Vazilip film-coated tablets 20 mg No. 28

Instructions for Vasilip film-coated tablets 20 mg No. 28

Composition

active ingredient: simvastatin;

1 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).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, slightly biconvex, white tablets, film-coated, with beveled edges.

Pharmacotherapeutic group

Hypolipidemic agents, monocomponent. HMG-CoA reductase inhibitors.

ATX code C10A A01.

Pharmacological properties

Pharmacodynamics.

After oral administration, simvastatin is hydrolyzed in the liver from the inactive lactone to the corresponding active beta-hydroxyacid form, which has potent activity in inhibiting 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 low-density lipoprotein (LDL) concentrations. LDL is derived from very low-density lipoprotein (VLDL) and is primarily catabolized by high-affinity LDL receptors. The mechanism of the LDL-lowering effect of simvastatin may be related to both a decrease in VLDL-cholesterol (VLDL-C) and an induction of LDL receptors, which results in a decrease in the production and an increase in the catabolism of LDL-cholesterol (VLDL-C). Simvastatin also significantly reduces apolipoprotein B levels. In addition, simvastatin modestly increases high-density lipoprotein (VLDL-C) cholesterol levels and reduces plasma triglyceride levels. These changes result in a decrease in the ratio of total cholesterol to HDL-C and LDL-C to HDL-C.

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 not available.

Absorption

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

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

Distribution

The binding of simvastatin and its active metabolites to plasma proteins is ≥ 95%.

Breeding

Simvastatin is a substrate of CYP3A4. The major metabolites of simvastatin in human plasma are the beta-hydroxyacid and 4 additional active metabolites. After oral administration of radiolabeled simvastatin, 13% of the drug is excreted in the urine and 60% in the feces within 96 hours. The material found in the feces represents the portion of the adsorbed drug excreted in the bile and the portion of the drug that was not absorbed. After intravenous administration of the beta-hydroxyacid metabolite, its half-life is 1.9 hours. On average, only 0.3% of the intravenous dose is excreted in the urine as inhibitors.

Simvastatin is actively taken up by hepatocytes using the OATP1B1 carrier.

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

Patients of special groups

SLCO1B1 polymorphism

Carriers of the c.521T>C allele of the SLCO1B1 gene have reduced OATP1B1 protein activity. The mean exposure (AUC) of the main active metabolite, simvastatin acid, is 120% in heterozygous carriers (CT) of the C allele and 221% in homozygous (CC) carriers 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 detected with a frequency of 1.5%. Patients with the SLCO1B1 gene polymorphism are at risk of increased exposure to simvastatin acid, which may increase the risk of rhabdomyolysis (see section "Special instructions").

Indication

Hypercholesterolemia

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

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

Reduction of cardiovascular mortality and morbidity in patients with overt atherosclerotic cardiovascular disease or diabetes mellitus, with normal or elevated cholesterol levels, as an adjunct to correction of other risk factors and to other cardioprotective therapy (see section "Pharmacological properties").

Contraindication

Hypersensitivity to simvastatin or any other component of the drug.

Acute liver disease or persistent elevation of serum transaminases of unknown origin.

Concomitant use of potent CYP3A4 inhibitors (drugs that increase AUC by 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 precautions for use”).

Concomitant use of gemfibrozil, cyclosporine or danazol (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”).

Pregnancy or breast-feeding (see section “Use during pregnancy or breast-feeding”).

Patients with homozygous familial hypercholesterolemia (FH) who are receiving lomitapide and simvastatin at doses greater than 40 mg simultaneously (see sections “Interaction with other medicinal products and other types of interactions”, “Special instructions for use” and “Method of administration and dosage”).

Interaction with other medicinal products and other types of interactions

Several mechanisms of drug action may contribute to the potential for interaction with HMG-CoA reductase inhibitors. Drugs and herbal preparations that inhibit some enzyme (e.g. CYP3A4) and/or transporter (e.g. OATP1B) activities may increase plasma concentrations of simvastatin and simvastatin acid and lead to an increased risk of myopathy/rhabdomyolysis.

Refer to the prescribing information for all concomitant medications for additional information on their potential interactions with simvastatin and/or changes that may occur with enzymes or transporters, and possible dose and regimen adjustments.

The interaction has only been studied in adult patients.

Pharmacodynamic interactions

Interaction with lipid-lowering drugs that, when taken separately, can cause myopathy

The risk of myopathy, including rhabdomyolysis, is increased when simvastatin is co-administered with fibrates and niacin (nicotinic acid) ≥ 1 g/day. In addition, there is a pharmacokinetic interaction with gemfibrozil, which leads to an increase in the level of simvastatin in the blood plasma. There is no evidence that the risk of myopathy is higher with the simultaneous use of simvastatin and fenofibrate than with the use of these drugs separately. For other fibrates, there are no adequate pharmacovigilance and pharmacokinetic data. In isolated cases, the occurrence of myopathy/rhabdomyolysis has been associated with the concomitant use of simvastatin and lipid-lowering doses of niacin ≥ 1 g/day (see section "Special instructions").

Pharmacokinetic interactions

Recommendations for the use of interacting agents are given in the table below (see also sections “Contraindications”, “Special instructions for use” and “Method of administration and dosage”).

Effects of other medicinal products on simvastatin

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 HMG-CoA reductase concentrations during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir and nefazodone. Concomitant administration of itraconazole results in an increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite) by more than 10-fold and to telithromycin by more than 11-fold.

The combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, as well as gemfibrozil, cyclosporine and danazol is contraindicated (see section "Contraindications"). If treatment with potent CYP3A4 inhibitors (drugs that increase AUC by 5 times or more) cannot be avoided, simvastatin therapy should be discontinued for the duration of the course of treatment. The use of simvastatin with some other less potent CYP3A4 inhibitors (fluconazole, verapamil and diltiazem) should be carried out with caution (see sections "Special instructions" and "Dosage and administration").

Fluconazole

Rare cases of rhabdomyolysis have been reported in association with concomitant administration of simvastatin and fluconazole (see section 4.4).

Cyclosporine

The risk of myopathy/rhabdomyolysis is increased when ciclosporin is used in combination with simvastatin, and this use is therefore contraindicated (see sections 4.3 and 4.4). Although the mechanism of action is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in simvastatin AUC is primarily due to inhibition of CYP3A4 and/or OATP1B1.

Danazol

Due to the increased risk of myopathy and rhabdomyolysis when danazol is used concomitantly with 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 through inhibition of the glucuronidation cascade and/or the OATP1B1 protein (see sections 4.3 and 4.4). Concomitant use with gemfibrozil is contraindicated.

Fusidic acid

The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is administered concomitantly with statins. Concomitant administration of this combination may result in increased plasma concentrations of both drugs. The mechanism of this interaction is not yet known. Isolated cases of rhabdomyolysis (including fatal cases) have been reported with simvastatin. If fusidic acid is considered necessary, simvastatin treatment should be discontinued for the duration of therapy (see section 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased when simvastatin is co-administered with amiodarone (see section 4.4). In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving this drug concomitantly with amiodarone.

Calcium channel blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased when verapamil is co-administered with simvastatin 40 or 80 mg (see section 4.4). Pharmacokinetic studies have shown that concomitant administration of verapamil results in 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/day in patients taking this drug concomitantly with verapamil.

Diltiazem

The risk of myopathy and rhabdomyolysis is increased when diltiazem is co-administered with simvastatin 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem resulted in a 2.7-fold increase in exposure to simvastatin acid, primarily due to inhibition of CYP3A4. Therefore, in patients receiving concomitant treatment with diltiazem, the dose of simvastatin should not exceed 20 mg/day.

Amlodipine

Patients taking amlodipine concomitantly with simvastatin are at increased risk of developing myopathy. In a pharmacokinetic study, concomitant administration of amlodipine resulted in a 1.6-fold increase in exposure to simvastatin acid. Therefore, the dose of simvastatin should not exceed 20 mg/day in patients taking this drug concomitantly with amlodipine.

Lomitapide

The risk of myopathy and rhabdomyolysis is increased when lomitapide and simvastatin are used concomitantly (see sections 4.3 and 4.4). Therefore, in patients with HoSH, the dose of simvastatin should not exceed 40 mg/day when co-administered with lomitapide.

Moderate CYP3A4 inhibitors

OATP1B1 transport protein inhibitors

Simvastatin acid is a substrate for the transport protein OATP1B1. Concomitant use of medicinal products known to inhibit the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see sections 4.3 and 4.4).

Breast cancer resistance protein (BCRP) inhibitors

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 4.4 and 4.2).

Daptomycin: Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors with daptomycin. Caution should be exercised when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when used alone. Simvastatin should be temporarily discontinued in patients receiving daptomycin.

Niacin (nicotinic acid)

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

Ticagrelor

Co-administration of ticagrelor with simvastatin increases simvastatin Cmax by 81% and AUC by 56%, and simvastatin acid Cmax by 64% and AUC by 52%, with some individual cases of a 2- to 3-fold increase in these values. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg/day may increase the adverse effects of simvastatin, so the decision to co-administer these drugs at these doses should be based on a risk-benefit assessment. No effect of simvastatin on ticagrelor plasma levels was observed. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg is not recommended.

Grapefruit juice

Grapefruit juice inhibits cytochrome P450ZA4 activity. Consumption of large amounts (more than 1 liter per day) of grapefruit juice in combination with simvastatin may increase the exposure of simvastatin acid by 7-fold. Consumption of 240 ml of grapefruit juice in the morning and administration of simvastatin in the evening also resulted in a 1.9-fold increase in exposure. Therefore, grapefruit juice should be avoided when taking simvastatin.

Colchicine

Myopathy and rhabdomyolysis have been reported in patients with renal impairment when colchicine and simvastatin are co-administered. Close monitoring is recommended in patients receiving this combination.

Rifampicin

Since rifampicin is a potent inducer of CYP3A4, loss of efficacy of simvastatin may occur in patients receiving it for a long time (e.g., tuberculosis therapy). In a pharmacokinetic study in healthy volunteers, the AUC of simvastatin acid was decreased by 93% when co-administered with rifampicin.

Effect of simvastatin on the pharmacokinetics of other drugs

Simvastatin does not inhibit cytochrome P450 3A4. Therefore, simvastatin is not expected to affect the plasma concentrations of substances metabolized by cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in healthy volunteers and the other in patients with hypercholesterolemia, simvastatin at a dose of 2-40 mg/day was found to moderately enhance the effect of coumarin anticoagulants: prothrombin time, expressed in terms of the international normalized ratio (INR), increased from a baseline value 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 taking coumarin anticoagulants, prothrombin time should be determined before starting treatment with simvastatin and then monitored during the initial period of treatment in order to detect possible significant changes in prothrombin time. After confirmation of stability of the prothrombin time, the study should be carried out at intervals recommended for patients taking coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the stability of prothrombin time should be re-confirmed. Treatment with simvastatin has not been associated with bleeding or changes in prothrombin time in patients not taking anticoagulants.

Application features

Myopathy/rhabdomyolysis: Simvastatin, like other HMG-CoA reductase inhibitors, can cause myopathy, manifested by muscle pain, tenderness or weakness and accompanied by an increase in creatine kinase activity to more than ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure due to myoglobinuria; very rarely, fatalities have been reported. The risk of myopathy is increased by the high inhibitory activity against HMG-CoA reductase in the blood plasma (increased plasma levels of simvastatin and simvastatin acid), which may be partly due to interactions with drugs that interfere with the metabolism and/or transport of simvastatin (see section 4.5).

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose-related. In a clinical trial database of 41,413 patients treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08%, and 0.61% for doses of 20, 40, and 80 mg/day, respectively. In these studies, patients were carefully monitored and some potentially interacting drugs were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg daily (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0%, compared with 0.02% for patients receiving 20 mg daily. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1% (see sections 5.1 and 4.8).

The risk of myopathy is greater in patients taking 80 mg of simvastatin compared with patients receiving other statins with similar efficacy in lowering LDL-C. Therefore, the 80 mg dose should only be used in patients with severe hypercholesterolemia and at increased risk of cardiovascular complications who have not achieved the effect of treatment with lower doses, when the benefits are expected to outweigh the potential risks. For patients taking simvastatin 80 mg and requiring concomitant therapy, a lower dose of simvastatin or another statin with less 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 forms of interaction” and “Method and dosage”).

In a clinical trial in which patients at high risk of cardiovascular disease received simvastatin 40 mg daily (median follow-up period 3.9 years), the incidence of myopathy was approximately 0.05% in non-Chinese patients (n=7367) compared with 0.24% in Chinese patients (n=5468). Although the Chinese population in this clinical trial was only represented by Chinese, caution should be exercised when simvastatin is used in Chinese patients and the lowest dose should be used.

In a few cases, statins have been reported to cause de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of exacerbation of symptoms, Vasilip® should be discontinued. Relapses have been reported when the same or a different statin was (re)administered.

Reduced function of transport proteins

Reduced function of hepatic OATP transport proteins may increase the AUC of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function may occur as a result of inhibition by interacting agents (e.g., cyclosporine) or in patients who are carriers of the SLCO1B1 (c.521T>C) genotype.

Patients carrying the SLCO1B1 (c.521T>C) allele, which encodes a less active OATP1B1 protein, have an increased AUC of simvastatin acid and an increased risk of myopathy. Without genetic testing, the risk of 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 in patients with the most common genotype (TT) is 0.3% (see section 5.1). Such specific genotyping is not commonly used in clinical practice. Whenever possible, before prescribing simvastatin 80 mg to individual patients, it should be considered appropriate to perform genotyping for the presence of the C allele as part of a benefit-risk assessment, and to avoid prescribing high doses to carriers of the CC genotype. However, the absence of this gene by genotyping does not exclude the possibility of myopathy in these patients.

Creatine kinase levels should not be measured after vigorous exercise or if there is any other cause for elevated creatine kinase, as this makes interpretation of the results difficult. If creatine kinase levels are significantly elevated at baseline (greater than 5 times the ULN), levels should be remeasured after 5–7 days to confirm the results.

Before treatment

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

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

elderly age (age ≥ 65 years) of the patient;

female gender;

kidney dysfunction;

uncontrolled hypothyroidism;

the presence of hereditary muscle disorders in a personal or family history;

history of statin or fibrate-induced muscle toxicity;

alcohol abuse.

In such situations, the risk of treatment should be weighed against the potential benefit, and clinical monitoring is recommended. If a patient has previously experienced muscle dysfunction while taking a fibrate or statin, treatment with another agent of this class should be initiated with caution.

If there is a significant initial increase in creatine kinase levels (more than 5 times the upper limit of normal), treatment should not be initiated.

During treatment

If a patient experiences pain, weakness, or cramps while taking a statin, creatine kinase levels should be measured. If these levels are found to be significantly elevated (>5 times the ULN) in the absence of strenuous exercise, treatment should be discontinued. If muscle symptoms are severe and cause daily discomfort, even if creatine kinase levels are <5 times the ULN, discontinuation of 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. IMMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that do not resolve despite discontinuation of statins (see section 4.8).

If symptoms resolve and creatine kinase levels return to normal, consideration should be given to reintroducing the same statin or an alternative statin at a low dose and under close monitoring.

A higher rate of myopathy was observed in patients who were titrated to 80 mg (see section 5.1). Periodic monitoring of creatine kinase is recommended as it may help to detect subclinical myopathy. However, there is no evidence that such monitoring can prevent the development of myopathy.

Simvastatin therapy should be temporarily discontinued in patients a few days prior to elective major surgery, and after medical or surgical interventions.

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

The risk of myopathy and rhabdomyolysis is significantly increased when simvastatin is co-administered with potent CYP3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat, as well as gemfibrozil, ciclosporin and danazol. The use of these medicinal products is contraindicated (see section 4.3).

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 4.3 and 4.5). If potent CYP3A4 inhibitors (drugs that increase AUC by 5-fold or more) cannot be discontinued, simvastatin therapy should be discontinued for the duration of these drugs (and an alternative statin should be considered). In addition, caution should be exercised when simvastatin is used concomitantly with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section 4.5). Grapefruit juice should be avoided with simvastatin.

The use of simvastatin with gemfibrozil is contraindicated (see section 4.3). Due to the increased risk of myopathy and rhabdomyolysis, the dose of simvastatin should not exceed 10 mg daily in patients taking simvastatin with fibrates other than fenofibrate (see sections 4.5 and 4.2). Fenofibrate should be prescribed with caution with simvastatin, as each of these drugs can cause myopathy.

Simvastatin should not be taken concomitantly with systemic fusidic acid-containing products or within 7 days of stopping fusidic acid. If systemic fusidic acid is necessary, statin treatment should be discontinued for the duration of fusidic acid treatment. Rhabdomyolysis (including some fatalities) has been reported in patients receiving the combination of fusidic acid and statins (see section 4.5). Patients should seek medical advice immediately if they experience muscle weakness or pain, pain or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases where long-term systemic fusidic acid treatment is necessary, e.g. for the treatment of severe infections, the need for concomitant simvastatin and fusidic acid should only be considered on a case-by-case basis and under close medical supervision.

The combined use of simvastatin at doses above 20 mg/day with amiodarone, amlodipine, verapamil or diltiazem should be avoided (see sections 4.5 and 4.2). In patients with HoSH, the risk of myopathy is increased when lomitapide and simvastatin are used concomitantly (see sections 4.3, 4.2 and 4.2).

Patients taking other drugs that have a moderate inhibitory effect on CYP3A4, concomitantly with simvastatin, especially with high doses of simvastatin, are at increased risk of developing myopathy. When simvastatin is co-administered with a moderate inhibitor of CYP3A4 (drugs that increase AUC 2-5-fold), a dose adjustment of simvastatin may be necessary. For use with certain moderate inhibitors of CYP3A4, such as diltiazem, a maximum dose of 20 mg of simvastatin is recommended (see section 4.2).

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

Concomitant use with BCRP inhibitors (e.g. elbasvir and grazoprevir) may result in increased plasma concentrations of simvastatin and an increased risk of myopathy, therefore, dose adjustment of simvastatin may be necessary. 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 elbasvir or grazoprevir-containing products (see section 4.5).

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

In a clinical trial (median follow-up of 3.9 years) in 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, no additional cardiovascular benefit was observed with the addition of lipid-modifying doses (≥ 1 g daily) of niacin (nicotinic acid).