Levosimendan-J - instructions for use, dose, side effects, contraindications

Active substanceLevosimendanLevosimendan

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Levosimendan-J

concentrate d / infusion

ESCO PHARMA, LLC

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concentrate d / infusion

NATIVA, LLC Russia

Simdax

concentrate d / infusion

Orion Corporation Finland

Dosage form: & nbspconcentrate for solution for infusion

Composition:

In 1 ml of concentrate for solution for infusion contains:

Active substance:

Levosimendan 2.5 mg

Excipients:

povidone 10.0 mg, citric acid 2.0 mg, ethanol to 1.0 ml.

Description:

Transparent solution from yellow or orange-yellow to orange.

Pharmacotherapeutic group:Cardiotonic agent of non-glycosidic structure

ATX: & nbsp

C.01.C.X Other cardiotonic drugs

C.01.C.X.08 Levosimendan

Pharmacodynamics:

Levosimendan increases the sensitivity to calcium of contractile proteins by binding to the troponin C of the myocardium (binding depends on calcium), increases the strength of the heartbeats, opens ATP-sensitive potassium channels in the smooth muscle of the vessels and induces the expansion of arteries, including coronary arteries, and veins. In vitro the selective inhibitory activity of levosimendan for phosphodiesterase III was demonstrated. The significance of this effect when using the drug in therapeutic concentrations is not established.In patients with chronic heart failure, the positive calcium-dependent inotropic and vasodilating action of levosimendan leads to an increase in the force of the heartbeats and a decrease in preload and postload, without worsening diastolic function. Activates ischemic myocardium in patients after percutaneous transluminal angioplasty of the coronary arteries or thrombolysis.

Studies of hemodynamics in healthy volunteers and in patients with chronic heart failure showed a dose-dependent effect of 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 ejection fraction and heart rate (HR), reduces systolic and diastolic blood pressure (BP), wedging pressure in the capillaries of the lung, right atrial pressure, and overall 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 stopping the 24-hour infusion of levosimendan.Levosimendan infusion causes an increase in coronary blood flow in patients who undergo 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 myocardial oxygen consumption. Significantly reduces endothelin 1 in patients with chronic heart failure. If the recommended rate of administration is observed, the preparation does not increase the concentration of catecholamines in the blood plasma.

Pharmacokinetics:

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

Distribution

The volume of levosimendan distribution (Vss) is about 0.2 l / kg. Levosimendan on 97-98% binds to blood plasma proteins, mainly with albumins. Binding of active metabolites (OR-1855 and OR-1896) with proteins - 39% and 42% respectively.

Metabolism

Levosimendan is mainly metabolized by conjugation with a 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 toaminophenylpyridazinone (OR-1855), which after reabsorption into the systemic bloodstream is biotransformed in blood plasma under the action of N-acetyltransferase to the active metabolite OR-1896. The rate of acetylation is genetically determined. In "fast acetylators" concentrations of the metabolite OR-1896 is slightly higher than that of the "slow" ones. However, this does not affect the clinically significant hemodynamic effects of the drug at recommended doses.

In the systemic circulation in significant quantities only 2 metabolites -OR-1855 and OR-1896. The "slow" acetylators are dominated by OR-1855, and for the "fast" OR-1896. However, the total number of these metabolites and the frequency of hemodynamic effects are the same in "fast" and "slow" acetylators. These metabolites can have a long-term effect on the parameters of hemodynamics (within 7-9 days after stopping the 24-hour infusion of levosimendan).

In vitro levosimendan and metabolites OR-1855 and OR-1896 in the concentration created by the application of the 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 under the influence of CYP3A inhibitors.

Excretion

The levosimendan clearance 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 as inactive metabolites. A small portion of the dose (0.05%) is excreted by the kidneys unchanged. Circulating metabolites OR-1855 and OR-1896 are formed and withdrawn slowly, their half-life is about 75-80 hours. Concentrations 0R- 1855 and OR-1896 in blood plasma reaches a maximum about 2 days after the cessation of levosimendan infusion. Active metabolites OR-1855 and OR-1896 undergo conjugation or renal filtration and are excreted mainly by the kidneys.

Special Groups

Children: a few data suggest 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 impairment of renal function and in patients on hemodialysis. In patients with severe renal failure, pharmacokinetic indices can be somewhat reduced.In patients with severe renal failure and those who are on hemodialysis, the free fraction of levosimendan is slightly elevated, a AUC (area under the concentration-time curve) of metabolites OR-1855 and OR-1896 higher by 170%.

It is assumed that mild and moderate renal failure have less effect on the pharmacokinetics of metabolites OR-1855 and OR-1896. Levosimendan not excreted by hemodialysis. Although metabolites OR-1855 and OR-1896 are excreted in hemodialysis, their clearance is low (approximately 8-23 ml / min).

Patients with impaired hepatic function: in patients with mild and moderate hepatic insufficiency with cirrhosis of the liver, the pharmacokinetics of levosimendan and its binding to proteins do not differ from those of healthy volunteers. Pharmacokinetics of levosimendan and metabolites OR-1855 and OR-1896 is the same in healthy volunteers and in patients with moderate hepatic impairment (Child-Pugh class B), except that the half-life of these metabolites is somewhat prolonged with moderate hepatic impairment.

In the population analysis, it was not revealed that age, ethnicity or sex influence the pharmacokinetics of levosimendan. However, the volume of distribution and the overall clearance depend on the body weight.

Indications:

Acute decompensation of severe chronic heart failure (for short-term therapy with ineffective standard therapy and the need for inotropic therapy).

Contraindications:

- Hypersensitivity to levosimendan or any of the excipients included in the formulation;

- mechanical obstruction, which prevents filling of the ventricles or ejection of blood from the ventricles;

- severe renal dysfunction (creatinine clearance <30 mL / min);

- severe violations of liver function (> 9 on the Child-Pugh scale);

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

- tachycardia (heart rate more than 120 beats per minute);

- fibrillation of the ventricles in the anamnesis;

- polymorphic ventricular tachycardia of the "pirouette" type in the anamnesis;

- unadjusted hypokalemia;

- uncorrected hypovolemia;

- children and the age of 18 years.

Carefully:

Renal and hepatic insufficiency of mild and moderate severity, tachycardia, arterial hypotension, atrial fibrillation with a high frequency of ventricular contraction, potentially life-threatening arrhythmias, concomitant myocardial ischemia, anemia, hypokalemia, lengthening of the interval QT regardless of etiology, simultaneous use with drugs that extend the interval QT, cardiac ischemia.

Conditions in which the application experience is inadequate:

No sufficient experience repeated use of levosimendan and experience in applying it in heart failure after surgery, with severe chronic heart failure in patients awaiting heart transplantation, in combination with vasoactive drugs, including drugs with inotropic effect (except digoxin).

Conditions in which there is no experience of use:

No data on the use of levosimendan in cardiogenic shock, restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, acute myocardial infarction of the right ventricle.

Pregnancy and lactation:

There is no experience of using levosimendan in pregnant women. Concerning levosimendan pregnant women can only be used if the benefit to the mother exceeds the possible risk to the fetus and / or the child. There is no information on deducing levosimendan with breast milk.Women should not breast-feed while using and within 14 days after levosimendan infusion.

Dosing and Administration:

Levosimendan-J is intended for use only in a hospital setting, which has the necessary equipment for appropriate monitoring indicators of hemodynamics and medical personnel with experience in working with cardiotonic drugs.

Concentrate of the drug should be used only in a diluted form!

Mode of administration: intravenously (there may be an injection, both into the central and peripheral veins).

The drug solution should be administered immediately after preparation!

Preparation of a solution for infusion

Levosimendan-J must be diluted immediately before administration as follows:

- To prepare an infusion solution with a concentration of 0.025 mg / ml, mix 5 ml of Levosimendan-J (2.5 mg / ml concentrate for solution for infusion) with 500 ml of a 5% solution of dextrose (glucose).

- To prepare an infusion solution with a concentration of 0.05 mg / ml, mix 10 ml of Levosimendan-J (2.5 mg / ml concentrate for solution for infusion) with 500 ml of a 5% solution of dextrose (glucose).

Dosing

Doses and duration of therapy are set individually, depending on the patient's condition, as well as his response to therapy.

The starting / loading dose is 6-12 μg / kg and is recommended for a duration of administration of no more than 10 minutes, then go on to a continuous continuous administration at a rate of 0.1 μg / kg / min. In patients receiving concomitant therapy with vasodilators and / or inotropic agents, a lower loading dose of 6 μg / kg is recommended. The loading dose of 24 mcg / kg / min has more pronounced hemodynamic effects, but the frequency of transient side effects may increase.

The response of the patient to therapy should be evaluated by the administration of a loading dose or within 30-60 minutes after the onset of administration or dose adjustment, or depending on the clinical picture. With pronounced changes in the parameters of hemodynamics (pronounced decrease in blood pressure, tachycardia), the rate of administration is reduced to 0.05 μg / kg / min or infusion is stopped. If the initial dose is well tolerated and the need for an increase in the hemodynamic effect, the rate of administration can be increased to 0.2 μg / kg / min. The recommended duration of the infusion is 24 h.

Table 1. Rates of administration for the initial and maintenance doses of the Levosimendan-J infusion solution at a concentration of 0.05 mg / ml

Body weight (kg)		Infusion rate of loading dose for 10 min (ml / h)		The rate of continuous infusion (ml / h)
Body weight (kg)		6 μg / kg	12 μg / kg	0.05 μg / kg / min.	0.1 μg / kg / min.	0.2 μg / 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
100	79		158	7	13	26
120	86		173	7	14	29

Table 2. Rates of administration for initial and maintenance doses of infusion solution of Levosimendan-J with a concentration of 0.025 mg / ml:

Body weight (kg)	Infusion rate of loading dose for 10 min (ml / h)		The rate of continuous infusion (ml / h)
Body weight (kg)	6 μg / kg	12 μg / kg	0.05 μg / kg / min.	01 μg / kg / min.	0.2 μg / 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
BY	158	317	13	26	53
120	173	346	14	29	58

At the completion of levosimendan infusions, there is no syndrome of "withdrawal" or any signs of addiction to the drug.

There is no experience of re-appointment of levosimendan. The experience of simultaneous use of other inotropic drugs (with the exception of digoxin) is limited.

Use of the drug in specific patient groups

Elderly patients

Dose adjustments for elderly patients are not required.

Impaired renal function

Levosimendan-J should be used with caution in patients with mild and moderate renal failure. It should not be administered to patients with severe impaired renal function (creatinine clearance less than 30 mL / min) (seesections "Pharmacokinetics", "Contraindications", "Special instructions").

Impaired liver function

Levosimendan-J should be used with caution in patients with mild (5-6 points on the Child-Pugh scale) or moderate (7-9 on the Child-Pugh scale), a violation of liver function, however, no dose adjustment is required. Levosimendan-J is contraindicated in patients with severe liver dysfunction (> 9 points by scale Child-Pugh) (see sections "Pharmacokinetics", "Contraindications", "Special instructions".

Compatiblecmь

Simultaneously with Levosimendan-J, you can enter:

- Furosemide 10 mg / ml

- Digoxin 0.25 mg / ml

- Nitroglycerin 0.1 mg / ml.

Side effects:

Frequency of occurrence of side effects (number of cases / number of observations): very often (≥ 1/10); often (≥ 1/100 to <1/10); infrequently (≥ 1/1000 to <1/100); rarely (≥ 1/10000 to <1/1000); very rarely, including individual messages (<1/10 000); frequency is not set (can not be calculated from available data).

From the side of metabolism:

Often: hypokalemia.

From the side of the psyche:

Often: insomnia.

From the gastrointestinal tract:

Often: nausea, constipation, diarrhea, vomiting.

From the side of the blood and lymphatic system:

Often: decrease in hemoglobin concentration.

From the nervous system:

Very often: dizziness, headache.

From the cardiovascular system:

Very often: atrial fibrillation, atrial flutter, tachycardia, ventricular extrasystole, ventricular tachycardia, arterial hypotension up to severe, heart failure, myocardial ischemia, extrasystole. When marketing the drug is reported on ventricular fibrillation.

Overdose:

Symptoms: a pronounced decrease in blood pressure and tachycardia, an increase in the active metabolite in the blood, QT.

Treatment: with a pronounced decrease in blood pressure, it is possible to use vasopressor drugs: dopamine in patients with chronic heart failure and epinephrine (adrenaline) after heart surgery.

A sharp decrease in the filling pressure of the ventricles of the heart can limit the effect of levosimendan; for the purpose of restoring pressure, parenteral administration of the liquid is indicated.

It is necessary to carry out constant ECG-control, re-determination of serum electrolytes and invasive monitoring of hemodynamic parameters.

Interaction:

Levosimendan should be used with caution in combination with intravenous vasodilators due to possibleincreased risk of hypotension. Research in vitro on microsomes of the human liver showed that levosimendan not should interact with drugs metabolized by cytochrome P450 isoenzymes (CYP), Due to low affinity for different isoenzymes CYP. With population pharmacokinetic analysis, there was no evidence of an interaction between digoxin and levosimendan. Levosimendan can be used in patients receiving beta-blockers, which does not affect the effectiveness of treatment. Simultaneous use of isosorbide mononitrate and levosimendan in healthy volunteers caused a significant increase in orthostatic hypotension.

Incompatibility

The drug should not be mixed with other drugs or solutions, other than those listed under Administration and Dosage / Compatibility.

Special instructions:

The drug can be used only in a hospital that has the necessary equipment to monitor vital functions and has medical personnel with experience with inotropes.The drug can be used if the expiration date has not expired, and storage was conducted in accordance with the instructions for use.

The initial hemodynamic effect of levosimendan is to reduce systolic and diastolic blood pressure, so it should be used with caution in patients with baseline low systolic and diastolic blood pressure or with a tendency to hypotension. For these patients, the use of low doses of the drug is recommended.

It is necessary to select the dose, the speed of administration and the duration of therapy, depending on the patient's condition and his response to therapy.

The expressed hypovolemia should be eliminated before the infusion of levosimendan. If there are significant changes or fluctuations in blood pressure and heart rate, it is necessary to reduce the infusion rate or stop the infusion.

Hemodynamic effects are usually observed within 7-10 days. Part of this is due to the circulation of the active metabolite, the concentration of which in the blood plasma reaches a maximum about 48 hours after the end of the infusion. Non-invasive monitoring is recommended to continue for at least 4-5 days after discontinuation of the infusion until the BP begins to rise again after the period of its maximum decrease.The control period may be longer than 5 days if the BP reduction continues, but it may be less than 5 days if the patient's condition has stabilized.

Levosimendan should be infused with caution in patients with mild to moderate renal or hepatic impairment. The available data on excretion of active metabolites in renal dysfunction are insufficient. Violations of kidney and liver function can lead to an increase in the concentration of active metabolites and more pronounced and persistent hemodynamic effects. It should be monitored for the functional state of the liver and kidneys for at least 5 days after the end of the infusion.

During treatment, it is advisable to carry out continuous monitoring of ECG, blood pressure and heart rate and to measure diuresis for at least 3 days after stopping the infusion or until the patient's condition is stabilized.

Infusion of levosimendan can cause a decrease in serum potassium concentration, therefore before infusion, hypokalemia should be eliminated and the serum potassium level monitored during treatment. Infusions of levosimendan, as well as other drugs intended for the treatment of chronic heart failure,may be accompanied by a decrease in the concentration of hemoglobin and hematocrit, so caution should be exercised in patients with ischemic heart disease and concomitant anemia.

Levosimendan should be infused with caution in patients with tachycardia or tahisystolic form of atrial fibrillation or potentially life-threatening arrhythmias.

The experience of repeated use of levosimendan, its use in heart failure after surgery and in severe heart failure in patients waiting for heart transplantation, is limited. Experience in the use of inotropes (excluding digoxin) simultaneously with levosimendan is also inadequate.

In each individual case it is necessary to evaluate the use and risk of prescribing such medications.

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

Levosimendan infusion should be performed under constant ECG monitoring in patients with persistent myocardial ischemia and an extended interval QT regardless of the etiology or with the simultaneous use of other drugs that cause lengthening of the interval QT.

Information on the use of levosimendan is absent in the following diseases: restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, myocardial infarction of the right ventricle. The experience with levosimendan in children and adolescents under the age of 18 is very limited, so it should not be used in patients under 18 years of age.

The prepared solution

Although the prepared levosimendan solution remains stable for 24 hours at 25 ° C, it should be administered immediately after preparation. If the solution has not been used immediately, the medical personnel are responsible for the duration and conditions of storage. In any case, the shelf life of the finished solution should not exceed 24 hours.

Effect on the ability to drive transp. cf. and fur:

No information.

Form release / dosage:

Concentrate for the preparation of a solution for infusions, 2.5 mg / ml.

Packaging:

By 5 ml or 10 ml of the drug in a vial of clear glass USP type I, sealed with a cork made of bromobutyl rubber, covered with an aluminum ring, it is possible to have a plastic cap.

For pharmacies: 1 bottle together with instructions for use in a cardboard box.

For hospitals: for 4, 7, 10 or 16 bottles together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of 2-8 ° C, do not freeze.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004308

Date of registration:22.05.2017

Expiration Date:22.05.2022

The owner of the registration certificate:ESCO PHARMA, LLCESCO PHARMA, LLC

Manufacturer: & nbsp

JODAS EXPOIM, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp22.06.2017

Illustrated instructions

Instructions

Levosimendan-J (Levosimendan-J)