Prescor

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

Composition:

Active substance: levosimendan;

1 ml of concentrate for solution for infusion contains 2.5 mg of levosimendan;

Excipients: povidone, citric acid anhydrous, ethanol anhydrous.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: clear solution of yellow, orange-yellow to orange 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 calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium-dependent manner. Levosimendan increases contractility 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 vasodilating 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) followed by continuous infusion at 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 after coronary surgery and improves myocardial perfusion in patients with heart failure. These benefits are achieved without significant increase in myocardial oxygen consumption. Levosimendan treatment significantly reduces circulating endothelin-1 levels in patients with congestive heart failure. This 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. The protein binding of 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 upon reabsorption is metabolized by N-acetyltransferase to the active metabolite acetylaminophenylpyridazinone (OR-1896). Concentrations of the OR-1896 metabolite are somewhat higher in patients with genetically high acetylation capacity compared to those with low acetylation capacity. However, this difference is not clinically significant regarding hemodynamic effects at recommended doses.

In systemic circulation, only two metabolites—OR-1855 and OR-1896—are present in significant amounts. These metabolites reach equilibrium in vivo through acetylation and deacetylation processes regulated by polymorphic N-acetyltransferase-2. In patients with genetically low acetylation capacity, OR-1855 is the predominant metabolite, whereas in patients with genetically high acetylation capacity, 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 (lasting 7–9 days after termination 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 and eliminated slowly. Peak plasma concentrations of metabolites occur about 2 days after termination of levosimendan infusion. The elimination half-life of the metabolites is 75–80 hours. The active metabolites OR-1855 and OR-1896 undergo conjugation or glomerular filtration and are primarily excreted in urine.

Patients with renal impairment. The pharmacokinetics of levosimendan have been studied in patients with various 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. In patients with severe renal impairment, the effect of levosimendan may be slightly reduced.

Compared to healthy volunteers, the free fraction of levosimendan was slightly increased, and the AUC (area under the plasma concentration-time curve) of metabolites (OR-1855 and OR-1896) was 170% higher in patients with severe renal impairment and in those on hemodialysis. 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 has not been established. 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 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 indicate that in children (aged 3 months to 6 years), the pharmacokinetics of levosimendan 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 showed that volume of distribution and total clearance depend on the child's 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.

Severe arterial hypotension and tachycardia.

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

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

Severe hepatic impairment.

History of ventricular tachycardia of the "torsades de pointes" type.

Interaction with other medicinal products and other forms of interactions.

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

Prexum® can be used effectively in patients receiving β-blockers and digoxin. Concomitant administration of isosorbide mononitrate and levosimendan in healthy volunteers resulted in 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 administered with caution to patients with low systolic and diastolic blood pressure or those at risk of arterial hypotensive episodes. Severe hypovolemia should be corrected prior to initiating levosimendan infusion. If excessive deviations in blood pressure or heart rate occur, the infusion rate should be reduced or 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 effects generally last 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 the infusion, until arterial blood pressure begins to rise again following its maximal decline. 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 impairment should undergo a longer monitoring period.

Prescor® should be administered with caution to patients with mild or moderate renal or hepatic impairment. Limited data are available regarding 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 concentrations. Therefore, low serum potassium levels should be corrected before administration of the medicinal product, and serum potassium levels should be monitored during treatment. As with other drugs used in the treatment of heart failure, levosimendan infusions may be associated with decreases in hemoglobin and hematocrit levels; thus, caution is required when administering the drug to patients with ischemic heart disease and concomitant anemia.

Infusion of Prescor® should be performed cautiously in patients with tachycardia, tachysystolic atrial fibrillation, or potentially life-threatening arrhythmias.

Patients with sustained ventricular tachycardia, non-sustained tachycardia not related to reperfusion, or life-threatening arrhythmias should be treated for arrhythmia prior to initiation of drug administration.

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

Prescor® should be administered with caution and under careful ECG monitoring to patients with coronary ischemia, prolonged QT interval regardless of etiology, or when administered concomitantly with medicinal products that prolong the QT interval.

Prescor® 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.

Limited experience exists with the use of the drug in the following situations: 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.

Prescor® contains ethanol as an excipient at a concentration of 785 mg/mL; therefore, use of the drug may be harmful for patients suffering from alcoholism. Caution should be exercised when administering the drug to pregnant women, breastfeeding women, children, and patients with liver disease or epilepsy.

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 breast milk, women receiving the drug should refrain from breastfeeding.

Effect on ability to drive or operate machinery. Given the clinical condition for which the medicinal product is prescribed, it is not expected that patients will be capable of driving or operating machinery.

Method of administration and dosage.

Prescor® is intended for use only in specialized healthcare facilities. It may be administered in hospitals equipped with appropriate monitoring and assessment capabilities for patients, and where staff have experience in the use of inotropic agents.

The concentrate is sterile. The concentrate must be diluted prior to administration. Dilution should be performed under aseptic conditions.

Prescor® infusion solution is intended for administration into central and peripheral veins.

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

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 when concomitant intravenous therapy with vasodilators and/or inotropic agents is used at the start of the infusion. Higher loading doses may produce a more pronounced hemodynamic response, which could be associated with a transient increase in the incidence of adverse reactions. The patient's clinical response should be assessed during administration of the loading dose or within 30–60 minutes after dose adjustment.

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

The recommended duration of administration in acute decompensated severe chronic heart failure is 24 hours. No signs of tolerance or rebound phenomenon have been observed after discontinuation of the drug. 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. Dose adjustment is not required.

Patients with renal impairment. Prescor® 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. Prescor® 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 administration of other vasoactive agents, including inotropic agents (except digoxin), together with or after levosimendan infusion is limited. In the REVIVE study, the lowest loading dose of 6 mcg/kg was used with concomitant vasoactive therapy.

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 and maintenance doses.

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 shows the 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 Levosimendan.

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

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

Children. Levosimendan is not recommended for use in children (under 18 years of age), as experience with the use of this medicinal product in this age group is limited.

Overdose

Levosimendan overdose may cause arterial hypotension and tachycardia. Arterial hypotension caused by levosimendan observed during clinical trials 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 may be corrected by parenteral fluid administration. High doses of levosimendan (0.4 mcg/kg/min or higher) administered by infusion for longer than 24 hours may increase pulse rate and, in some cases, lead to QT interval prolongation.

In case of levosimendan overdose, prolonged ECG monitoring, repeated determination of serum electrolytes, and invasive hemodynamic monitoring should be performed. Overdose of levosimendan may result in increased plasma concentrations of the active metabolite and, consequently, in a more pronounced and prolonged effect on pulse rate, requiring an extended observation period.

Adverse Reactions

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

The frequency of adverse reactions is defined as follows: very common — ≥ 1/10;
common — ≥ 1/100, < 1/10.

Metabolism and nutritional 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.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

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

Storage conditions. Store at 2 to 8 °C. Do not freeze.

Keep out of the reach of children.

Incompatibilities. Prescor® must not be mixed with other medicinal products or solvents except those specified in the section "Dosage and administration".

Packaging. 2.5 ml or 5 ml in a glass vial. 1 vial per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.