Simdax

Simdax is a non-glycoside cardiotonic drug.

In people with heart failure, the positive inotropic and vasodilatory properties of levosimendan result in increased myocardial contractility and a reduction in post- and preload without negative effects on diastolic activity.[ 1 ]

Levosimendan helps to activate the damaged myocardium in people who have undergone thrombolysis or coronary angioplasty. [ 2 ]

Indications Simdax

It is used for short-term therapy in the active stage of severe decompensated CHF (when standard treatment is ineffective and when inotropic influence is required).

Release form

The therapeutic substance is released in the form of a concentrate for infusion fluid - inside 5 ml vials; there is 1 such vial in a pack.

Pharmacodynamics

Levosimendan potentiates the sensitivity of contractile proteins to calcium, synthesizing with cardiotropin C using a calcium-dependent method. The substance potentiates contractile force without disrupting ventricular relaxation. At the same time, the drug opens ATP-sensitive potassium channels inside the smooth muscles of blood vessels, which stimulates vasodilation of the common and coronary arteries, as well as common veins. Levosimendan selectively inhibits PDE-3 in vitro.

Pharmacodynamic properties were studied in volunteers and patients with unstable and stable heart failure. It was found that the effectiveness of the drug depends on the size of the portion administered intravenously in a saturation dose (within 3-24 mcg/kg), as well as through continuous infusion (in a portion of 0.05-0.2 mcg/kg). [ 3 ]

Compared with placebo, Simdax increases cardiac output with stroke volume, heart rate and ejection fraction, and also reduces diastolic and systolic blood pressure, intrapulmonary capillary pressure and right atrium, as well as peripheral vascular resistance.

Infusion of the drug increases coronary circulation in individuals recovering from coronary surgery and improves myocardial perfusion in individuals with CHF. With the development of these benefits, myocardial oxygen consumption does not increase. Therapy using the drug significantly reduces circulating endothelin-1 levels in individuals with CHF. This avoids an increase in plasma catecholamine values when infusing at the recommended rate.

Pharmacokinetics

Levosimendan has linear pharmacokinetic parameters within the range of medicinal dosages of 0.05-0.2 mcg/kg/minute.

Distribution processes.

The distribution volume of the drug is approximately 0.2 l/kg. The active substance is 97-98% involved in protein synthesis (mainly with albumin). In OR-1855 and OR-1896, the degree of synthesis of the metabolic element and protein is 39% and 42%, respectively.

Exchange processes.

Metabolic processes of levosimendan are carried out by conjugation with cyclic or N-acetylated conjugates (cysteine and cysteinylglycine). About 5% is involved in intestinal metabolism through reduction to the substance aminophenylpyridazinone (OR-1855), which then (after the reabsorption process) is involved in metabolism by N-acetyltransferase to the active metabolic component OR-1896.

Levels of the metabolic product OR-1896 are slightly higher in individuals with genetically higher acetylation rates. However, when administered at recommended doses, this does not affect the clinical hemodynamic effects.

Excretion.

The clearance rate of levosimendan is approximately 3 ml/minute/kg and the half-life is approximately 1 hour.

54% of the dose is excreted in urine and 44% in faeces. Over 95% of the dose is excreted over a 7-day period. A small amount of unchanged levosimendan (<0.05% of the dose) is excreted in urine. Circulating metabolic products OR-1855 and OR-1896 are formed and excreted at a low rate.

Plasma Cmax of metabolic components is observed after 2 days from the end of Simdax infusion. The half-life of metabolic elements is 75-80 hours. OR-1855 and OR-1896 components participate in conjugation or intrarenal filtration and are excreted mainly in urine.

Dosing and administration

Simdax is used exclusively in a hospital setting – when equipment is readily available to monitor and assess the patient’s condition; healthcare workers must also have experience using inotropic agents.

The medicinal concentrate is diluted before infusion. The medicine should be administered intravenously (peripheral and central veins).

As with any parenteral substance, the dissolved liquid is carefully inspected before administration to exclude the presence of solid elements or a change in color.

The portion size and duration of the course are selected individually, taking into account the response to therapy and the clinical condition of the patient.

Therapy is initiated with a saturation dose of 6-12 mcg/kg, administered over a period of at least 10 minutes, followed by continuous infusion at a rate of 0.1 mcg/kg per minute. A reduction in the saturation dose to 6 mcg/kg is prescribed for individuals who are simultaneously receiving intravenous treatment with inotropic or vasodilatory drugs.

The largest saturation doses cause a strong hemodynamic response (possibly due to a short-term increase in the number of adverse effects). The clinically significant patient response to therapy is assessed during the administration of the saturation dose or within 0.5-1 hour after the dosage change.

If the patient reacts excessively to the infusion (development of tachycardia or decrease in blood pressure), the rate of fluid administration can be reduced to 0.05 mcg/kg per minute (or the infusion is stopped). If the initial dosage is well tolerated, it is necessary to potentiate the hemodynamic effect - the infusion rate is increased to 0.2 mcg/kg per minute.

The duration of infusion in severe decompensated CHF is usually 24 hours. No symptoms of habituation or rebound effects were observed after completion of the procedure. The hemodynamic effect lasts at least 24 hours and is observed for up to 9 days after completion of the 24-hour procedure.

Persons with renal insufficiency.

It is necessary to use the medicine very carefully in mild and moderate stages of the disorder. It is prohibited to use it in people with severe renal dysfunction (CC values <30 ml/minute).

People with liver failure.

In mild to moderate forms of the disorder, Simdax is used very carefully. In severe dysfunction, it is not prescribed.

• Application for children

The drug is not recommended for use in pediatrics (under 18 years of age) because there is limited information regarding its use in this age group.

Use Simdax during pregnancy

There is no experience of using levosimendan during pregnancy. The drug is prescribed only in situations where the probable benefit is more expected than the risks to the development of the fetus.

Since there is no information on whether Simdax is excreted in breast milk, breastfeeding should be discontinued when the drug is administered.

Contraindications

Main contraindications:

• severe intolerance to levosimendan or additional components of the drug;
• a sharp decrease in blood pressure and tachycardia;
• significant mechanical obstacles that affect the blood filling of the cardiac ventricles or impede the blood outflow from them;
• severe renal dysfunction (creatinine clearance level is <30 ml/minute);
• severe forms of liver dysfunction;
• history of torsades de pointes.

Side effects Simdax

Side effects include:

• metabolic disorders: hypokalemia often develops;
• mental disorders: insomnia often appears;
• problems with the nervous system function: headaches occur most often. Dizziness also often appears;
• symptoms related to the work of the cardiovascular system: most often, ventricular tachycardia develops or the blood pressure indicator decreases. Tachycardia, heart failure, atrial fibrillation, extrasystoles, myocardial ischemia and ventricular extrasystole also often occur;
• gastrointestinal disorders: diarrhea, nausea, constipation or vomiting often develop;
• systemic manifestations and signs in the injection area: symptoms of intolerance;
• laboratory test results: a decrease in hemoglobin levels is often noted.

Ventricular fibrillation has been reported in postmarketing use.

Overdose

Levosimendan poisoning may cause tachycardia and a decrease in blood pressure. In clinical trials, the decrease in blood pressure associated with levosimendan was corrected with vasoconstrictors (for example, dopamine (in people with CHF) or adrenaline (in people after cardiac surgery)). Due to an excessive decrease in the filling pressure of the ventricles, the clinical response to the drug may be limited - this can be eliminated by parenteral fluid administration. Large doses of the drug during infusion lasting more than 24 hours increase the pulse rate and sometimes cause prolongation of the QT interval.

In case of overdose with levosimendan, prolonged monitoring of ECG readings, repeated monitoring of serum electrolytes, and invasive hemodynamic monitoring are performed. Intoxication may increase plasma levels of the active metabolic element, which may result in a stronger and more prolonged effect on heart rate – therefore, the observation period should be extended.

Interactions with other drugs

Levosimendan should be prescribed with extreme caution together with other vasoactive substances for intravenous injection, as this increases the likelihood of a decrease in blood pressure.

The medication is used in combination with digoxin and β-blockers without loss of medicinal effectiveness.

Combining the drug with isosorbide mononitrate in volunteers caused a significant increase in orthostatic collapse.

Storage conditions

Simdax should be stored in a place closed to small children. The temperature level is within the range of 2-8°C. Do not freeze the medicinal liquid.

Shelf life

Simdax can be used within 24 months from the date of manufacture of the pharmaceutical product.

Analogues

Analogues of the drug are Dopamine, Dobutamine with Levosimendan, Dopamine and Kudesan.

Reviews

Simdax receives generally contradictory reviews. It is quite effective in the treatment of CHF of the decompensated type, but at the same time it has quite a large number of side effects (mainly vomiting, dizziness, a strong decrease in blood pressure and heart rhythm disorders). In addition, the rather high cost of the drug is noted as a disadvantage.