Simdax® [Levosimendan]

Brand Orion Corporation

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Available since: 2019-09-19

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Clinical Pharmacology

Pharmacodynamics
Levosimendan increases calcium sensitivity of contractile proteins by binding to troponin C of the myocardium (binding depends on calcium), increases the strength of heart contractions, opens ATP-sensitive potassium channels in vascular smooth muscles and induces dilation of arteries, including coronary, and veins. In vitro demonstrated selective inhibitory activity of levosimendan against phosphodiesterase III. The value of this effect when using the drug in therapeutic concentrations is not installed. In patients with chronic heart failure, a positive calcium-dependent inotropic and vasodilating action of levosimendan leads to an increase in the strength of heart contractions and a decrease in preload and afterload, without worsening the diastolic function. Activates ischemic myocardium in patients after percutaneous transluminal angioplasty of the coronary arteries or thrombolysis.
Hemodynamic studies in healthy volunteers and in patients with chronic heart failure showed a dose-dependent effect of the loading dose (3 mcg / kg body weight) and prolonged infusion (0.05 - 0.2 mcg / 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), jamming pressure in the capillaries of the lungs, pressure in the right atrium and total peripheral vascular resistance. With the introduction of the drug 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 undergoing intervention in 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 the content of endothelin 1 in patients with chronic heart failure. At observance of the recommended speed of administration the drug does not increase the concentration of catecholamines in the 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 dyspnea alone. The continuation of previous therapy was permitted, with the exception of intravenous milrinone.
The results showed that the majority of patients improved, and a smaller number of patients worsened. In the Simdax group, a slight increase in the mortality rate was observed on day 90 compared with the control group (15% and 12%, respectively). It is shown that the initial level of systolic blood pressure SURVIVE.

In a double-blind, multicenter, comparative study of levosimendan and dobutamine, in 1327 patients with acute decompensated chronic heart failure and the ineffectiveness of prior diuretic therapy and vasodilators compared the 180-day mortality rates. In percentage, the advantage was for levosimendan on day 5 (4% levosimendan, 6% dobutamine). This advantage persisted for 31 days (12% levosimendan, 14% dobutamine), especially in those patients who initially received beta-blockers. In patients with 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, levosimendan was obtained (loading dose 24 μg / kg for 10 minutes, and then continuous infusion 0.1-0.2 mcg / kg / min for 24 hours) or dobutamine 5-10 mcg / kg / min for 24 hoursAn increase in cardiac output of> 30% and a simultaneous decrease in seizure of 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). Dyspnea 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, the primary goal of which was to study safety, 504 patients with decompensated chronic heart failure after acute myocardial infarction who needed inotropic therapy received levosimendan or placebo for 6 hours. The groups did not differ significantly in the incidence of arterial hypotension and myocardial ischemia.
In a retrospective analysis of the results of two studies of LIDO and RUSSLAN, the undesirable influence of levosimendan on 6-month survival was not revealed.

Pharmacokinetics

Pharmacokinetics of levosimendan in therapeutic doses from 0.05 to 0.2 mcg / 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 albumin. The binding of active metabolites (OR-1855 and OR-1896) with proteins is 39% and 42%, respectively.

Metabolism
Levosimendan is mainly metabolized by conjugation with cyclic or N-acetylated cysteinylglycine 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, biotransformed in plasma under the action of N-acetyltransferase to the active metabolite OR-1896. The acetylation rate is genetically determined. The "fast acetylators" have a slightly higher concentration of OR-1896 metabolite than the "slow ones." However, this does not affect the clinically significant hemodynamic effects of the drug at the recommended doses.
In the systemic circulation, only 2 metabolites —OR-1855 and OR-1896 are determined in significant quantities. OR-1855 prevails in slow acetyls, and OR-1896 dominates in fast ones. However, the total amount of these metabolites and the frequency of hemodynamic effects are the same for “fast” and “slow” acetylators. These metabolites can have a lasting effect on hemodynamic parameters (within 7–9 days after stopping the 24-hour infusion of levosimendan).
In vitro, levosimendan and OR-1855 and OR-1896 metabolites in the concentration created by applying 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 impaired by CYP3A inhibitors.

Removal
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 eliminated within 1 week as inactive metabolites. A minor part of the dose ( Special groups
Children: The few data suggest that the pharmacokinetics of levosimendan after a single injection in children (aged 3 months to 6 years) is similar to that in adults. The pharmacokinetics of the active metabolite have not been studied in children. Levosimendan should not be used in children.

Patients with impaired renal function: levosimendan pharmacokinetics is similar in patients with mild or moderate renal impairment and in patients on hemodialysis. In patients with severe renal insufficiency, pharmacokinetic indicators may be somewhat reduced. In patients with severe renal failure and those on hemodialysis, the free fraction of levosimendan is slightly increased, and the AUC (area under the concentration-time curve) of OR-1855 and OR-1896 metabolites is 170% higher. Mild and moderate renal insufficiency is expected to have less effect on the pharmacokinetics of OR-1855 and OR-1896 metabolites. Levosimendan is not displayed during hemodialysis.Although metabolites OR-1855 and OR-1896 are eliminated during hemodialysis, their clearance is low (approximately 8-23 ml / min).
Patients with impaired liver function: In patients with mild and moderate liver failure with liver cirrhosis, the pharmacokinetics of levosimendan and its binding to proteins do not differ from those of healthy volunteers. The pharmacokinetics of levosimendan and OR-1855 and OR-1896 metabolites are the same in healthy volunteers and in patients with moderate hepatic impairment (class B according to Child-Pyuga classification), except that the half-life of these metabolites is somewhat longer with moderate hepatic failure.
A population analysis did not reveal that age, ethnicity or gender affect the pharmacokinetics of levosimendan. However, the volume of distribution and overall clearance depends on body weight.

Indications

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

Composition

1 ml contains:

Active substance: Levosimendan 2.5 mg.

Excipients: Povidone for parenteral administration, citric acid b / v for parenteral administration, ethanol b / c.

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Dosage and Administration

Only for use in the hospital!
Simdax concentrate 2.5 mg / ml should be used only in diluted form!
Infusion solution preparation and infusion rate
To prepare a solution for infusion of 0.05 mg / ml, 10 ml of a concentrate of levosimendan 2.5 mg / ml should be diluted in 500 ml of a 5% dextrose (glucose) solution. Table 1 shows the infusion rate for the loading and maintenance dose of 0.05 mg / ml levosimendan solution depending on body weight:

**Table 1.**
Body weight (kg)	The loading dose infusion rate for 10 min (ml / h)		Continuous infusion rate (ml / h)
Body weight (kg)	6 mcg / kg	12 mcg / kg	0.05 mcg / kg / min.	O1 mcg / 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 solution for infusion of 0.025 mg / ml, 5 ml of levosimendan 2.5 mg / ml concentrate should be diluted in 500 ml of 5% dextrose (glucose) solution.
Table 2 shows the infusion rate for a loading and maintenance dose of 0.025 mg / ml Simdax depending on body weight:

**Table 2.**
Body weight (kg)	The loading dose infusion rate for 10 min (ml / h)		Continuous infusion rate (ml / h)
Body weight (kg)	6 mcg / kg	12 mcg / kg	0.05 mcg / kg / min.	O1 mcg / 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

Simdaksa concentrate 2.5 mg / ml is intended for single use only!
Before infusion, the diluted solution, like other parenteral preparations, 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 preparation.

Infusion can be performed through peripheral or central veins.
The dose and duration of treatment are selected individually, taking into account the clinical condition of the patient and the therapeutic effect.
Treatment begins with a loading dose of 6–12 mcg / kg, which is administered for 10 minutes (see Table 1 and 2). A continuous infusion is then performed 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 agents. The appointment of a higher loading dose of 12 mcg / 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 with the introduction of a loading dose or within 3060 minutes after adjusting the dose or depending on the clinical picture.
In case of 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 tolerability of the initial dose and the need for a more pronounced hemodynamic effect, the infusion rate can be increased to 0.2 mcg / kg / min. The recommended duration of infusion is 24 hours. After the discontinuation of Simdax infusion, no signs of tolerance or “withdrawal” syndrome have been identified. Hemodynamic effects are observed for at least 24 hours and may not persist for 9 days after the completion of the 24-hour infusion.
Elderly patients
Dose adjustment in elderly patients is not required.
Renal dysfunction
Simdax should be used with caution in patients with mild to moderate renal failure. It should not be administered to patients with severe impaired renal function (creatinine clearance less than 30 ml / min) (see sections Pharmacokinetics, Contraindications, Special Instructions).
Liver dysfunction
Simdax should be used with caution in patients with mild (5-6 points according to Child-Pyuga classification) or moderate (7-9 points on Child-Pyuga classification) abnormal liver function, but dose adjustment is not required. It should not be administered to patients with severe liver dysfunction (> 9 points according to Child-Pyuga classification) (see sections Pharmacokinetics, Contraindications, Special Instructions).

Children
Simdax should not be used in children and adolescents under the age of 18 years (see sections Pharmacokinetics, Contraindications, Special Instructions)
The experience of repeated infusions of Simdax and its use in combination with other inotropic drugs (with the exception of digoxin) is limited.
Compatibility
Simultaneously with Simdax you can enter

Furosemide 10 mg / ml
Digoxin 0.25 mg / ml
Nitroglycerin 0.1 mg / ml

Adverse reactions

The most frequent adverse effects (in 53% of patients) recorded in clinical studies (REVIVE) were headache, marked reduction in blood pressure, and ventricular tachycardia.
In the SURVIVE clinical trial, 18% of patients had: ventricular tachycardia, atrial fibrillation, marked reduction in blood pressure, ventricular extrasystole, tachycardia, headache.
The following are the adverse effects that have been reported during clinical trials (REVIVE I, REVIVE AND, SURVIVE, LIDO, RUSSLAN) in> 1% of patients. Adverse events were distributed in frequency as follows: very often (> 1/10), often (> 1/100, Often
Metabolism: hypokalemia. From the side of mental status: insomnia.
From the gastrointestinal tract: nausea, constipation, diarrhea, vomiting.
From the laboratory indicators: decrease in hemoglobin concentration.
Often
From the side of the central nervous system: dizziness, headache. Since the cardiovascular system: atrial fibrillation, atrial flutter, tachycardia, ventricular premature beats, ventricular tachycardia, arterial hypotension up to severe, heart failure, myocardial ischemia, extrasystole.
With the marketing use of the drug, ventricular fibrillation is reported.

Carefully: mild to moderate renal and hepatic failure, tachycardia, arterial hypotension, atrial fibrillation with a high frequency of ventricular contraction, potentially life-threatening arrhythmias, concomitant myocardial ischemia, anemia, hypokalemia, lengthening of the QT interval regardless of etiology, simultaneous use with drugs, prolonged QT interval, coronary heart disease.
There is not enough experience with repeated use of Simdax, as well as experience with heart failure after surgical interventions, with severe chronic heart failure in patients awaiting heart transplantation, in combination with vasoactive drugs, including drugs with inotropic effect (other than digoxin). There are no data on the use of Simdax in cardiogenic shock, restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, acute right ventricular myocardial infarction.

Drug interactions

Levosimendan should be used with caution in combination with intravenous vasodilators due to the possible increased risk of arterial hypotension. In vitro studies on human liver microsomes have shown that levosimendan should not interact with drugs metabolized by cytochrome P450 (CYP) isoenzymes, due to its low affinity for various CYP isoenzymes. In a population-based pharmacokinetic analysis, no signs of interaction between digoxin and levosimendan were found. Levosimendan can be used in patients receiving beta-blockers, which does not affect the effectiveness of treatment. The 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 except those listed in the section Dosage and administration / Compatibility.

Pregnancy and Lactation

Experience of levosimendan use in pregnant women is not. 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 the child. Information about the removal of levosimendan with breast milk is not. Women should not breastfeed when used and for 14 days after levosimendan infusion.

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 inotropic drugs.
The drug can be used if the shelf life has not expired, and storage was carried out 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 initially low systolic and diastolic blood pressure or with a tendency to arterial hypotension. For these patients, the use of low doses of the drug is recommended.

It is necessary to adjust the dose, the rate of administration and the duration of therapy, depending on the patient’s condition and response to therapy.
Severe hypovolemia must be eliminated before the infusion of the drug Simdax. If there are significant changes or fluctuations in blood pressure and heart rate, it is necessary to reduce the rate of infusion or stop the infusion.
Hemodynamic effects are usually observed within 7-10 days. This is partly due to the circulation of the active metabolite, whose concentration in the blood plasma reaches a maximum approximately 48 hours after the end of the infusion. Non-invasive monitoring is recommended to continue for at least 4-5 days after stopping the infusion until the BP starts to rise again after the period of its maximum decrease. The monitoring period may be longer than 5 days if the BP continues to decrease, but it may be less than 5 days if the patient's condition has stabilized.

Simdax infusion should be carried out with caution in patients with mild or moderate renal or hepatic impairment. Available data on the removal of active metabolites in violation of renal function are insufficient. Impaired kidney and liver function can lead to an increase in the concentration of active metabolites and more pronounced and persistent hemodynamic effects. It should monitor 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 continuously monitor the ECG, blood pressure and heart rate and measure diuresis for at least 3 days after stopping the infusion or until the patient's condition has stabilized.
Simdax infusion can cause a decrease in the serum potassium concentration, so hypokalemia should be eliminated before the infusion and the serum potassium level should be monitored during treatment. Simdax infusions, like other drugs intended for the treatment of chronic heart failure, may be accompanied by a decrease in the concentration of hemoglobin and hematocrit, so care should be taken in patients with coronary heart disease and concomitant anemia.
Simdax infusion should be carried out carefully in patients with tachycardia or a tachysystolic form of atrial fibrillation or potentially life-threatening arrhythmias.

Experience re-use of Simdaks, use of Simdaks in heart failure after surgery and in severe heart failure in patients awaiting heart transplantation is limited. The experience of using inotropic drugs (excluding digoxin) simultaneously with Simdax is also insufficient.
In each individual case, it is necessary to evaluate the benefits and risks of prescribing such drugs.
The use of Simdax in cardiogenic shock has not been studied.
Simdax infusion should be carried out under constant ECG control in patients with persistent myocardial ischemia and an increased QT interval, regardless of etiology or with the simultaneous use of other drugs that cause lengthening of the QT interval.

Information on the use of Simdax is not available for the following diseases: restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, right ventricular myocardial infarction. The experience of using Simdax in children and adolescents under the age of 18 is very limited; therefore, it should not be used in patients under the age of 18.
Ready solution
Although the prepared Simdax solution is stable for 24 hours at 25 ° C, it should be injected immediately after preparation. If the solution is not immediately used, the medical staff is responsible for the duration and storage conditions. In any case, the duration of storage of the finished solution should not exceed 24 hours.

Overdosage

Symptoms: a pronounced decrease in blood pressure and tachycardia, an increase in the blood content of the active metabolite, prolongation of the QT interval is possible.
Treatment: with a marked decrease in blood pressure, it is possible to use vasopressor agents: dopamine in patients with chronic heart failure and epinephrine (adrenaline) after heart surgery.
A sharp decrease in ventricular filling pressure can limit the effect of levosimendan; in order to restore pressure, parenteral administration of a liquid is indicated.
It is necessary to carry out continuous ECG monitoring, re-determination of serum electrolytes and invasive monitoring of hemodynamic parameters.