Vazilip film-coated tablets 40 mg No. 28

Instructions for Vasilip film-coated tablets 40 mg No. 28

Composition

active ingredient: simvastatin;

1 film-coated tablet contains 40 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 film-coated tablets with a beveled edge and a score on one side.

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-CoA 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) cholesterol levels. 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 LDL-cholesterol production and an increase in LDL-C catabolism. Simvastatin also significantly reduces apolipoprotein B levels. In addition, simvastatin modestly increases high-density lipoprotein (HDL-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.

Coronary heart disease (CHD)

In the HPS (Heart Protection Study), the effect of simvastatin therapy was evaluated in 20,536 patients (aged 40 to 80 years) with or without hypolipidemia, coronary heart disease and other occlusive arterial diseases, or diabetes mellitus. In this study, which lasted for about 5 years, 10,269 patients took simvastatin at a dose of 40 mg per day, 10,267 patients took placebo. At baseline, 6,793 patients (33%) had LDL-C levels below 116 mg/dL, 5,063 patients (25%) had levels between 116 mg/dL and 135 mg/dL, and 8,680 patients (42%) had levels above 135 mg/dL.

Treatment with simvastatin 40 mg daily significantly reduced all-cause mortality in patients compared with placebo (1328, or 12.9%, versus 1507, or 14.7%, respectively; p=0.0003), due to an 18% reduction in myocardial infarction mortality (587, or 5.7%, versus 707, or 6.9%; p=0.0005; absolute risk reduction of 1.2%). The reduction in nonvascular mortality did not reach statistical significance. Simvastatin also reduced the risk of major coronary events (a composite endpoint of nonfatal myocardial infarction and CHD mortality) by 27% (p<0.0001). Simvastatin reduces the need for coronary artery revascularization procedures (including coronary artery bypass grafting or transluminal coronary angioplasty) and peripheral and non-coronary vascular revascularization procedures by 30% (p<0.0001) and 16% (p=0.006), respectively.

In the 4S study (Scandinavian Simvastatin Survival Study), the effect on all-cause mortality was assessed in 4444 patients with coronary artery disease and a cholesterol level of 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients with angina or previous myocardial infarction (MI) were treated with a usual care diet, simvastatin 20-40 mg/day (n=2221) or placebo (n=2223) for a mean treatment duration of 5.4 years. Simvastatin was shown to reduce the risk of death by 30% (absolute risk reduction of 3.3%). The risk of death from coronary artery disease was reduced by 42% (absolute risk reduction of 3.5%). Simvastatin also reduced the risk of major coronary events (fatal CHD and asymptomatic nonfatal myocardial infarction) by 34%. In addition, simvastatin significantly reduced the risk of fatal and nonfatal cardiovascular events (stroke and transient ischemic attack) by 28%. There was no statistically significant difference between groups in the incidence of non-cardiovascular death.

Primary hypercholesterolemia and combined hyperlipidemia

In studies comparing the efficacy and safety of simvastatin 10 mg, 20 mg, 40 mg, and 80 mg daily in patients with hypercholesterolemia, the mean reductions in LDL-C were 30%, 38%, 41%, and 47%, respectively. In studies of patients with combined (mixed) hyperlipidemia who received simvastatin 40 mg and 80 mg, the mean reductions in triglycerides were 28% and 33%, respectively (placebo 2%), and the mean increases in HDL-C were 13% and 16%, respectively (placebo 3%), respectively.

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 food intake 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 (see sections 4.3 and 4.5). The major metabolites of simvastatin in human plasma are the beta-hydroxyacid and 4 additional active metabolites. Following oral administration of radiolabelled simvastatin, 13% of the drug is excreted in the urine and 60% in the faeces within 96 hours. The material recovered in the faeces represents the fraction of the absorbed drug excreted in the bile and the fraction 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.

Cardiovascular prevention

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

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 and nefazodone (see sections 4.4 and 4.5).

Concomitant use of gemfibrozil, cyclosporine or danazol (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions").

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

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

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.

Interactions have 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 (see below "Pharmacokinetic interactions" and the sections "Contraindications" and "Special instructions for use"). 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 for use").

Pharmacokinetic interactions

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

Interactions with other drugs associated with an increased risk of myopathy/rhabdomyolysis

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 (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, as well as gemfibrozil, cyclosporine, danazol and with medicinal products containing cobicistat 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 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 "Method of administration and dosage", "Special instructions for use").

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 concomitantly with simvastatin; therefore, such use is 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).

"Special warnings and precautions for use"). 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 (pharmacodynamics and/or pharmacokinetics) is currently unknown. Rhabdomyolysis (including some fatal cases) has been reported in patients receiving this combination. If fusidic acid is considered necessary, simvastatin treatment should be discontinued for the time being (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 simvastatin concomitantly with amiodarone.

Calcium channel blockers

Verapamil

The risk of myopathy and rhabdomyolysis increases with concomitant use of verapamil with simvastatin at a dose of 40 mg or 80 mg (see section "Special warnings and precautions for use").

Pharmacokinetic studies have shown that concomitant use 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.

Patients taking other medicinal products that have a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, especially with higher doses of simvastatin, are at increased risk of developing myopathy (see section 4.4).

OATP1B1 carrier protein inhibitors

Simvastatin acid is a substrate for the OATP1B1 carrier protein. Concomitant administration of medicinal products known to inhibit the OATP1B1 carrier protein 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 4.2 and 4.4).

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

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 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 rifampicin was co-administered.

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 20-40 mg/day was found to moderately potentiate 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 taking coumarin anticoagulants, prothrombin time should be determined before starting treatment with simvastatin and monitored during the initial period of treatment to detect possible significant changes. Once the stability of the prothrombin time has been confirmed, the studies should be carried out at intervals recommended for patients taking coumarin anticoagulants. If the dose of simvastatin is changed or its administration is discontinued, the stability of the prothrombin time should be confirmed again. Treatment with simvastatin has not been associated with bleeding events 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 10 times the upper limit of normal. Myopathy can manifest as rhabdomyolysis, sometimes accompanied by acute renal failure due to myoglobinuria. The risk of myopathy increases with increasing plasma HMG-CoA reductase inhibitory activity.

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% at doses of 20, 40, and 80 mg/day, respectively. Patients were carefully monitored in these studies and some interacting drugs were excluded.

In a clinical study in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up period 6.7 years), the incidence of myopathy was approximately 1.0%, compared with 0.02% for patients receiving 20 mg/day. 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 4.8 and 5.1).

The risk of myopathy is greater in patients taking 80 mg of simvastatin compared with patients receiving other statins with similar LDL-C-lowering efficacy. 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”, “Method of administration and dosage”, “Interaction with other medicinal products and other forms of interaction”).

In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (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 systemic exposure to 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 increased systemic exposure to 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 (designated as 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 widely available 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 measurement

Creatine kinase levels should not be measured after vigorous exercise or in the presence of any other cause of elevated creatine kinase, as this makes interpretation of the results difficult. If creatine kinase levels are significantly elevated at baseline (more than 5 times the upper limit of normal), levels should be remeasured after 5 to 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 (≥ 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;

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 in this class should be initiated with caution.

If creatine kinase levels are significantly elevated at baseline (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 (more than 5 times the upper limit of normal) 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 less than 5 times the upper limit of normal, discontinuation of treatment should be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

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 that persist despite discontinuation of statins, evidence of necrotizing myopathy on muscle biopsy without significant inflammation, and improvement with immunosuppressive agents (see section 4.8).

If symptoms resolve and creatine kinase levels return to normal, consideration should be given to reintroducing the same 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 before elective major surgery, as well as 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, danazol. The use of these medicinal products is contraindicated (see section "Contraindications").

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil or diltiazem with certain doses of simvastatin (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, is increased by concomitant use of fusidic acid with statins (see section 4.5). In patients with HoSH, this risk is increased by 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 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 4.2 and 4.5). Fenofibrate should be prescribed with caution with simvastatin, as each of these drugs can cause myopathy.

Simvastatin should not be taken