Vazilip®

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

Composition:

Active ingredient: simvastatin;

One film-coated tablet contains 40 mg of simvastatin;

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

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

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white, round, slightly biconvex film-coated tablets with bevelled edges and a score line on one side.

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 has potent inhibitory activity against 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 levels of low-density lipoprotein cholesterol (LDL-C). LDL particles are derived from very-low-density lipoproteins (VLDL) and are primarily catabolized by high-affinity LDL receptors. The mechanism of LDL-lowering effect of simvastatin may involve both a reduction in VLDL cholesterol (VLDL-C) levels and upregulation of LDL receptors, leading to decreased production and increased catabolism of LDL-C. Additionally, simvastatin significantly reduces levels of apolipoprotein B. Furthermore, simvastatin moderately increases high-density lipoprotein cholesterol (HDL-C) and reduces plasma triglyceride levels. As a result of these changes, the ratios of total cholesterol to HDL-C and LDL-C to HDL-C are reduced.

Ischemic Heart Disease (IHD)

In the Heart Protection Study (HPS), the effects of simvastatin therapy were evaluated in 20,536 patients (aged 40–80 years) with or without hyperlipidemia, who had ischemic heart disease and other occlusive arterial diseases or diabetes mellitus. In this study, which lasted approximately 5 years, 10,269 patients received simvastatin 40 mg daily and 10,267 received 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 compared to placebo (1,328 [12.9%] vs. 1,507 [14.7%], respectively; p=0.0003), due to a 18% reduction in mortality from myocardial infarction (587 [5.7%] vs. 707 [6.9%]; p=0.0005; absolute risk reduction 1.2%). The reduction in non-vascular mortality was not statistically significant. Simvastatin also reduced the risk of major coronary events (a composite endpoint of non-fatal myocardial infarction and death from IHD) by 27% (p<0.0001). Simvastatin reduced the need for coronary revascularization procedures (including aortocoronary bypass surgery or percutaneous transluminal coronary angioplasty) and peripheral and non-coronary vascular revascularization procedures by 30% (p<0.0001) and 16% (p=0.006), respectively.

Simvastatin reduced the risk of stroke by 25% (p<0.0001), and ischemic stroke by 30% (p<0.0001). Moreover, in the subgroup of patients with diabetes mellitus, simvastatin reduced the risk of macrovascular complications, including the need for peripheral vascular revascularization (surgery or angioplasty), lower-limb amputations, and reduced the risk of foot ulcers by 21% (p=0.0293). The proportional reduction in event rates was consistent across all subgroups: patients without coronary heart disease but with cerebrovascular or peripheral vascular disease, men and women under or over 70 years of age, with or without hypertension at baseline, and even in those with LDL-C levels below 3.0 mmol/L.

In the 4S (Scandinavian Simvastatin Survival Study), the effect on total mortality was assessed in 4,444 patients with IHD and total cholesterol levels between 212–309 mg/dL (5.5–8.0 mmol/L). This multicenter, randomized, double-blind, placebo-controlled study involved patients with angina pectoris or a history of myocardial infarction (MI) who were treated with diet plus usual care, simvastatin 20–40 mg daily (n=2,221), or placebo (n=2,223), with a mean treatment duration of 5.4 years. Simvastatin reduced the risk of death by 30% (absolute risk reduction 3.3%). The risk of death from IHD was reduced by 42% (absolute risk reduction 3.5%). Simvastatin also reduced the risk of major coronary events (fatal IHD and asymptomatic non-fatal MI) by 34%. Additionally, simvastatin significantly reduced the risk of fatal and non-fatal cerebrovascular events (stroke and transient ischemic attack) by 28%. There was no statistically significant difference between groups in mortality from non-cardiovascular causes.

Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia

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

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 beta-hydroxyacid in the systemic circulation accounts for less than 5% of the dose. Maximum plasma concentrations of active inhibitors are reached approximately 1–2 hours after administration of simvastatin. Concomitant food intake does not affect drug absorption.

Pharmacokinetic studies of single or multiple doses of simvastatin showed no accumulation of the drug after repeated administration.

Distribution

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

Elimination

Simvastatin is a substrate of CYP3A4 (see sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction»). 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 was excreted in urine and 60% in feces within 96 hours. The substance found in feces represents both unabsorbed drug and drug absorbed and excreted via 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 by hepatocytes via the OATP1B1 transporter.

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

Patients in Special Populations

SLCO1B1 Polymorphism

Carriers of the SLCO1B1 gene allele c.521T>C exhibit reduced OATP1B1 protein activity. The average exposure (AUC) of the main 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 in the European population with a frequency of 18%, and the homozygous CC genotype is found with a frequency of 1.5%. Patients with SLCO1B1 polymorphism have an increased risk of elevated simvastatin acid exposure, which may increase the risk of developing rhabdomyolysis (see section «Special Warnings and Precautions for Use»).

Clinical characteristics.

Indications

Hypercholesterolemia

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

Treatment of homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (e.g., low-density lipoprotein apheresis), when such treatments 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 correction of other risk factors and to 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 transaminase levels.
• Concomitant use of strong CYP3A4 inhibitors (medicinal products 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 "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of gemfibrozil, cyclosporine, or danazol (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Pregnancy or breastfeeding (see section "Use in pregnancy or lactation").
• Patients with homozygous familial hypercholesterolemia who are concurrently receiving lomitapide and simvastatin at doses exceeding 40 mg (see sections "Dosage and administration", "Special precautions for use", and "Interaction with other medicinal products and other forms of interaction").

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 transporter activity (e.g., OATP1B1) may increase plasma concentrations of simvastatin and simvastatin acid, thereby increasing the risk of myopathy/rhabdomyolysis.

Refer to the prescribing information for all concomitantly used 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 (see below "Pharmacokinetic interactions" and sections "Contraindications" and "Special precautions for use"). There is no evidence that the risk of myopathy is higher with concomitant use of simvastatin and fenofibrate than with either agent used alone. For other fibrates, adequate pharmacovigilance and pharmacokinetic data are lacking. Isolated cases of myopathy/rhabdomyolysis have been associated with concomitant use of simvastatin and lipid-lowering doses of niacin ≥ 1 g/day (see section "Special precautions for use").

Pharmacokinetic interactions

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

Interaction with other medicinal products associated with increased risk of myopathy/rhabdomyolysis

Substances that interact	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 patients of Mongoloid race
Amiodarone amlodipine verapamil diltiazem elbasvir grazoprevir	do not exceed 20 mg simvastatin per day
Daptomycin	Consider temporary discontinuation of simvastatin in patients taking daptomycin if benefit does not outweigh risk (see section "Special precautions").
Lomitapide	In patients with HoFH (homozygous familial hypercholesterolemia), simvastatin should be administered at doses no higher than 40 mg daily.
Ticagrelor	Doses of simvastatin exceeding 40 mg per day are not recommended
Grapefruit juice	avoid consumption is recommended

Effects of Other Medicinal Products on Simvastatin

Interactions Involving CYP3A4

Simvast inflamm 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 administration of itraconazole increases 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 (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, as well as gemfibrozil, cyclosporine, danazol, and medicinal products containing cobicistat is contraindicated (see section "Contraindications"). If treatment with potent CYP3A4 inhibitors (agents increasing AUC by 5-fold or more) cannot be avoided, simvastatin therapy should be suspended for the duration of treatment. Use of simvastatin with some other less potent CYP3A4 inhibitors—fluconazole, verapamil, and diltiazem—should be performed with caution (see sections "Dosage and Administration" and "Special Warnings and Precautions").

Fluconazole

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

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"). 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 through inhibition of CYP3A4 and/or the OATP1B1 transporter protein.

Danazol

Due to the increased risk of myopathy and rhabdomyolysis with concomitant use of danazol and simvastatin, such combination is contraindicated (see sections "Contraindications" and "Special Warnings and Precautions").

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly via inhibition of the glucuronidation pathway and/or the OATP1B1 transporter 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 when systemic fusidic acid is used concomitantly with statins. Concomitant use of this combination may lead to increased plasma concentrations of both agents. The mechanism of this interaction (pharmacodynamic and/or pharmacokinetic) is currently unknown. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination. If use of fusidic acid is considered necessary, treatment with simvastatin should be discontinued during this period (see section "Special Warnings and Precautions").

Amiodarone

The risk of myopathy and rhabdomyolysis increases with concomitant use of simvastatin and amiodarone (see section "Special Warnings and Precautions"). In a clinical trial, 6% of patients receiving simvastatin 80 mg and amiodarone reported myopathy. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant amiodarone.

Calcium Channel Blockers

• Verapamil

The risk of myopathy and rhabdomyolysis increases with concomitant use of verapamil and simvastatin at doses of 40 mg or 80 mg (see section "Special Warnings and Precautions").

Pharmacokinetic studies have shown that concomitant administration 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 receiving concomitant verapamil.

• 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"). In a pharmacokinetic study, concomitant administration of diltiazem increased exposure to simvastatin acid by 2.7-fold, primarily due to inhibition of CYP3A4. Thus, in patients receiving concomitant diltiazem, 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 receiving concomitant amlodipine.

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").

Inhibitors of the OATP1B1 Transporter Protein

Simvastatin acid is a substrate of the OATP1B1 transporter protein. Concomitant administration of medicinal products known to inhibit the OATP1B1 transporter protein may increase plasma concentrations of simvastatin acid and increase the risk of myopathy (see sections "Contraindications" and "Special Warnings and Precautions").

Inhibitors of Breast Cancer Resistance Protein (BCRP)

Concomitant use with BCRP inhibitors (including medicinal products containing elbasvir or grazoprevir) may increase plasma concentrations of simvastatin and increase the risk of myopathy (see sections "Dosage and Administration" and "Special Warnings and Precautions").

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

Tickagrelor

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 simvastatin-related adverse reactions; therefore, decisions on concomitant use at these doses should be based on a benefit-risk assessment. No effect of simvastatin on plasma levels of ticagrelor was observed. Concomitant use of ticagrelor with simvastatin doses above 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. Drinking 240 mL of grapefruit juice in the morning and taking simvastatin in the evening also increased its effect by 1.9-fold. Therefore, grapefruit juice should be avoided during simvastatin therapy.

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 receiving this combination.

Rifampicin

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

Effect of Simvastatin on the Pharmacokinetics of Other Medicinal Products

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

Oral Anticoagulants

In two clinical studies—one involving healthy volunteers and the other involving patients with hypercholesterolemia—simvastatin at doses of 20–40 mg/day moderately enhanced 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 initiating simvastatin therapy 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 simvastatin dose 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 presents as muscle pain, tenderness or weakness, and is associated with increased creatine kinase activity more than 10 times above the upper limit of normal. Myopathy may manifest as rhabdomyolysis, which sometimes is accompanied by acute renal failure due to myoglobinuria. The risk of myopathy increases with elevated plasma HMG-CoA reductase inhibitory activity.

As with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis is dose-dependent.

In the clinical trial database, where 41,413 patients received simvastatin, of whom 24,747 (approximately 60%) were enrolled in studies with a mean observation period of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08%, and 0.61% at doses of 20, 40, and 80 mg/day, respectively. During these trials, patients were closely monitored and certain interacting drugs were excluded.

In a clinical study in which patients with a history of myocardial infarction received simvastatin 80 mg/day (mean observation period 6.7 years), the incidence of myopathy was approximately 1.0%, compared to 0.02% in patients receiving 20 mg/day. Approximately half of these cases of myopathy occurred within the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1% (see sections “Adverse reactions” and “Pharmacological properties”).

The risk of myopathy is higher in patients receiving 80 mg of simvastatin compared to patients receiving other statins with similar efficacy in lowering LDL-C. Therefore, the 80 mg dose should be used only in patients with severe hypercholesterolemia and high cardiovascular risk who have not achieved treatment goals with lower doses, when the expected benefit outweighs potential risks. For patients receiving concomitant therapy while on simvastatin 80 mg, a lower dose of simvastatin or another statin with lower interaction potential should be considered (see below “Measures to reduce the risk of myopathy/rhabdomyolysis”, see sections “Contraindications”, “Dosage and administration”, “Interaction with other medicinal products and other forms of interaction”).

In a clinical study in which patients at high risk of cardiovascular disease received simvastatin 40 mg/day (median observation period 3.9 years), the incidence of myopathy was approximately 0.05% among non-Chinese patients (n = 7,367), compared to 0.24% among Chinese patients (n = 5,468). Although the Mongoloid population in this clinical study was represented only by Chinese ethnicity, simvastatin should be used cautiously in patients of Mongoloid race, and the lowest dose should be prescribed.

There have been several reports of statins causing de novo or exacerbating pre-existing myasthenia gravis or ocular myasthenia (see section “Adverse reactions”). If symptoms worsen, treatment with Vazilip® should be discontinued. Recurrences have been reported when the same or another statin was (re)introduced.

Impaired transporter protein function

Reduced function of hepatic transporter proteins of the OATP family may increase systemic exposure to simvastatin acid and elevate the risk of myopathy and rhabdomyolysis. Reduced function may result from inhibition by interacting agents (e.g., cyclosporine) or in patients who are carriers of the SLCO1B1 (c.521T>C) genotype.

In patients carrying the SLCO1B1 (c.521T>C) allele encoding a less active OATP1B1 protein, increased systemic exposure to simvastatin acid and an elevated risk of myopathy have been observed. Regardless of genetic testing, the risk of developing myopathy associated with high doses (80 mg) of simvastatin is approximately 1%. SEARCH study results show that homozygous carriers of the C allele (designated CC), taking simvastatin 80 mg, have a 15% risk of developing myopathy within one year, while heterozygous carriers of the C allele (CT) have a 1.5% risk.

The corresponding risk in patients with the most common genotype (TT) is 0.3% (see section “Pharmacological properties”). Such specific genotyping is not widely used in clinical practice. If possible, before prescribing simvastatin 80 mg to individual patients, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment, and high doses should be avoided in carriers of the CC genotype. However, absence of this gene by genotyping does not exclude the possibility of 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 interpretation of results. If markedly elevated creatine kinase levels are observed at baseline (more than 5 times the upper limit of normal), levels should be re-measured after 5–7 days to confirm results.

Prior to treatment

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

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

• advanced age (≥ 65 years);
• female sex;
• 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 weighed against potential benefit, and clinical monitoring is recommended. If a patient previously experienced muscle disorders while taking a fibrate or statin, treatment with another agent of this class should be initiated cautiously.

Treatment should not be initiated if baseline creatine kinase levels are markedly elevated (more than 5 times the upper limit of normal).

During treatment

If pain, weakness, or cramps occur during statin therapy, creatine kinase levels should be measured. If levels are found to be significantly elevated (more than 5 times the upper limit of normal) in the absence of strenuous 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 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 statin therapy. IMNM is clinically characterized by persistent weakness of proximal muscles 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 agents (see section “Adverse reactions”).

If symptoms resolve and creatine kinase levels return to normal, reinitiation of the same 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 measurement of creatine kinase levels is recommended, as this may help detect subclinical cases of myopathy. However, there are no reliable data indicating that such monitoring can prevent the development of myopathy.

Simvastatin therapy should be temporarily discontinued in patients several days before planned major surgical procedures, as well as after medical or surgical interventions.

Measures to reduce the risk of drug interaction-induced myopathy (also see section “Interaction with other medicinal products and other forms of interaction”)

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

The risk of developing myopathy and rhabdomyolysis is also increased when amiodarone, amlodipine, verapamil, or diltiazem are co-administered with certain doses of simvastatin (see sections “Dosage and administration”, “Interaction with other medicinal products and other forms of interaction”). The risk of developing myopathy, including rhabdomyolysis, increases when fusidic acid is co-administered with statins (see section “Interaction with other medicinal products and other forms of interaction”). In patients with HoFH, this risk increases with concomitant use of lomitapide and simvastatin.

Concomitant use of simvastatin with CYP3A4 inhibitors, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated (see sections “Contraindications”, “Interaction with other medicinal products and other forms of interaction”). If therapy with potent CYP3A4 inhibitors (agents increasing AUC by 5-fold or more) cannot be discontinued, simvastatin therapy should be stopped for the duration of treatment with these agents (and consideration given to using an alternative statin). Additionally, caution should be exercised when co-administering simvastatin with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section “Interaction with other medicinal products and other forms of interaction”). Grapefruit juice should be avoided with simvastatin.

Concomitant use of simvastatin with gemfibrozil is contraindicated (see section “Contraindications”). Due to the increased risk of myopathy and rhabdomyolysis, the simvastatin dose should not exceed 10 mg daily in patients receiving simvastatin with other fibrates, except fenofibrate (see sections “Dosage and administration”, “Interaction with other medicinal products and other forms of interaction”). Fenofibrate should be prescribed cautiously with simvastatin, as each of these agents may cause myopathy.

Simvastatin should not be taken concurrently with systemic medicinal products containing fusidic acid, or within 7 days after discontinuation of fusidic acid. If systemic fusidic acid is required, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving a combination of fusidic acid and statins (see section “Interaction with other medicinal products and other forms of interaction”). Patients should seek immediate medical attention if they experience muscle weakness or pain, or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases, when prolonged systemic treatment with fusidic acid is necessary, e.g., for treatment of severe infections, 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 “Dosage and administration”, “Interaction with other medicinal products and other forms of interaction”). In patients with HoFH, the risk of myopathy increases with concomitant use of lomitapide and simvastatin (see sections “Dosage and administration”, “Contraindications”, and “Interaction with other medicinal products and other forms of interaction”).

Patients receiving other medicinal products with moderate CYP3A4 inhibitory effects concomitantly with simvastatin, especially with high simvastatin doses, have an increased risk of developing myopathy. When simvastatin is co-administered with a moderate CYP3A4 inhibitor (agents increasing AUC by 2–5 times), dose adjustment of simvastatin may be required. For concomitant use with specific moderate CYP3A4 inhibitors, e.g., diltiazem, a maximum simvastatin dose of 20 mg is recommended (see section “Dosage and administration”).

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

Concomitant use with BCRP inhibitors (e.g., elbasvir and grazoprevir) may lead to increased simvastatin plasma concentration and increased risk of 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 in patients receiving concomitant therapy with medicinal products containing elbasvir or grazoprevir (see section “Interaction with other medicinal products and other forms of interaction”).

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

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

Physicians considering combination therapy with simvastatin and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or niacin-containing products should carefully weigh potential benefits and risks and closely monitor patients for muscle pain or weakness, particularly during the first months of therapy and when increasing the dose of either medicinal product.

In the study, the incidence of myopathy was approximately 0.24% among Chinese patients receiving simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg, compared to 0.24% of Chinese patients receiving simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg plus a combination product of modified-release nicotinic acid/laropiprant 2000 mg/40 mg. Although the Asian population in this clinical study was represented only by Chinese patients, since the incidence of myopathy is higher in Chinese patients than in non-Chinese patients, concomitant use of simvastatin and lipid-modifying doses (≥ 1 g/day) 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 muscle toxicity cannot be excluded.

Daptomycin

Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., simvastatin) and daptomycin. HMG-CoA reductase inhibitors should be prescribed cautiously with daptomycin, as either agent may cause myopathy and/or rhabdomyolysis when used alone. Consideration should be given to temporarily discontinuing simvastatin in patients receiving daptomycin if benefit does not outweigh risk. Information on daptomycin prescribing should be consulted for 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 forms of interaction”).

Liver effects

In clinical trials, some adult patients receiving simvastatin showed persistent elevations in liver enzymes (more than 3 times the upper limit of normal). Upon discontinuation of the drug, transaminase activity usually returned gradually to baseline levels. Before starting treatment, and subsequently as clinically indicated, all patients should undergo liver function tests. In patients for whom the simvastatin dose is planned to be increased to 80 mg daily, liver function tests should be performed before dose titration, then 3 months after reaching 80 mg daily, and periodically repeated (e.g., once every 6 months) during 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 start of treatment and more frequently than usual thereafter. In cases where transaminase levels rise, especially with persistent elevations exceeding 3 times the upper limit of normal, the drug should be discontinued. It should be noted that alanine aminotransferase may 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, therapy should be immediately discontinued. If no alternative etiology is found, reinitiation of the drug should not be considered. The drug should be used cautiously in patients who abuse alcohol.

During treatment with simvastatin, as with other lipid-lowering agents, mild (less than 3 times the upper limit of normal) increases in serum transaminase activity have been observed. These changes appeared soon after starting treatment, were often transient, occurred without symptoms, and did not require discontinuation of therapy.

Diabetes mellitus

Some data suggest that statins as a class increase blood glucose levels and may cause hyperglycemia in some patients at high risk of developing diabetes in the future, levels at which initiation of diabetes treatment may be recommended. However, the benefit of statins in reducing vascular risk outweighs this risk, so this should not be a reason to discontinue statin therapy. Clinical and biochemical monitoring of patients at certain risk (fasting glucose 5.6–6.9 mmol/L, BMI > 30 kg/m², elevated triglycerides, arterial hypertension) should be performed according to national guidelines.

Lung interstitial disease

Rare cases of interstitial lung disease have been observed after taking some statins, including simvastatin, particularly with long-term therapy. Characteristic features of interstitial lung disease may include dyspnea, non-productive cough, and worsening general health (fatigue, weight loss, fever). If interstitial lung disease is suspected in a patient, statin therapy should be discontinued.

Ophthalmological examination

In the absence of any pharmacological treatment, progression of lens opacities is considered part of the aging process. Available clinical studies do not indicate a harmful effect of simvastatin on the human eye lens.

Use in elderly patients

The efficacy of simvastatin in patients over 65 years of age treated during controlled clinical trials was evaluated relative to reductions in total and LDL-C cholesterol levels and was found to be similar to that in the general population. No increase in clinically or laboratory-significant adverse effects was observed.

Special warnings regarding excipients

The product contains lactose. Patients with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome should not take this product.

Use during pregnancy or breastfeeding.

Pregnancy

Simvastatin is contraindicated in pregnant women.

No controlled clinical studies in pregnant women have been conducted, and safety has not been established. There are rare reports of congenital anomalies following in utero exposure to HMG-CoA reductase inhibitors.

Rare reports of congenital anomalies have been received following in utero exposure to HMG-CoA reductase inhibitors. However, analysis of approximately 200 prospectively followed pregnancies with first-trimester exposure to simvastatin or another similar HMG-CoA reductase inhibitor showed a rate of congenital anomalies comparable to that in the general population. This number of pregnancy cases was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies compared to the general population rate.

Although there is no evidence that the rate of congenital anomalies in offspring of patients who took simvastatin or another similar HMG-CoA reductase inhibitor differs from that in the general population, maternal treatment with simvastatin may reduce fetal mevalonate levels, a precursor in cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering agents during pregnancy usually has minimal impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, simvastatin must not be prescribed to pregnant women, women attempting to become pregnant, or women suspected of being pregnant. Simvastatin use should be suspended for the duration of pregnancy or until pregnancy is ruled out (see section “Contraindications”).

Breastfeeding

It is unknown whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in breast milk and serious adverse reactions are possible, 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 or female rats.

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

Simvastatin has no or negligible effect on the ability to drive vehicles or operate machinery. However, when driving vehicles or operating machinery, rare reports of dizziness should be taken into account.

Method of Administration and Dosage.

The daily dose of Vasilep® ranges from 10 mg to 80 mg (use the dosage form with the appropriate strength) administered orally once daily in the evening. Dose titration of Vasilep® should be performed at intervals of at least 4 weeks up to the maximum daily dose of 80 mg, taken once daily in the evening. The 80 mg dose is recommended only for patients with severe hypercholesterolemia and high cardiovascular risk who have not achieved treatment goals with lower doses, and when the expected benefit outweighs potential risks (see sections "Special Warnings and Precautions for Use", "Pharmacodynamics").

Hypercholesterolemia

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

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

Homozygous Familial Hypercholesterolemia

The recommended initial dose of Vasilep® is 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 therapies are unavailable.

For patients concomitantly taking lomitapide with Vasilep®, the dose of Vasilep® should not exceed 40 mg/day (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Cardiovascular Prevention

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

Concomitant Therapy

Vasilep® 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 a bile acid sequestrant.

For patients taking Vasilep® concomitantly with fibrates (except gemfibrozil; see section "Contraindications") or fenofibrate, the dose of Vasilep® should not exceed 10 mg/day. For patients taking Vasilep® concomitantly with amiodarone, amlodipine, verapamil, diltiazem, or medicinal products containing elbasvir or grazoprevir, the daily dose of Vasilep® should not exceed 20 mg (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Dosage in Renal Impairment

No dose adjustment is required for patients with mild to moderate renal impairment.

For patients with severe renal impairment (creatinine clearance < 30 mL/min), the benefit of initiating treatment with a dose of 10 mg once daily should be carefully weighed, and if such dosage is considered 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 higher and girls who have had at least 1 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 simvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained during simvastatin treatment.

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

Experience with the use of the drug in prepubertal children is limited.

Children.

The safety and efficacy of simvastatin in patients aged 10–17 years with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial involving boys at Tanner stage II and girls who had had menarche at least 1 year prior. The adverse effect profile in patients receiving simvastatin was similar to that in patients receiving placebo. Doses higher than 40 mg have not been studied in this patient group. The study did not identify any effect of simvastatin on growth, sexual development, or 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 (see sections "Contraindications", "Use in Pregnancy and Lactation").

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

The long-term impact of simvastatin on physical, intellectual, and sexual development is unknown.

Overdose.

There have been a few reported cases of overdose, with the maximum 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 based on their incidence rates observed in large, long-term, placebo-controlled clinical studies, including HPS and 4S, involving 20,536 and 4,444 patients, respectively (see section "Pharmacodynamics"). In HPS, only serious adverse reactions, myalgia, serum transaminase elevations, and creatine kinase elevations were recorded. In 4S, all the adverse reactions listed below were documented. If incidence rates during these studies were lower or similar with simvastatin compared to placebo, and spontaneous reports of events with a reasonable causal relationship were similar, such 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), safety profiles were comparable between simvastatin and placebo groups over a mean study duration 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. Transaminase elevations (>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 patients receiving placebo.

Adverse reaction frequency categories: very common (> 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), 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. Not known: depression.

Nervous system disorders

Rare: headache, paraesthesia, dizziness, peripheral neuropathy; Very rare: memory impairment, myasthenia gravis.

Eye disorders

Rare: blurred vision, visual disturbances. Very rare: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders

Not known: interstitial lung disease (see section "Special warnings and 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 (see section "Special warnings and precautions for use"), myalgia, muscle spasms, cramps, myositis, polymyositis. Very rare: muscle rupture.

Tendinopathy, sometimes complicated by tendon ruptures, immune-mediated necrotizing myopathy (IMNM)**.

* During 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).

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

Reproductive system and breast disorders

Very rare: gynaecomastia. Not known: erectile dysfunction.

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, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea, and malaise.

Investigations

Rare: increased serum transaminase levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase) (see section "Special warnings and precautions for use. Effect on the liver"), increased alkaline phosphatase levels, increased serum creatine kinase levels (see section "Special warnings and precautions for use").

With statin use, including Vazilip®, increases in HbA1c and fasting plasma 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; onset time (from 1 day to several years) and symptom resolution (average 3 weeks) varied.

Very rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use, have been observed. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy.

Additional adverse effects observed with some statins

• Sleep disturbances, including insomnia and nightmares;
• Sexual dysfunction;

Diabetes mellitus: frequency depends on 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 history) aged 10–17 years with heterozygous familial hypercholesterolemia (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, intellectual, and sexual development is unknown. There is insufficient data beyond one year of treatment (see sections "Special warnings and 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 and patients, or 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 the reach and sight of children.

Packaging.

7 tablets in a blister; 2, 4, or 12 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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