Симдакс®

General characteristics. Structure:

Active ingredient: 2,5 mg of a levosimendan in 1 ml of solution.

Excipients: povidone for parenteral administration, citric acid / in for parenteral administration, ethanol / century.

Симдакс (левосимендан) treats neglikozidny cardiotonic means and is the representative of a new class of drugs - calcium sensitizator. Effectiveness and clinical performance of a levosimendan is based on its unique mechanism of action. Renders positive the inotropic, vasodilating and anti-ischemic effects. Provides significant decrease in risk of death of patients with a left ventricular failure at a myocardial infarction.

Pharmacological properties:

Pharmacodynamics. Levosimendan increases sensitivity to calcium of sokratitelny proteins, communicating with troponiny From a myocardium (binding depends on calcium), increases force of cordial reductions, opens ATP-sensitive potassium channels in unstriated muscles of vessels and induces an arteriectasia, including coronary, and veins. In vitro is shown the selection inhibiting activity of a levosimendan concerning phosphodiesterase III. Value of this effect at use of drug in therapeutic concentration is not established. At patients with chronic heart failure positive kaltsiyzavisimy inotropic and vazodilatiruyushchy action of a levosimendan leads to increase in force of cordial reductions and decrease in preloading and afterload, without worsening diastolic function. Activates an ischemic myocardium at patients after transdermal transluminal angioplasty of coronary arteries or a thrombolysis.

Studying of a hemodynamics at healthy volunteers and at patients with chronic heart failure showed dozozavisimy effect of a load dose (3 mkg/kg of body weight) and long infusion (0,05 - 0,2 mkg/kg of body weight in 1 minute). Levosimendan increases cordial emission, a stroke output, increases fraction of emission and the heart rate (HR), reduces the systolic and diastolic arterial pressure (AP), jamming pressure in capillaries of lungs, pressure in the right auricle and the general peripheric vascular resistance. At administration of drug in the recommended dose one active metabolite which gives similar with levosimendany hemodynamic effects is formed. They remain within 7-9 days after the termination of 24-hour infusion of a levosimendan.
Infusion of a levosimendan causes increase in a coronary blood-groove in the patients who transferred intervention on coronary arteries and improves perfusion of a myocardium at patients with chronic heart failure. These positive effects are not followed by significant increase in consumption an oxygen myocardium. Considerably reduces the content of endothelin 1 at patients with chronic heart failure. At observance of the recommended rate of administering drug does not increase concentration of catecholamines in a blood plasma.

REVIVE I and REVIVE II programs. The REVIVE programs compared efficiency of a levosimendan and placebo in a combination to standard therapy at patients to an acute decompensation of chronic heart failure with fraction of emission of a left ventricle of ≤35% and an asthma at rest. Continuation of the previous therapy except for intravenous administration of a milrinon was allowed.

Results showed that at the most part of patients there occurred improvement, at smaller number of patients the state worsened. In Simdaks's group insignificant increase in frequency of mortality for the 90th day in comparison with control group was observed (15% and 12% respectively). It is shown that the initial level of the systolic ABP <100 mm of mercury or the diastolic ABP <60 mm of mercury. increase risk of mortality.

SURVIVE. In a double blind multicenter comparative research of a levosimendan and Dobutaminum at 1327 patients and with inefficiency of the previous therapy by diuretics and vazodilatator compared indicators of 180-day mortality to acute dekompensirovanny chronic heart failure. In percentage frequency advantage was for levosimendany for the 5th day (4% левосимендан, 6% Dobutaminum). This advantage remained for 31 days (12% левосимендан, 14% Dobutaminum), especially at those patients who initially received beta adrenoblockers. At patients with initially more than an ABP low level rates of mortality were worse in both groups.

LIDO. In a double blind multicenter research of 203 patients with heavy chronic heart failure with low cordial emission (fraction of emission <0,35 cardiac index <2.5 l/min., jamming pressure in pulmonary capillaries> 15 mm of mercury.), needing inotropic therapy, received левосимендан (a load dose of 24 mkg/kg within 10 min., and then continuous infusion of 0,1-0,2 mkg/kg/min. within 24 hours) or Dobutaminum of 5-10 mkg/kg/min. during 24 h. Increases in cordial emission> 30% and simultaneous pressure decrease of jamming in pulmonary capillaries for 25% and more in 24 h were succeeded to achieve from 28% of the patients receiving левосимендан and from 15% of the patients receiving Dobutaminum (р =0.025). An asthma decreased at 68% and 59% of patients respectively, fatigue - at 63 and 47%. Indicators of 31-day mortality made 7,8% in group of a levosimendan and 17% in group of Dobutaminum.

RUSSLAN. In a double blind multicenter research which primary purpose was a studying of safety 504 patients with dekompensirovanny chronic heart failure after an acute myocardial infarction needing inotropic therapy received левосимендан or placebo within 6 hours. Groups authentically did not differ on the frequency of development of arterial hypotension and ischemia of a myocardium.

In the retrospective analysis of results of two researches LIDO and RUSSLAN of undesirable influence of a levosimendan on 6-month survival it is not revealed.

The pharmacokinetics Pharmacokinetics of a levosimendan in therapeutic doses from 0,05 to 0,2 mkg/kg/min. is linear.

Distribution. The volume of distribution of a levosimendan (Vss) makes about 0,2 l/kg. Levosimendan for 97-98% contacts proteins of a blood plasma, generally albumine. Linkng of active metabolites (OR-1855 and OR-1896) with proteins - 39% and 42% respectively.

Metabolism. Levosimendan is generally metabolized by a konjyugirovaniye with cyclic or N-acetylized tsisteinilglitsiny and cysteine conjugates. Only about 5% of a dose of a levosimendan are metabolized in a small intestine by oxidation to an aminofenilpiridazinon (OR-1855) which after a reabsorption in a system blood stream biotransformirutsya in a blood plasma under the influence of N-acetyltransferase to an active metabolite of OR-1896. Speed of acetylation is genetically determined. At "bystry acetylizers" concentration of a metabolite of OR-1896 are slightly higher, than at "slow". However it does not affect clinically significant hemodynamic effects of drug in the recommended doses.

In a system blood-groove in significant amounts only 2 metabolites - OR-1855 and OR-1896 are defined. At "slow" acetylizers OR-1855, and at "bystry" - OR-1896 prevails. However total quantity of these metabolites and frequency of development of hemodynamic effects identical at "bystry" and "slow" acetylizers. These metabolites can exert long impact on hemodynamics indicators (within 7-9 days after the termination of 24-hour infusion of a levosimendan).

In vitro левосимендан and metabolites of OR-1855 and OR-1896 in the concentration which is created at use of the recommended drug doses do not inhibit CYP1A2, CYP 2A6, CYP2C19, CYP2E1, CYP2C9, CYP2D6, or CYP3A4. Levosimendan does not inhibit CYP 1A1, and his metabolism is not broken under the influence of CYP3A of inhibitors.

Removal. The clearance of a levosimendan makes about 3,0 ml/min., and an elimination half-life - about 1 h. More than 95% of a dose of a levosimendan are removed within 1 week in the form of inactive metabolites. An insignificant part of a dose (<0,05%) is removed by kidneys in not changed look. The circulating metabolites of OR-1855 and OR-1896 are formed and removed slowly, their elimination half-life about 75-80 hours. Concentration of OR-1855 and OR-1896 in a blood plasma reach a maximum approximately in 2 days after the termination of infusion of a levosimendan. Active metabolites of OR-1855 and OR-1896 are exposed to conjugation or renal filtering and are removed preferential by kidneys.

Special groups. Children: Not numerous data demonstrate that the pharmacokinetics of a levosimendan after single introduction at children (aged from 3 months up to 6 years) is similar to that at adults. The pharmacokinetics of an active metabolite at children was not studied. Levosimendan it is not necessary to apply at children.

Patients with a renal failure: the pharmacokinetics of a levosimendan is similar at patients to easy or moderate renal failures and at the patients who are on a hemodialysis. At patients with a heavy renal failure pharmacokinetic indicators can be a little lowered. At patients with a heavy renal failure and at those which are on a hemodialysis the free fraction of a levosimendan is slightly raised, an AUC (the area under a curve "concentration time") is 170% higher than metabolites of OR-1855 and OR-1896. It is supposed that a slight and moderate renal failure exert smaller impact on pharmacokinetics of metabolites of OR-1855 and OR-1896. Levosimendan is not brought at a hemodialysis. Though metabolites of OR-1855 and OR-1896 are removed at a hemodialysis, their clearance low (about 8-23 ml/min.).

Patients with an abnormal liver function: Patients with a slight and moderate liver failure at cirrhosis have a pharmacokinetics of a levosimendan and its linkng with proteins do not differ from those at healthy doborovolets. Pharmacokinetics of a levosimendan and metabolites of OR-1855 and OR-1896 identical at healthy doborovolets and at patients with a moderate abnormal liver function (a class B on classification of Chayld-Pyyuga) except that the elimination half-life of these metabolites is a little extended at a moderate liver failure.

In the population analysis it is not revealed that age, the ethnic origin or a floor influence pharmacokinetics of a levosimendan. However, the volume of distribution and the general clearance depend on body weight.

Indications to use:

Acute decompensation of heavy chronic heart failure (for short-term therapy at inefficiency of standard therapy and need of maintenance of sokratitelny function of a myocardium).

Route of administration and doses:

Only for use in a hospital!

Simdaks's concentrate of 2,5 mg/ml should be applied only in a divorced look!

Preparation of solution for infusion and infusion speed. To prepare solution for infusion of 0,05 mg/ml, it is necessary to dissolve with 10 ml of a concentrate of a levosimendan of 2,5 mg/ml in 500 ml 5% of solution of a dextrose (glucose). Infusion speed for a load and maintenance dose of 0,05 mg/ml of solution of a levosimendan depending on body weight is specified in table 1:

Table 1.

Body weight (kg)	Speed of infusion of a load dose within 10 min. (ml/h)		Speed of continuous infusion (ml/h)
	6 mkg/kg	12 mkg/kg	0,05 mkg/kg/min.	Mkg/kg/min. O1.	0,2 mkg/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 solution for infusion of 0,025 mg/ml, it is necessary to dissolve with 5 ml of a concentrate of a levosimendan of 2,5 mg/ml in 500 ml 5% of solution of a dextrose (glucose).
Infusion speed for a load and maintenance dose of 0,025 mg/ml of Simdaks depending on body weight is specified in table 2:

Table 2.

Body weight (kg)	Speed of infusion of a load dose within 10 min. (ml/h)		Speed of continuous infusion (ml/h)
	6 mkg/kg	12 mkg/kg	0,05 mkg/kg/min.	Mkg/kg/min. O1.	0,2 mkg/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

Simdaks's concentrate of 2,5 mg/ml is intended only for single use!

Before infusion divorced solution, as well as other drugs for parenteral use, it is necessary to check for existence of foreign particles and discoloration. At storage color of a concentrate can change on orange that is not followed by drug decrease of the activity.

Infusion can be carried out through peripheral or central veins.

The dose and duration of treatment are selected individually taking into account a clinical condition of sick and therapeutic effect.

Treatment begin with a load dose 6-12 mkg/kg which is entered within 10 minutes (see table 1 and 2). Then carry out continuous infusion with a speed of 0,1 mkg/kg/min. Lower dose of 6 mkg/kg is recommended at the patients receiving the accompanying intravenous therapy by vazodilatator and/or inotropic means. Purpose of higher load dose of 12 mkg/kg will be followed by stronger hemodynamic effect, but at the same time is not excluded that the frequency of passing side effects will also increase.

Reaction of the patient to therapy is estimated at introduction of a load dose or within 3060 minutes after correction of a dose or depending on a clinical picture.

At the expressed changes of indicators of a hemodynamics (arterial hypotension, tachycardia) it is necessary to reduce infusion speed to 0,05 mkg/kg/min. or to stop infusion. At good tolerance of an initial dose and need for more expressed hemodynamic effect it is possible to increase the speed of infusion to 0,2 mkg/kg/min. The recommended duration of infusion makes 24 h. After the termination of infusion of Simdaks of signs of development of tolerance or a syndrome of "cancellation" it was not revealed. Hemodynamic effects are observed during at least 24 h and N within 9 days after completion of 24-hour infusion can remain.

Patients of advanced age. Dose adjustment is not required from patients of advanced age.

Renal failure. Симдакс it is necessary to apply with care at patients with a slight and moderate renal failure. It should not be entered the patient with a heavy renal failure (clearance of creatinine less than 30 ml/min.) (see the sections Pharmacokinetics, Contraindications, Special instructions).

Abnormal liver function. Симдакс it is necessary to apply with care at patients with a lung (5-6 points on classification of Chayld-Pyyuga) or moderated (7-9 points on classification of Chayld-Pyyuga) an abnormal liver function, however dose adjustment is not required. It should not be entered the patient with a heavy abnormal liver function (> 9 balls on classification of Chayld-Pyyuga) (see the sections Pharmacokinetics, Contraindications, Special instructions).

Children. Симдакс it is not necessary to apply at children and teenagers aged up to 18 years.

Experience of repeated infusions of Simdaks and his use in a combination with other inotropic means (except for digoxin) is limited.

Compatibility. Along with Simdaks it is possible to enter:

• Furosemide of 10 mg/ml
• Digoxin of 0,25 mg/ml
• Nitroglycerine of 0,1 mg/ml

Features of use:

Drug can be used only in the conditions of the hospital having the necessary equipment for control of the vital functions and having medical personnel with experience with inotropic means.

Drug can be used if the period of validity did not expire, and storage was carried out according to the application instruction.

The initial hemodynamic effect of a levosimendan consists in decrease in the systolic and diastolic ABP therefore it has to be applied with care at patients with initially low systolic and diastolic ABP or with tendency to arterial hypotension. For these patients use of low doses of drug is recommended.

It is necessary to select a dose, rate of administering and duration of therapy depending on a condition of the patient and his response to therapy.

The expressed hypovolemia needs to be eliminated before performing infusion of drug of Simdaks. If considerable changes or fluctuations of the ABP and ChSS are observed, then it is necessary to reduce the speed of infusion or to stop infusion.

Hemodynamic effects are usually observed within 7-10 days. Partially it is connected with circulation of an active metabolite which concentration in a blood plasma reaches a maximum approximately in 48 hours after completion of infusion. Noninvasive monitoring is recommended to be continued during, at least, 4-5 days after the infusion termination until again the ABP after the period of its maximum decrease does not begin to raise. The period of control can be longer than 5 days if decrease in the ABP continues, but maybe less than 5 days if the condition of the patient was stabilized.

Simdaks's infusion should be carried out with care at patients with an easy or moderate renal failure or a liver. The available data on removal of active metabolites at a renal failure are insufficient. A renal failure and a liver can lead to increase in concentration of active metabolites and more expressed and lasting hemodynamic effects. It is necessary to make observation of a functional condition of a liver and kidneys within not less than 5 days after the end of infusion.

During treatment it is reasonable to carry out continuous control of an ECG, the ABP and ChSS and to measure a diuresis during, at least, 3 days after the termination of infusion or before stabilization of a condition of the patient.

Simdaks's infusion can cause decrease in serumal potassium concentration therefore before infusion it is necessary to eliminate a hypopotassemia and to control the serumal level of potassium during treatment. Simdaks's infusions, as well as other means intended for treatment of chronic heart failure can be followed by decrease in concentration of hemoglobin and a hematocrit therefore it is necessary to be careful at patients with coronary heart disease and the accompanying anemia.

Simdaks's infusion should be carried out carefully at patients with tachycardia or a takhisistolichesky form of a ciliary arrhythmia or potentially life-threatening arrhythmias.

Experience of repeated use of Simdaks, Simdaks's use at heart failure after surgical intervention and at heavy heart failure at the patients expecting transplantation of heart is limited. Experience of use of inotropic means (excepting digoxin) along with Simdaks is also insufficient.

In each individual case it is necessary to estimate advantage and risk of purpose of similar medicines.

Simdaks's use at cardiogenic shock is not studied.

Simdaks's infusion should be carried out under constant control of an ECG at patients with the remaining ischemia of a myocardium and the increased QT interval irrespective of an etiology or at simultaneous use of other medicines which cause lengthening of an interval of QT.

Information on Simdaks's use is absent at the following diseases: restrictive cardiomyopathy, hypertrophic cardiomyopathy, heavy insufficiency of the mitral valve, rupture of a myocardium, cardiac tamponade, myocardial infarction of a right ventricle. Experience of use of Simdaks for children and teenagers aged up to 18 years is very limited therefore it should not be applied at patients up to 18 years.

Ready solution. Though the prepared Simdaks's solution keeps stability during 24 h at a temperature of 25 °C, it should be entered right after preparation. If solution was not used at once, then the medical personnel are responsible for duration and conditions of its storage. Anyway the storage period of ready solution should not exceed 24 h.

Side effects:

The headache, the expressed decrease in the ABP, ventricular tachycardia were the most frequent adverse effects (at 53% of patients) registered in clinical trials (REVIVE).

In clinical trial of SURVIVE, at 18% of patients were observed: ventricular tachycardia, a ciliary arrhythmia, the expressed decrease in the ABP, ventricular premature ventricular contraction, tachycardia, a headache.

Adverse effects which are registered at conduct of clinical trials (REVIVE I, REVIVE I, SURVIVE, LIDO, RUSSLAN) at> in 1% of patients are listed below. The adverse phenomena were distributed on frequency as follows: very often (> 1/10), it is frequent (> 1/100, <1/10).

Often:
From a metabolism: hypopotassemia. From the mental status: sleeplessness.

From digestive tract: nausea, lock, diarrhea, vomiting.

From laboratory indicators: decrease in concentration of hemoglobin.

Very often:
From the central nervous system: dizziness, headache. From cardiovascular system: a ciliary arrhythmia, an atrial flutter, tachycardia, ventricular premature ventricular contraction, ventricular tachycardia, arterial hypotension up to expressed, heart failure, myocardium ischemia, premature ventricular contraction.

At marketing use of drug it is reported about fibrillation of ventricles.

Interaction with other medicines:

Levosimendan it is necessary to apply with care in combination with intravenous vazodilatator owing to possible increase in risk of arterial hypotension. The researches in vitro on microsomes of a liver of the person showed that левосимендан should not interact with the drugs which are metabolized under the influence of isoenzymes of P450 (CYP) cytochrome thanks to low affinity to various isoenzymes of CYP. In the population pharmacokinetic analysis signs of interaction between digoxin and levosimendany were not revealed. Levosimendan can be applied at the patients receiving beta adrenoblockers that does not affect efficiency of treatment. Simultaneous use of isosorbide of mononitrate and a levosimendan for healthy volunteers caused considerable strengthening of orthostatic hypotension.

Incompatibility. Drug cannot be mixed with other medicines or solutions except for listed in the section Route of administration and dose/compatibility.

Contraindications:

• Hypersensitivity to a levosimendan or any inactive component of drug;
• The mechanical obstruction interfering filling and/or emission of blood from ventricles;
• The expressed renal failure (clearance of creatinine less than 30 ml/min.)
• The expressed liver failure (> 9 points on classification of Chayld-Pyyuga);
• The expressed arterial hypotension (systolic the ABP less than 90 mm hg)
• The expressed tachycardia (ChSS more than 120 beats/min.);
• Ventricular tachycardia on the pirouette type in the anamnesis;
• Age up to 18 years.
• Not corrected hypopotassemia
• Not corrected hypovolemia

With care: a renal and liver failure of easy and moderate severity, tachycardia, arterial hypotension, a ciliary arrhythmia with high frequency reductions of ventricles, potentially life-threatening arrhythmias, the accompanying myocardium ischemia, anemia, a hypopotassemia, lengthening of an interval of QT irrespective of an etiology, simultaneous use with the medicines extending QT interval, coronary heart disease.

There is no sufficient experience of repeated use of Simdaks, and also experience of use at heart failure after surgical interventions, at heavy chronic heart failure at the patients expecting transplantation of heart in combination with vasoactive medicines, including drugs with an inotropic effect (except digoxin). There are no data on Simdaks's use at cardiogenic shock, a restrictive cardiomyopathy, a hypertrophic cardiomyopathy, heavy insufficiency of the mitral valve, a rupture of a myocardium, a cardiac tamponade, an acute myocardial infarction of a right ventricle.

Overdose:

Symptoms: the expressed decrease in the ABP and tachycardia, increase in content in blood of an active metabolite, is possible lengthening of an interval of QT.

Treatment: at the expressed decrease in the ABP use of angiotonic means is possible: a dopamine at patients with chronic heart failure and Epinephrinum (adrenaline) after heart operations.

Sharp pressure decrease of filling of ventricles of heart can limit effect of a levosimendan; for the purpose of recovery of pressure parenteral administration of liquid is shown.

It is necessary to carry out constant ECG control, repeated definition of electrolytes of blood serum and invasive monitoring of indicators of a hemodynamics.

Storage conditions:

At a temperature of 2-8 °C (in the refrigerator). Not to freeze. At storage the concentrate can gain orange color, however it does not mean decrease in its efficiency if the period of validity of drug did not expire and storage conditions were met. After cultivation drug keeps stability for 24 h at a temperature of 25 °C.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 2,5 mg/ml. On 5 or 10 ml in a bottle from transparent colourless glass like I (Evr. T) with the rubber bung covered with a polymericfluorine film and an aluminum cap under a running in with the coming-off lid. On 1,4 or 10 bottles in a cardboard pack with the application instruction.