Levolim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOLIM (LEVOLIM)

Composition:

Active substance: levosimendan;

1 ml of solution contains 2.5 mg of levosimendan;

Excipients: povidone, anhydrous citric acid, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear solution, practically free of visible particles, yellow to orange-yellow in color.

Pharmacotherapeutic group. Medicinal products used in cardiovascular diseases. Medicinal products used in heart diseases. Non-glycoside cardiotonic agents. Other cardiotonic agents. Levosimendan. ATC code C01CX08.

Pharmacological Properties.

Pharmacodynamics.

Levosimendan enhances the calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium-dependent manner. Levosimendan increases contractile force without impairing ventricular relaxation. Additionally, levosimendan opens ATP-sensitive potassium channels in vascular smooth muscle, thereby promoting vasodilation of systemic arteries, coronary arteries, and systemic veins. Levosimendan is a selective inhibitor of phosphodiesterase III in vitro. In patients with heart failure, the positive inotropic and vasodilatory effects of levosimendan result in increased myocardial contractility and reduced preload and afterload, without adverse effects on diastolic function. Levosimendan activates impaired myocardium in patients following coronary angioplasty or thrombolysis.

Pharmacodynamic studies involving healthy volunteers and patients with stable and unstable heart failure demonstrated dose-dependent effects of intravenous levosimendan administered as a loading dose (3–24 mcg/kg) and as a continuous infusion at doses of 0.05–0.2 mcg/kg/min. Compared to placebo, levosimendan increases cardiac output, stroke volume, ejection fraction, and heart rate, while reducing systolic and diastolic blood pressure, pulmonary capillary wedge pressure, right atrial pressure, and systemic vascular resistance.

Drug infusion increases coronary blood flow in patients recovering from coronary surgery and improves myocardial perfusion in patients with heart failure. These benefits are achieved without significant increases in myocardial oxygen consumption. Levosimendan treatment significantly reduces circulating endothelin-1 levels in patients with congestive heart failure. It does not lead to increased plasma catecholamine levels at recommended infusion rates.

Pharmacokinetics.

The pharmacokinetics of levosimendan are linear within the therapeutic dose range of 0.05–0.2 mcg/kg/min.

Distribution. The volume of distribution (Vss) of levosimendan is approximately 0.2 L/kg. Levosimendan is 97–98% bound to plasma proteins, primarily albumin. Protein binding for metabolites OR-1855 and OR-1896 is 39% and 42%, respectively.

Metabolism. Levosimendan is primarily metabolized via conjugation into cyclic or N-acetylated cysteinylglycine and cysteine conjugates. Approximately 5% of the dose is metabolized in the gut to aminophenylpyridazinone (OR-1855), which, after reabsorption, is metabolized by N-acetyltransferase to the active metabolite acetylaminophenylpyridazinone (OR-1896). Concentrations of metabolite OR-1896 are slightly higher in patients with genetically high acetylation capacity compared to those with lower acetylation capacity. However, this difference is not clinically significant regarding hemodynamic effects at recommended doses.

Only two metabolites—OR-1855 and OR-1896—are present in significant amounts in systemic circulation. These metabolites reach equilibrium in vivo through acetylation and deacetylation processes regulated by N-acetyltransferase-2, a polymorphic enzyme. In patients with genetically low acetylation capacity, metabolite OR-1855 predominates, whereas in patients with genetically high acetylation capacity, metabolite OR-1896 predominates. The total amount of these two metabolites and the frequency of hemodynamic effects are similar in both patient groups. These metabolites may exert prolonged hemodynamic effects (up to 7–9 days after discontinuation of a 24-hour levosimendan infusion).

Elimination. The clearance of levosimendan is approximately 3 mL/min/kg, and the elimination half-life is about one hour. Approximately 54% of the dose is excreted in urine and 44% in feces. Over 95% of the dose is eliminated within one week. Only negligible amounts of unchanged levosimendan (<0.05% of dose) are excreted in urine. Circulating metabolites OR-1855 and OR-1896 are formed slowly and eliminated slowly. Peak plasma concentrations of these metabolites occur approximately 2 days after infusion cessation. The elimination half-life of the metabolites is 75–80 hours. The active metabolites OR-1855 and OR-1896 undergo conjugation or renal filtration and are primarily excreted in urine.

Patients with Renal Impairment

The pharmacokinetics of levosimendan have been studied in patients with varying degrees of renal impairment in the absence of heart failure. The effect of levosimendan was similar in patients with mild to moderate renal impairment and in those undergoing hemodialysis, although the effect of levosimendan may be slightly lower in patients with severe renal impairment.

Compared to healthy volunteers, the free fraction of levosimendan was slightly increased, and the area under the plasma concentration-time curve (AUC) of metabolites (OR-1855 and OR-1896) was 170% higher in patients with severe renal impairment and in those on hemodialysis. The pharmacokinetic effects of OR-1855 and OR-1896 in patients with mild to moderate renal impairment are expected to be less pronounced than in those with severe impairment. The impact of hemodialysis on the pharmacokinetics of levosimendan is not well defined. Although OR-1855 and OR-1896 are dialyzable, their clearance is low (approximately 8–23 mL/min), and the overall elimination effect during a 4-hour dialysis session is very low.

Patients with Hepatic Impairment

No differences in the pharmacokinetics or protein binding of levosimendan were observed in patients with mild to moderate hepatic cirrhosis compared to healthy volunteers. The pharmacokinetics of levosimendan, OR-1855, and OR-1896 are similar to those in healthy volunteers and in patients with moderate hepatic impairment (Child-Pugh class B), except that the elimination half-life of OR-1855 and OR-1896 is slightly prolonged in patients with moderate hepatic impairment.

Children

Limited data suggest that the pharmacokinetics of levosimendan in children (aged 3 months to 6 years) after a single dose are similar to those in adults. The pharmacokinetics of the active metabolite in children have not been studied.

Population analysis did not reveal any influence of age, ethnicity, or gender on the pharmacokinetics of levosimendan. However, this same analysis indicated that volume of distribution and total clearance are dependent on body weight.

Clinical characteristics.

Indications.

Short-term treatment of severe acute decompensated chronic heart failure when traditional therapy is ineffective and in conditions requiring inotropic support.

Contraindications.

Hypersensitivity to levosimendan or to any of the excipients of the medicinal product.

Severe arterial hypotension and tachycardia.

Significant mechanical obstructions affecting ventricular filling with blood and/or impeding blood outflow from the ventricles.

Severe renal impairment (creatinine clearance < 30 mL/min).

Severe hepatic impairment.

History of torsades de pointes ventricular tachycardia.

Interaction with other medicinal products and other forms of interaction.

Levosimendan should be used with caution when administered concomitantly with other intravenous vasoactive agents due to an increased risk of developing arterial hypotension.

Levosimendan may be used effectively in patients receiving β-blockers and digoxin. Concomitant administration of isosorbide mononitrate and levosimendan in healthy volunteers leads to a significant potentiation of orthostatic hypotension.

Special precautions for use.

The initial hemodynamic effect of levosimendan may cause a reduction in systolic and diastolic blood pressure; therefore, levosimendan should be used with caution in patients with low systolic and diastolic blood pressure or at risk of episodes of arterial hypotension. Severe hypovolemia must be corrected prior to initiating levosimendan infusion. If excessive changes in blood pressure or heart rate occur, the infusion rate should be reduced or the infusion discontinued.

The favorable hemodynamic effect on cardiac output and pulmonary capillary wedge pressure persists for at least 24 hours after termination of a 24-hour infusion. The exact duration of all hemodynamic effects has not been fully established, but overall, the effect generally lasts from 7 to 10 days. This is partly due to the circulation of the active metabolite, whose plasma concentration reaches a maximum approximately 48 hours after the end of infusion. Non-invasive monitoring is recommended for at least 4–5 days after discontinuation of infusion, until arterial blood pressure begins to rise again following its period of maximal decrease. The monitoring period may exceed 5 days if arterial hypotension persists, but may also be shorter than 5 days if the patient's condition stabilizes. Patients with mild or moderate hepatic or renal insufficiency should undergo a longer monitoring period.

Levolum should be administered with caution to patients with mild or moderate renal or hepatic insufficiency. Limited data are available on the elimination of active metabolites in patients with impaired renal function. Impaired liver or kidney function may lead to increased metabolite concentrations, potentially resulting in a more pronounced and prolonged effect on heart rhythm.

Infusion of the drug may lead to decreased serum potassium concentration. Therefore, low serum potassium levels should be corrected prior to drug administration, and serum potassium levels should be monitored during treatment. As with other drugs used in the treatment of heart failure, infusion of the drug may be associated with decreases in hemoglobin and hematocrit; thus, caution is required when administering the drug to patients with ischemic heart disease and concomitant anemia.

Levosimendan infusion should be administered cautiously in patients with tachycardia or tachyarrhythmia, including tachyarrhythmic atrial fibrillation, or potentially life-threatening arrhythmias.

Patients with sustained ventricular tachycardia, non-sustained tachycardia unrelated to reperfusion, or life-threatening arrhythmias should be treated for arrhythmia prior to initiation of levosimendan infusion.

Experience with repeated administration of the drug is limited. Experience with concomitant or subsequent use of other vasoactive agents, including inotropic agents (except digoxin), with or after levosimendan infusion is limited. The benefits and risks of concomitant use must be evaluated individually for each patient.

Levosimendan must be administered with caution and under close ECG monitoring in patients with coronary ischemia, prolonged QT interval regardless of etiology, or when administered concomitantly with medicinal products that prolong the QT interval.

Levosimendan should be used with caution in patients with tachycardia, atrial fibrillation with rapid ventricular response, or potentially life-threatening arrhythmias.

The use of levosimendan in cardiogenic shock has not been studied.

There are no data on the use of levosimendan in the following conditions: restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, or right ventricular infarction.

Experience with the use of the drug in the following situations is limited: acute heart failure due to non-cardiac causes, severe worsening of heart failure after surgery, and severe heart failure in patients awaiting heart transplantation. Therefore, special safety measures are required.

Levosimendan contains 785 mg/mL ethanol as an excipient; therefore, the use of this medicinal product may be harmful in patients with alcoholism. Caution should be exercised when administering the drug to pregnant women, breastfeeding women, children, and patients with liver disease or epilepsy.

Opalescence/precipitation at high concentration

Due to post-marketing reports of medical errors involving opalescence and precipitation after dilution of levosimendan to concentrations higher than the maximum recommended concentration of 0.05 mg/mL,

levosimendan should not exceed the recommended concentration after dilution.

Use during pregnancy or breastfeeding.

There is no experience with the use of levosimendan in pregnant women. Levosimendan should be used during pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Since it is unknown whether levosimendan is excreted in human breast milk, women receiving this drug should avoid breastfeeding.

Fertility

Animal studies have shown adverse effects on reproduction.

Ability to affect reaction speed when driving or operating machinery.

Given the clinical condition for which the drug is prescribed, it is not expected that patients will be capable of driving or operating machinery.

Method of Administration and Dosage

Levosimendan is intended for use only in specialized medical facilities. It should be administered in hospitals equipped with the necessary equipment for monitoring and assessing the patient's condition, and where the staff have experience in using inotropic agents.

The concentrate is sterile and must be diluted before administration. Dilution should be performed under aseptic conditions.

The Levolim infusion solution is intended for administration via central and peripheral veins.

As with all parenteral medicinal products, the diluted solution should be carefully inspected prior to administration for the presence of particulate matter and discoloration.

The dosage and duration of treatment are determined individually, depending on the patient's clinical condition and response to therapy.

Treatment should be initiated with a loading dose of 6–12 mcg/kg administered over at least 10 minutes, followed by continuous infusion at a rate of 0.1 mcg/kg/min. A reduced loading dose of 6 mcg/kg is recommended for patients receiving concomitant intravenous therapy with vasodilators and/or inotropic agents at the start of infusion. Higher loading doses may result in a stronger hemodynamic response, which could be associated with a transient increase in the frequency of adverse reactions. The patient's clinically evident response to treatment should be assessed during administration of the loading dose or within 30–60 minutes after dose adjustment.

If the patient's clinical response to administration is considered excessive (hypotension, tachycardia), the infusion rate may be reduced to 0.05 mcg/kg/min or infusion may be discontinued. If the initial dose is well tolerated and a stronger hemodynamic effect is required, the infusion rate may be increased to 0.2 mcg/kg/min.

The recommended duration of infusion in acute decompensated severe chronic heart failure is 24 hours. After discontinuation of the drug, no signs of tachyphylaxis or rebound phenomenon have been observed. Hemodynamic effects persist for at least 24 hours and may continue to be observed for up to 9 days after termination of the 24-hour infusion.

Elderly Patients

Dosage adjustment is not required.

Patients with Renal Impairment

Levosimendan should be used with caution in patients with mild to moderate renal impairment. It is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min).

Patients with Hepatic Impairment

The medicinal product Levolim should be used with caution in patients with mild to moderate hepatic impairment. It is contraindicated in patients with severe hepatic impairment.

Repeated Administration

Experience with repeated administration of the drug is limited. Experience with concomitant or subsequent use of other vasoactive agents, including inotropic agents (except digoxin), with or after levosimendan infusion is limited. In the REVIVE study, the lowest loading dose of 6 mcg/kg was used with concomitant administration of vasoactive agents.

To prepare an infusion solution with a concentration of 0.05 mg/mL, mix 10 mL of concentrate with 500 mL of 5% glucose solution. Table 1 provides infusion rates for the solution with a concentration of 0.05 mg/mL for the loading dose and maintenance dose.

Table 1

To prepare an infusion solution with a concentration of 0.025 mg/ml, mix 5 ml of concentrate with 500 ml of 5% glucose solution. Table 2 provides infusion rates for the 0.025 mg/ml solution for loading and maintenance doses.

Table 2

Drugs such as furosemide 10 mg/mL, digoxin 0.25 mg/mL, and nitroglycerin 0.1 mg/mL may be administered simultaneously with the medicinal product Levoleem.

During storage, the concentrate may acquire an orange color, but this does not indicate loss of efficacy. If a color change occurs, the preparation may still be used up to the indicated expiry date, provided storage conditions have been maintained.

The shelf life of the prepared solution after dilution should not exceed 24 hours. Responsibility for storage conditions and duration of the diluted preparation lies with the medical personnel.

Children.

Levosimendan is not recommended for use in children (under 18 years of age) due to limited experience with the drug in this patient population.

Overdose.

Levosimendan overdose may cause arterial hypotension and tachycardia. Arterial hypotension caused by levosimendan during clinical studies was successfully managed with vasoconstrictors (e.g., dopamine in patients with chronic heart failure and adrenaline in patients after cardiac surgery). Excessive reduction in ventricular filling pressure may limit the clinical response to levosimendan and can be corrected by parenteral fluid administration. High doses of levosimendan (0.4 mcg/kg/min or higher) administered by infusion for more than 24 hours increase heart rate and may occasionally lead to QT interval prolongation.

In case of levosimendan overdose, prolonged ECG monitoring, repeated determination of serum electrolytes, and invasive hemodynamic monitoring are required. Levosimendan overdose may lead to increased plasma concentrations of the active metabolite, resulting in a more pronounced and prolonged effect on heart rate, thus requiring an extended observation period.

Adverse Reactions

The adverse reactions listed below were observed in more than 1% of patients during clinical trials.

Frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10).

Metabolism and nutrition disorders

Common: hypokalemia.

Psychiatric disorders

Common: insomnia.

Nervous system disorders

Very common: headache.

Common: dizziness.

Cardiovascular disorders

Very common: ventricular tachycardia, arterial hypotension.

Common: atrial fibrillation, tachycardia, ventricular extrasystoles, heart failure, myocardial ischemia, extrasystoles.

Gastrointestinal disorders

Common: nausea, constipation, diarrhea, vomiting.

General disorders

Hypersensitivity reactions, injection site reactions.

Laboratory investigations

Common: decreased hemoglobin levels.

During post-marketing use, ventricular fibrillation has been reported in patients treated with levosimendan.

Shelf life. 24 months.

Storage after dilution. The prepared solution may be stored for up to 24 hours at 25 °C. From a microbiological standpoint, the solution should be used immediately after preparation.

Storage conditions. Store in the original packaging in a refrigerator at 2–8 °C. Do not freeze. Keep out of reach of children.

Incompatibilities. Levosimendan must not be mixed with other medicinal products or solvents except those mentioned in the section "Instructions for use and dosage".

Packaging. 5 ml in a glass vial; 1 glass vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Farmideya".

Manufacturer's address and location of business activity.

Rupnica street 4, Olaine, Olaine district, LV-2114, Latvia.