levosimendan | Simdax vials 2.5 mg / ml 5 ml, 1 pc.

Latin name

SIMDAX

Release form

Concentrate for solution for infusion.

Packing

Bottle 5 ml.

Pharmacological action of

Pharmacodynamics of

Levosimendan increases the sensitivity of calcium to contractile proteins by binding to myocardial troponin C (binding depends on calcium), increases the strength of heart contractions, opens ATP-sensitive potassium channels in vascular smooth muscle and induces artery expansion, including coronary, and veins. In vitro, the selective inhibitory activity of levosimendan against phosphodiesterase III was demonstrated.

The significance of this effect when using the drug in therapeutic concentrations has not been established. In patients with chronic heart failure, a positive calcium-dependent inotropic and vasodilating effect of levosimendan leads to an increase in heart rate and a decrease in preload and afterload, without worsening diastolic function. Activates ischemic myocardium in patients after percutaneous transluminal angioplasty of coronary arteries or thrombolysis.

Hemodynamic studies in healthy volunteers and in patients with chronic heart failure showed a dose-dependent effect of a loading dose (3 μg / kg body weight) and prolonged infusion (0.05 - 0.2 μg / kg body weight per 1 minute). Levosimendan increases cardiac output, stroke volume, increases the ejection fraction and heart rate (HR), reduces systolic and diastolic blood pressure (BP), wedge pressure in the capillaries of the lungs, pressure in the right atrium and total peripheral vascular resistance. When the drug is administered in the recommended dose, one active metabolite is formed, which gives hemodynamic effects similar to levosimendan. They persist for 7–9 days after discontinuation of the 24-hour infusion of levosimendan.

Levosimendan infusion causes an increase in coronary blood flow in patients undergoing surgery on the coronary arteries and improves myocardial perfusion in patients with chronic heart failure. These positive effects are not accompanied by a significant increase in oxygen consumption by the myocardium. Significantly reduces the content of endothelin 1 in patients with chronic heart failure. Subject to the recommended rate of administration, the drug does not increase the concentration of catecholamines in blood plasma.

Programs REVIVE I and REVIVE II.

REVIVE programs compared the efficacy of levosimendan and placebo in combination with standard therapy in patients with acute decompensation of chronic heart failure with a left ventricular ejection fraction of ≥ 35% and shortness of breath at rest. Allowed the continuation of previous therapy with the exception of intravenous administration of milrinone.

The results showed that in most patients there was an improvement, in a smaller number of patients the condition worsened. The Simdax group showed a slight increase in the mortality rate on day 90 compared with the control group (15% and 12%, respectively). It was shown that the initial level of systolic blood pressure is SURVIVE.

In a double-blind, multicenter, comparative study of levosimendan and dobutamine in 1327 patients with acute decompensated chronic heart failure and previous treatment with diuretics and vasodilators, 180-day mortality rates were compared. In the percentage frequency, preference was for levosimendan on day 5 (4% ​​levosimendan, 6% dobutamine). This advantage continued for 31 days (12% levosimendan, 14% dobutamine), especially in those patients who initially received beta-blockers. In patients with an initially lower blood pressure, mortality rates were worse in both groups.

LIDO

In a double-blind, multicenter study of 203 patients with severe chronic heart failure with low cardiac output (ejection fraction 15 mmHg) who needed inotropic therapy, received levosimendan (loading dose of 24 mcg / kg for 10 minutes, and then a continuous infusion of 0.1-0.2 mcg / kg / min for 24 hours) or dobutamine 5-10 mcg / kg / min for 24 hours An increase in cardiac output> 30% and a simultaneous decrease in jamming pressure in the pulmonary capillaries by 25% or more after 24 hours was achieved in 28% of patients receiving levosimendan and in 15% of patients receiving dobutamine (p = 0.025). Shortness of breath decreased in 68% and 59% of patients, respectively, fatigue in 63 and 47%. The 31-day mortality rate was 7.8% in the levosimendan group and 17% in the dobutamine group.

RUSSLAN

In a double-blind, multicenter study with safety as the primary goal, 504 patients with decompensated chronic heart failure after acute myocardial infarction, Those in need of inotropic therapy received levosimendan or placebo for 6 hours. The groups did not significantly differ in the incidence of arterial hypotension and myocardial ischemia.

A retrospective analysis of the results of two studies of LIDO and RUSSLAN revealed no undesirable effects of levosimendan on 6-month survival.

Pharmacokinetics

Pharmacokinetics of levosimendan in therapeutic doses from 0.05 to 0.2 μg / kg / min. is linear.

Distribution

The volume of distribution of levosimendan (Vss) is approximately 0.2 l / kg. Levosimendan is 97-98% bound to plasma proteins, mainly with albumin. The binding of active metabolites (OR-1855 and OR-1896) to proteins is 39% and 42%, respectively.

Metabolism

Levosimendan is mainly metabolized by conjugation with cyclic or N-acetylated cysteinyl glycine and cysteine ​​conjugates. Only about 5% of the dose of levosimendan is metabolized in the small intestine by oxidation to aminophenylpyridazinone (OR-1855), which, after reabsorption into the systemic circulation, is biotransformed in the blood plasma under the action of N-acetyltransferase to the active metabolite OR-1896. Acetylation rate is genetically determined. In fast acetylators, the concentration of OR-1896 metabolite is slightly higher than in slow ones. However, this does not affect the clinically significant hemodynamic effects of the drug in recommended doses.

Only 2 metabolites —OR-1855 and OR-1896 — are detected in significant quantities in the systemic circulation. In "slow" acetylators, OR-1855 predominates, and the “fast” - OR-1896. However, the total number of these metabolites and the frequency of development of hemodynamic effects are the same for “fast” and “slow” acetylators. These metabolites can have a long-term effect on hemodynamic parameters (within 7-9 days after the 24-hour infusion of levosimendan is stopped).

In vitro levosimendan and metabolites OR-1855 and OR-1896 in the concentration created by the use of recommended doses of the drug do not inhibit CYP1A2, CYP 2A6, CYP2C19, CYP2E1, CYP2C9, CYP2D6, or CYP3A4. Levosimendan does not inhibit CYP 1A1, and its metabolism is not disturbed by exposure to CYP3A inhibitors.

Excretion

The clearance of levosimendan is about 3.0 ml / min / kg and the half-life is about 1 hour. More than 95% of the dose of levosimendan is excreted within 1 week in the form of inactive metabolites. An insignificant part of the

dose Special groups of

Children: A few data indicate that the pharmacokinetics of levosimendan after a single administration in children (aged 3 months to 6 years) is similar to that in adults. The pharmacokinetics of the active metabolite in children has not been studied. Levosimendan should not be used in children.

Patients with impaired renal function:

pharmacokinetics of levosimendan is similar in patients with mild or moderate impaired renal function and in patients on hemodialysis. In patients with severe renal failure, pharmacokinetic parameters may be slightly reduced. In patients with severe renal failure and those on hemodialysis, the free fraction of levosimendan is slightly increased. a AUC (area under the concentration-time curve) of OR-1855 and OR-1896 metabolites is 170% higher.

Mild to moderate renal failure is thought to have less effect on the pharmacokinetics of OR-1855 and OR-1896 metabolites. Levosimendan is not excreted during hemodialysis. Although OR-1855 and OR-1896 metabolites are excreted during hemodialysis, their clearance is low (approximately 8-23 ml / min).

Patients with impaired liver function:

In patients with mild to moderate hepatic insufficiency with cirrhosis, the pharmacokinetics of levosimendan and its binding to proteins do not differ from those in healthy volunteers.

The pharmacokinetics of levosimendan and the metabolites OR-1855 and OR-1896 are the same in healthy volunteers and in patients with moderate hepatic impairment (class B according to the Child-Pyug classification), except that the half-life of these metabolites is somewhat lengthened with moderate liver failure.

Population analysis did not reveal that age, ethnicity, or gender affect the pharmacokinetics of levosimendan. However, the volume of distribution and overall clearance depend on body weight.

Indications

Short-term treatment of acute decompensation of severe chronic heart failure (CHF) with failure of standard therapy and the need for inotropic therapy.

Pregnancy and lactation

Pregnant women have no experience with levosimendan.

In this regard, levosimendan in pregnant women can be used only if the benefit to the mother outweighs the possible risk to the fetus and / or child.

There is no information on the excretion of levosimendan with breast milk.

Women should not breast-feed during use and within 14 days after the infusion of levosimendan.

Composition

1 ml contains:

Active ingredient:

levosimendan 2.5 mg.

Excipients:

povidone for parenteral administration,

b / w citric acid for parenteral administration,

b / w ethanol.

Dosage and administration

For inpatient use only!

Simdax Concentrate 2.5 mg / ml should be used only in diluted form!

Preparation of the infusion solution and infusion rate

To prepare the 0.05 mg / ml infusion solution, 10 ml of 2.5 mg / ml levosimendan concentrate should be diluted in 500 ml of 5% dextrose (glucose) solution. Table 1 shows the infusion rate for the loading and maintenance doses of 0.05 mg / ml levosimendan solution depending on body weight:

Table 1.

Body weight (kg) loading dose infusion rate for 10 min (ml / h) Continuous speed infusion (ml / h)

6 mcg / kg 12 mcg / kg 0.05 mcg / kg / min. O1 μg / kg / min. 0.2 mcg / kg / min.

40 29 58 2 5 10

50 36 72 3 6 12

60 43 86 4 7 14

70 50 101 4 8 17

80 58 115 5 10 19

90 65 130 5 11 22

100 72 144 6 12 24

110 79 158 7 13 26

120 86 173 7 14 29

To prepare a 0.025 mg / ml infusion solution, 5 ml of 2.5 mg / ml levosimendan concentrate should be diluted in 500 ml of 5% dextrose (glucose) solution.

Table 2 shows the infusion rate for the loading and maintenance doses of 0.025 mg / ml Symdax depending on body weight:

Table 2.

Body weight (kg) Infusion rate for the loading dose for 10 min (ml / h) Continuous infusion rate ( ml / h)

6 μg / kg 12 μg / kg 0.05 μg / kg / min. O1 μg / kg / min. 0.2 mcg / kg / min.

40 58 115 5 10 19

50 72 144 6 12 24

60 86 173 7 14 29

70 101 202 8 17 34

80 115 230 10 19 38

90 130 259 11 22 43

100 144 288 12 24 48

110 158 317 13 26 53

120 173 346 14 29 58

Simdax Concentrate 2.5 mg / ml is for single use only!

Before infusion, the diluted solution, like other drugs for parenteral use, should be checked for foreign particles and discoloration. During storage, the color of the concentrate may change to orange, which is not accompanied by a decrease in the activity of the drug.

Infusion can be carried out through peripheral or central veins.

Dose and duration of treatment are selected individually, taking into account the clinical condition of the patient and therapeutic effect.

Treatment begins with a loading dose of 6-12 mcg / kg, which is administered for 10 minutes (see table 1 and 2). Then a continuous infusion is carried out at a rate of 0.1 μg / kg / min. A lower dose of 6 mcg / kg is recommended in patients receiving concomitant intravenous therapy with vasodilators and / or inotropic drugs. The appointment of a higher loading dose of 12 μg / kg will be accompanied by a stronger hemodynamic effect, but it is possible that the frequency of transient side effects will also increase.

The patient's response to therapy is assessed by administering a loading dose or within 3060 minutes after dose adjustment or depending on the clinical presentation.

With pronounced changes in hemodynamic parameters (arterial hypotension, tachycardia), the infusion rate should be reduced to 0.05 mcg / kg / min or the infusion should be stopped. With good tolerance to the initial dose and the need for a more pronounced hemodynamic effect, the infusion rate can be increased to 0.2 μg / kg / min. The recommended duration of the infusion is 24 hours. After the termination of the Simdax infusion, there were no signs of the development of tolerance or “withdrawal” syndrome. Hemodynamic effects are observed for at least 24 hours and may not persist for 9 days after completion of the 24-hour infusion.

Elderly patients

Dose adjustment in elderly patients is not required.

Impaired renal function

Symdax should be used with caution in patients with mild to moderate renal failure. It should not be administered to patients with severe renal impairment (creatinine clearance less than 30 ml / min) (see Pharmacokinetics, Contraindications, Special instructions).

Impaired liver function

Symdax should be used with caution in patients with mild (5-6 points according to the Child-Pyug classification) or moderate (7-9 points according to the Child-Pyug classification) impaired liver function, however, dose adjustment is not required. It should not be administered to patients with severe hepatic impairment (> 9 points according to the Child-Pyug classification) (see sections Pharmacokinetics, Contraindications, Special Instructions).

Children

Simdax should not be used in children and adolescents under the age of 18 years (see Pharmacokinetics, Contraindications, Special Instructions)

Experience with repeated infusions of Simdax and its use in combination with other inotropic drugs (except digoxin) is limited.

Compatibility

Simdax can be administered simultaneously with

furosemide 10 mg / ml

digoxin 0.25 mg / ml

nitroglycerin 0.1 mg / ml

Side effects of

The most common adverse effects (53% of patients) reported in clinical trials (REVIVE) were headache, a marked decrease in blood pressure, ventricular tachycardia.

In a SURVIVE clinical trial, 18% of patients observed: ventricular tachycardia, atrial fibrillation, marked decrease in blood pressure, ventricular extrasystole, tachycardia, headache.

The adverse effects reported during clinical trials (REVIVE I, REVIVE AND, SURVIVE, LIDO, RUSSLAN) in> 1% of patients are listed below. Adverse events were distributed in frequency as follows: very often (> 1/10), often (> 1/100, often

From the side of metabolism: hypokalemia. From the side of mental status: insomnia.

From the gastrointestinal tract: nausea, constipation, diarrhea, vomiting.

On the part of laboratory parameters: a decrease in hemoglobin concentration. Very often

on the part of the central nervous system: dizziness, headache.

From the cardiovascular system: atrial fibrillation, atrial flutter, tachycardia, ventricular extrasystole, ventricular tachycardia, arterial hypotension up to severe, heart failure, myocardial ischemia, extrasystole.

Ventricular fibrillation has been reported in marketing uses of the drug.

Drug Interaction

Levosimendan should be used with caution in combination with intravenous vasodilators due to the potential increased risk of arterial hypotension.

In vitro studies on human liver microsomes have shown that levosimendan should not interact with drugs metabolised by cytochrome P450 (CYP) isoenzymes due to its low affinity for various CYP isoenzymes. In a population pharmacokinetic analysis, no evidence of an interaction between digoxin and levosimendan was detected.

Levosimendan can be used in patients receiving beta-blockers, which does not affect the effectiveness of treatment. The co-administration of isosorbide mononitrate and levosimendan in healthy volunteers caused a significant increase in orthostatic hypotension.

Incompatibility

The product must not be mixed with other medicines or solutions except as listed in the section Application and dose / Compatibility.

overdose

Symptoms: marked decrease in BP and tachycardia, increase in blood content of active metabolite, QT interval may be prolonged.

Treatment: Vasopressor agents may be used for severe BP reduction: dopamine in patients with chronic heart failure and epinephrine (epinephrine) after cardiac surgery.

A sharp decrease in the ventricular filling pressure of the heart can limit the effect of levosimendan for the purpose of restoring pressure shown by parenteral administration of fluid.

Constant ECG monitoring, re-determination of serum electrolytes, and invasive monitoring of hemodynamic parameters should be performed.

Storage conditions

Store at 2 ° to 8 РC

Do not freeze.

Keep out of the reach of children.

The Expiration of

is 3 years.

Deystvuyuschee substances

levosimendan

Pharmacy leave conditions

Prescription

Dosage form

Dosage form

solution for infusion