any significant changes. After confirming stability of prothrombin time, monitoring should continue at intervals recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, prothrombin time stability should be reconfirmed. Simvastatin treatment has not been 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 is manifested by muscle pain, tenderness or weakness and is accompanied by an increase in creatine kinase activity more than ten times above the upper limit of normal (ULN). Myopathy sometimes develops into rhabdomyolysis with or without acute renal failure due to myoglobinuria; very rarely, fatal cases have been reported. The risk of myopathy increases with high inhibitory activity against HMG-CoA reductase in blood plasma (increased plasma levels of simvastatin and simvastatin acid), which may be partially related to interactions with medicinal products that interfere with the metabolism and/or transport of simvastatin (see section "Interaction with other medicinal products and other types of interactions").

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, 24,747 (approximately 60%) of whom 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 studies, patients were closely monitored, and certain potentially interacting medicinal products 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% for patients receiving 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 "Side effects and reactions").

The risk of developing myopathy is higher in patients taking 80 mg of simvastatin compared to patients receiving therapy with other statins with similar efficacy in lowering LDL cholesterol. Therefore, the 80 mg dose should be used only in patients with severe hypercholesterolemia and an increased risk of cardiovascular complications who have not achieved the desired effect with lower doses, when the expected benefit outweighs the potential risks. For patients taking simvastatin 80 mg who require concomitant therapy, a lower dose of simvastatin or another statin with a lower potential for drug interactions should be used (see below "Measures to reduce the risk of myopathy/rhabdomyolysis", see sections "Contraindications", "Interaction with other medicinal products and other types of interactions", and "Dosage and administration").

In a clinical trial in which patients at high risk of cardiovascular disease received simvastatin at a dose of 40 mg daily (median observation period was 3.9 years), the incidence of myopathy was approximately 0.05% among non-Chinese patients (n=7367), compared to 0.24% among Chinese patients (n=5468). Despite the fact that in this clinical trial the Mongoloid race population was represented only by Chinese nationality, simvastatin should be used with caution in patients of Mongoloid race and the lowest dose should be prescribed.

In several cases, statins have been reported to cause de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Side effects"). If symptoms worsen, administration of the medicinal product Vazilip® should be discontinued. Recurrences have been reported when (re)introducing the same or another statin.

Reduced function of transport proteins

With reduced function of hepatic OATP family transport proteins, the AUC of simvastatin acid may increase and the risk of myopathy and rhabdomyolysis may rise. 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, an increased AUC of simvastatin acid and an increased risk of myopathy are observed. Regardless of genetic testing, the risk of developing myopathy associated with high doses (80 mg) of simvastatin is approximately 1%. The results of the SEARCH study show that homozygous carriers of the C allele (CC) taking simvastatin at a dose of 80 mg have a 15% risk of developing myopathy within a year, while the risk in heterozygous carriers of the C allele (CT) is 1.5%.

The corresponding risk indicator in patients with the most common genotype (TT) is 0.3% (see section "Pharmacological properties"). Such specific genotyping is not widespread in clinical practice. If possible, before prescribing simvastatin at a dose of 80 mg to individual patients, genotyping for the presence of the C allele should be considered appropriate as part of the benefit-risk assessment, and high doses should be avoided in carriers of the CC genotype. However, the absence of this gene according to genotyping results 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 cause of elevated creatine kinase, as this complicates the interpretation of results. In case of significant elevation of creatine kinase levels at baseline (more than 5 times above ULN), levels should be re-measured after 5–7 days to confirm results.

Prior to treatment

All patients starting therapy with simvastatin, as well as patients whose dose of simvastatin has been increased, should be warned about the possibility of developing myopathy and the need to seek immediate medical attention in case of any unexplained muscle pain or muscle weakness.

Caution should be exercised in patients with risk factors for developing rhabdomyolysis. Creatine kinase levels should be measured before starting treatment in the following cases:

• advanced age (age ≥ 65 years) of the patient;
• female gender;
• impaired renal function;
• uncontrolled hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of toxic muscle injury caused by statins or fibrates;
• alcohol abuse.

In such situations, the risk of treatment should be considered relative to the possible benefit, and clinical monitoring is also recommended. If the patient previously had muscle disorders while taking fibrates or statins, treatment with another agent of this class should be initiated with caution.

Treatment should not be initiated if there is a significant initial increase in creatine kinase levels (more than 5 times above ULN).

During treatment

If pain, weakness, or cramps occur during the patient's intake of statins, creatine kinase levels should be measured. If these levels are found to be significantly elevated (more than 5 times above ULN) in the absence of serious physical exertion, treatment should be discontinued. If muscle symptoms are severe and cause daily discomfort, even if creatine kinase levels are less than 5 times above UL0, the need to discontinue treatment should be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been observed during or after treatment with statins. IMNM is clinically characterized by persistent weakness of proximal muscles and elevated serum creatine kinase levels, which do not resolve despite discontinuation of statins (see section "Side effects").

If symptoms resolve and creatine kinase levels return to normal, the feasibility of reinitiating 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 (see section "Pharmacological properties. Pharmacodynamics"). Periodic determination of creatine kinase levels is recommended, as this helps detect subclinical cases of myopathy. However, there are no reliable data 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.

Measures to reduce the risk of myopathy caused by interactions with other medicinal products (also see section "Interaction with other medicinal products and other types of interactions")

The risk of developing myopathy and rhabdomyolysis significantly increases with concomitant use of simvastatin 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 also increases with concomitant use of amiodarone, amlodipine, verapamil, or diltiazem with certain doses of simvastatin (see sections "Interaction with other medicinal products and other types of interactions" and "Dosage and administration"). The risk of developing myopathy, including rhabdomyolysis, increases with concomitant use of fusidic acid with statins (see section "Interaction with other medicinal products and other types of interactions"). In patients with HoFH, this risk increases with concomitant use of lomitapide and simvastatin.

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 types of interactions"). If therapy with potent CYP3A4 inhibitors (agents that increase AUC by 5 times or more) cannot be discontinued, simvastatin therapy should be discontinued for the duration of treatment with these agents (and the use of an alternative statin should be considered). In addition, simvastatin should be used with caution concomitantly with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section "Interaction with other medicinal products and other types of interactions"). Grapefruit juice should be avoided with simvastatin.

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 for patients taking simvastatin with other fibrates, except fenofibrate (see sections "Interaction with other medicinal products and other types of interactions" and "Dosage and administration"). Fenofibrate should be prescribed with caution concomitantly with simvastatin, as each of these drugs can cause myopathy.

Simvastatin should not be taken simultaneously with systemic preparations containing fusidic acid or within 7 days after discontinuation of fusidic acid. If systemic fusidic acid is necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Reports of rhabdomyolysis (including several fatal cases) have been reported in patients taking a combination of fusidic acid and statins (see section "Interaction with other medicinal products and other types of interactions"). The patient should seek immediate medical attention if they experience muscle weakness or pain, pain or tenderness. Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases, when long-term systemic treatment with fusidic acid is necessary, for example, to treat severe infections, the need for concomitant use of simvastatin and fusidic acid should be considered only on a case-by-case basis and under close medical supervision.

Concomitant use of simvastatin in doses exceeding 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided (see sections "Interaction with other medicinal products and other types of interactions" and "Dosage and administration"). In patients with HoFH, the risk of myopathy increases with concomitant use of lomitapide and simvastatin (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions" and "Dosage and administration").

Patients taking other medicinal products with a moderate inhibitory effect on CYP3A4, concomitantly with simvastatin, especially with high doses of simvastatin, have an increased risk of developing myopathy. When co-administering simvastatin with a moderate CYP3A4 inhibitor (agents that increase AUC by 2–5 times), dose adjustment of simvastatin may be required. For use with certain moderate CYP3A4 inhibitors, such as diltiazem, the maximum recommended dose is 20 mg of simvastatin (see section "Dosage and administration").

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

Concomitant use with BCRP inhibitors (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of developing myopathy; therefore, dose adjustment of simvastatin may be necessary. Concomitant use of elbasvir and grazoprevir with simvastatin has not been studied, but the daily dose of simvastatin should not exceed 20 mg for patients receiving concomitant therapy with medicinal products containing elbasvir or grazoprevir (see section "Interaction with other medicinal products and other types of interactions").

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

In a clinical trial (median observation period was 3.9 years), involving patients at high risk of cardiovascular disease and with well-controlled LDL cholesterol levels on simvastatin 40 mg daily with or without ezetimibe 10 mg, additional cardiovascular benefit from adding lipid-modifying doses (≥ 1 g daily) of niacin (nicotinic acid) was not observed.

Physicians prescribing combination therapy with simvastatin and lipid-modifying doses (≥ 1 g daily) of niacin (nicotinic acid) or preparations containing niacin should carefully weigh the potential benefits and risks and closely monitor patients for the development of muscle pain, tenderness, or weakness, especially during the first months of therapy and when increasing the dose of either of these medicinal products.

In the study, the incidence of myopathy was approximately 0.24% among Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg, compared to 0.24% of Chinese patients who were prescribed simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg together with a combination preparation of modified-release nicotinic acid/laropiprant 2000 mg/40 mg. Despite the fact that in this clinical trial the Asian population was represented only by Chinese, 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 daily) of niacin (nicotinic acid) is not recommended in patients of Mongoloid race.

Acipimox is structurally similar to niacin. Although acipimox has not been studied, the risk of toxic effects on muscles is not excluded (may be similar to that with niacin).

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

Daptomycin

Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., simvastatin) with daptomycin. HMG-CoA reductase inhibitors should be prescribed with caution with daptomycin, as either of these drugs can cause myopathy and/or rhabdomyolysis when used alone. Consideration should be given to temporarily discontinuing simvastatin in patients taking daptomycin if the benefit of concomitant use does not outweigh the risk. Information on daptomycin administration should be reviewed to obtain additional information on this potential interaction with HMG-CoA reductase inhibitors (e.g., simvastatin) and further guidance on monitoring (see section "Interaction with other medicinal products and other types of interactions").

Liver effects

In clinical trials, some adult patients receiving simvastatin showed persistent increases in liver enzyme levels (more than 3 times above ULN). Upon discontinuation of the drug, transaminase activity usually gradually returns to baseline levels. Before starting treatment, and subsequently according to clinical indications, all patients are recommended to undergo liver function tests. In patients for whom the dose of simvastatin is planned to be increased to 80 mg daily, liver function tests should be performed before starting titration, then 3 months after reaching the dose of 80 mg daily, followed by periodic repetition (e.g., once every 6 months) throughout the first year of treatment. Particular attention should be paid to patients with elevated serum transaminase levels. These patients should have liver function monitored at the beginning of treatment and subsequently more frequently than usual. In cases where transaminase levels increase, especially with persistent elevation exceeding 3 times the ULN, the drug should be discontinued. It should be noted that alanine aminotransferase may originate from muscle tissue; therefore, elevated alanine aminotransferase with 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 the drug, therapy should be immediately discontinued. If no alternative etiology is found, the drug 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, a moderate (less than 3 times above ULN) increase in serum transaminase activity has been observed. These changes occurred soon after the start of treatment, were often transient, were not accompanied by symptoms, and did not require discontinuation of therapy.

Diabetes mellitus

Some data indicate 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 requiring initiation of diabetes treatment. However, the benefit of statins in reducing vascular risk outweighs this risk, and therefore it should not be a reason for discontinuing statin therapy. Monitoring of patients at risk (fasting glucose 5.6–6.9 mmol/L, body mass index > 30 kg/m², elevated triglycerides, arterial hypertension) should be performed both clinically and biochemically according to national guidelines.

Interstitial lung disease

Rare cases of interstitial lung disease have been observed after taking some statins, especially with long-term use. Characteristic signs of interstitial lung disease 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 medication, an increase in the area of lens opacity is considered a consequence of the aging process. Available clinical studies do not indicate a harmful effect of simvastatin on the human eye lens.

Use in elderly individuals

The efficacy of simvastatin use in patients aged 65 years and older was evaluated in controlled clinical trials regarding reduction of total cholesterol and LDL cholesterol levels and was found to be similar to that in the general population. An increase in the frequency of adverse effects was not observed.

Special warnings regarding excipients

The drug contains lactose; therefore, it should not be used in patients with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

The use of simvastatin in pregnant women is contraindicated.

No controlled clinical trials involving pregnant women have been conducted; safety has not been established. There are rare reports of congenital anomalies after intrauterine exposure to HMG-CoA reductase inhibitors.

Rare reports of congenital anomalies have been received after in utero exposure to HMG-CoA reductase inhibitors. However, an analysis of approximately 200 pregnancies prospectively observed, with exposure to simvastatin 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 an increase in the number of congenital anomalies by 2.5 times or more compared to the frequency in the general population.

Although there is no evidence that the frequency of congenital anomalies in offspring of patients taking simvastatin or other HMG-CoA reductase inhibitors differs from that observed in the general population, treatment of the mother with simvastatin may reduce mevalonate levels, which is a precursor in cholesterol synthesis in the fetus.

Atherosclerosis is a chronic process. Discontinuation of lipid-lowering drugs during pregnancy is not expected to significantly affect the outcomes of long-term treatment of primary hypercholesterolemia. Therefore, simvastatin should not be used in pregnant women or women who are trying to become pregnant or suspect they are pregnant.

Simvastatin intake should be suspended for the entire duration of pregnancy or until it is confirmed that the woman is not pregnant. The use of simvastatin should be suspended for the entire duration of pregnancy or until it is confirmed that the woman is not pregnant (see section "Contraindications").

Period of breastfeeding

It is unknown whether simvastatin or its metabolites pass into breast milk. Since many medicinal products pass into breast milk and there is a possibility of serious adverse reactions, women taking simvastatin should discontinue breastfeeding. (See section "Contraindications").

Fertility

Clinical studies on the effect of simvastatin on human fertility have not been conducted. Simvastatin has no effect on 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 a car and operate machinery. However, when driving a car or operating machinery, rare reports of dizziness should be taken into account.

Method of Administration and Dosage

The daily doses of Vasilip® range from 5 mg (use the dosage form with the corresponding strength) to 80 mg, taken orally once daily in the evening. Dose titration of Vasilip® 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 the potential risk (see sections "Pharmacodynamics" and "Special Warnings").

Hypercholesterolemia

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

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

Homozygous Familial Hypercholesterolemia

The recommended initial dose of Vasilip® − 40 mg once daily in the evening. The drug should be used as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such treatment is unavailable.

For patients taking Vasilip® concomitantly with lomitapide, the drug 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 Vasilip® for patients at high risk of developing ischemic heart disease (IHD), with or without hyperlipidemia, is 20**−**40 mg once daily in the evening. Pharmacological therapy may be initiated simultaneously with diet and exercise. Dose adjustments, if necessary, should be performed as described above.

Concomitant Therapy

Vasilip® is effective as monotherapy as well as in combination with bile acid sequestrants. The dose should be taken either at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant.

For patients taking Vasilip® concomitantly with fibrates other than gemfibrozil (see section "Contraindications") or with fenofibrate, the drug dose must not exceed 10 mg daily. For patients taking Vasilip® concomitantly with amiodarone, amlodipine, verapamil, or diltiazem, the daily dose of Vasilip® 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 for patients with moderate renal impairment.

For patients with severe renal impairment (creatinine clearance < 30 mL/min), the appropriateness of initiating therapy at a dose of 10 mg 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 initial dose is 10 mg once daily in the evening. Prior to initiating treatment with simvastatin, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained during simvastatin therapy.

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

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

Children.

The safety and efficacy of simvastatin in patients aged 10–17 years with heterozygous familial hyperlipidemia were evaluated in a controlled clinical trial involving boys at Tanner stage II and adolescent girls who had started menstruation at least one year prior. The adverse effect profile in patients receiving simvastatin was similar to that in patients receiving placebo. Doses higher than 40 mg were not studied in this patient group. The study did not detect any effect of simvastatin on growth or sexual development in adolescents, or on menstrual cycle duration in girls (see sections "Method of Administration and Dosage", "Adverse Reactions").

Girls should be informed about the need for contraception during simvastatin use.

The use of simvastatin has not been studied in patients under 10 years of age or in girls who have not yet started menstruation.

For patients under 18 years of age, efficacy and safety have not been studied beyond treatment periods of 48 weeks. The impact of long-term use on physical, intellectual, and sexual development is unknown.

Overdose.

There have been a few reported cases of overdose, with the highest ingested dose being 3.6 g; no specific symptoms were observed in any of the patients. All patients recovered without complications. In case of overdose, symptomatic and supportive measures should be undertaken, as there is no specific antidote.

Adverse Reactions

The frequency of the adverse reactions listed below, reported during clinical trials and/or in the post-marketing period, has been classified according to their incidence levels observed in large, long-term, placebo-controlled clinical trials, including HPS and 4S, involving 20,536 and 4,444 patients, respectively (see section "Pharmacodynamics"). In HPS, only serious adverse reactions, myalgia, elevated serum transaminases, and creatine kinase were recorded. In 4S, all adverse reactions listed below were documented. If the incidence during these studies was lower or similar with simvastatin compared to placebo, and spontaneous reports of events with a reasonable causal relationship were similar, these adverse reactions were classified as rare.

In the HPS study (see section "Pharmacodynamics"), involving 20,536 patients receiving 40 mg/day of simvastatin (n=10,269) or placebo (n=10,267), the safety profiles were comparable between simvastatin and placebo groups over a mean follow-up of 5 years. Discontinuation rates due to adverse effects were similar (4.8% in patients receiving 40 mg simvastatin vs. 5.1% in placebo group). The incidence of myopathy was <0.1% in patients receiving simvastatin. Elevated transaminases (>3 times the upper limit of normal, confirmed by repeat testing) occurred in 0.21% (n=21) of patients receiving simvastatin compared to 0.09% (n=9) of those receiving placebo.

Classification of adverse reaction frequencies: 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 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, myasthenia gravis.

Respiratory, thoracic and mediastinal disorders. Frequency not known: 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. Very rare: lichenoid drug eruption.

Musculoskeletal and connective tissue disorders. Rare: myopathy* (including myositis), rhabdomyolysis with or without renal impairment, myalgia, muscle spasms, cramps, myositis, polymyositis. Very rare: muscle rupture.

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

Frequency not known: tendonopathy, sometimes complicated by ruptures, (IMNM)**.

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

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

Eye disorders. Rare: blurred vision, visual disturbance. Very rare: ocular myasthenia.

General disorders and administration site conditions. Rare: asthenia. Rare cases of severe hypersensitivity reactions have been reported, including some of the following manifestations: angioneurotic oedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis and arthralgia, urticaria, photosensitization, fever, flushing, dyspnoea, and weakness.

Effects on laboratory and instrumental test results.

Rare: increased serum transaminase levels (alanine aminotransferase, aspartate aminotransferase, γ-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 use of statins, including Vazilip®, increases in HbA1c and fasting serum glucose levels have been reported.

Cognitive impairment (e.g., memory loss, forgetfulness, memory disturbance, confusion) has been reported with statin use, including simvastatin. Overall, these cases were non-serious and reversible upon discontinuation of the statin; the time to onset of symptoms (from one day to several years) and resolution (on average 3 weeks) varied.

Additional adverse effects observed with some statins:

• Sleep disturbances, including insomnia and nightmares;
• Sexual dysfunction;
• Diabetes mellitus: incidence depends on the presence/absence of risk factors (fasting 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 involving children and adolescents (boys at Tanner stage II or above and girls with at least one year of menstrual cycles) aged 10–17 years with heterozygous familial hypercholesterolaemia (n=175), the safety and tolerability profile in patients receiving simvastatin was generally similar to that in patients receiving placebo. The long-term impact on physical, cognitive, and sexual development is unknown. There is insufficient data beyond one year of treatment (see sections "Special precautions for use" and "Dosage and administration").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

10 mg tablets: 7 tablets per blister, 2 or 4 blisters per cardboard box.

20 mg tablets: 7 tablets per blister, 2, 4, or 12 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.