Guidance

Marketing Authorization No.: ЛП-003689

Trade name: Normacor®

Generic name: Potassium Chloride + Magnesium Sulfate + Mannitol

Dosage form: cardioplegia solutions delivery set

Description

Clear, colorless liquid.

Pharmacotherapeutic group: cardioplegic agent

ATC code: В05ХА16

Physical properties

pH:

7.6–8.0

Pharmacological properties

Pharmacodynamics

Normacor® is a set consisting of two solutions for various stages of cardioplegia: Solution No. 1 (enriched with potassium) is for achieving rapid asystole under normothermic conditions of blood cardioplegia and Solution No. 2 (low potassium) is for maintening asystole under normothermic conditions of blood cardioplegia.

Normacor® prolongs myocardium resistance to hypoxia due to the blockade of energy-intensive processes, reducing myocardial energy needs to a minimum. It provides effective protection against myocardial ischemia and reperfusion injuries under normothermia or moderate hypothermia and it does not limit duration of the surgeries.

Potassium ions are involved in the processes of transmission and transfer of nerve impulse to the innervated organs. They reduce excitability and conductivity of the myocardium and, in high doses, depress automatism.

Magnesium ions are an important intracellular cation and play a certain part in neuromuscular stimulation.

Mannitol has a decongestant, diuretic effect.

Trometamol reduces concentration of hydrogen ions and improves the blood alkaline reserve, thereby eliminating acidemia. It penetrates the cell membrane and helps eliminate intracellular acidosis.

Pharmakokinetics

Pharmacokinetics of Normacor® is completely dependent on the composition of its components.

After intravenous injection, potassium and chlorine ions get involved in the common pool of body ions.

Magnesium is excreted by the kidneys (increasing the diuresis) trough filtration, renal excretion is proportional to the plasma concentration. 93–99 % of magnesium ions is subjected to reverse reabsorption in the proximal and distal renal tubules.

Mannitol is excreted by the kidneys, when 100 g is administered intravenously, 80 % is detected in the urine within 3 h.

Trometamol is excreted by the kidneys in an unmodified form, 75 % is excreted after 8 h.

Indications

Cardiac surgery: patients with preserved and reduced contractility of the heart in cases of chronic dysfunction, with severe injury of the coronary bed and myocardium, in the case of urgent or emergency surgery due to unstable angina or acute myocardial infarction, under emergency switch to cardiopulmonary bypass during surgery using a minimally invasive procedure.

Contraindications

Individual intolerance to the solution components.

Efficacy and safety of Normacor® in children and adolescents under the age of 18 years have not been established.

Pregnancy and lactation

Efficacy and safety of Normacor® in pregnant and breast-feeding women have not been established. The use of Normacor® is possible if the benefit to the mother outweighs the potential risk to the fetus and child.

Posology and method of administration

1. Ancillary instruments

Perfusion system for blood cardioplegia of the required length and internal diameter without heat exchanger;
Perfusion cannulas (internal diameter of 2.5 mm to 6 mm);
Clips for tubes;
Cardioplegic attachment of the CPB pump with two roller pumps.

2.Cardiac tolerance to ischemia

Cardiac tolerance to ischemia is defined by the perfect perfusion from its very beginning, and by the temperature of myocardium, the temperature at the site of extracorporeal circulation, as well as by the existing heart damage.

In general, under normothermia (36 °C–37 °C) and moderate hypothermia
(30 °С–35 °С), aortic compression is well tolerated by the heart without limiting the surgery duration subject to the drug dosage regimens (see item 6 Posology).

If atrial activity during the artificial cardiac arrest is found, it should be ignored. If ventricular activity during the artificial cardiac arrest is found, perfusion of additional Normacor® should be carried out in accordance with this Guidance.

It should be remembered that achievement of long-term protection of the myocardium requires the entry of the entire volume of the injected cardioplegic mixture (Normacor® and the patient’s oxygenated blood) to the coronary bed.

3. Precautions for use

There are the following reasons of incomplete enter of Normacor® as part of the mixture into the coronary bed:

- incomplete clamping of the ascending aorta;

- insufficient closure of the aortic valve leaflets.

If a smaller amount of Normacor® enters the coronary bed, an earlier resumption of ventricular activity should be expected at the stage of aortic cross-clamping after reaching asystole.

If there is insufficient entry of the cardioplegic mixture into the coronary bed, asystole may not occur.

If Normacor® as part of the mixture does not completely enter the coronary bed, the following actions must be taken:

- In case of impossibility of complete ascending aorta cross-clamping with the clamp due to the significant atherosclerotic changes of the aortic root, as well as under severe aortic valve insufficiency, one should switch from antegrade to retrograde delivery of cardioplegic mixture in order to provide its entry into the coronary bed in accordance with this Guidance.

- when the aortic valve surgery is undertaken due to its significant insufficiency, antegrade cardiac arrest should be performed by supplying a cardioplegic mixture into the ostia of coronary arteries to ensure its complete entry into the coronary bed.

Given the important role of non-coronary cardiac blood flow at the stage of cardioplegia action, it is also necessary to constantly monitor the adequacy of the drainage of the left ventricle in order to exclude overstretching of the chambers of the heart.

Possible symptoms of atrial activity during the main phase of the surgeries are not a problem, and this activity should be ignored. It depends on the patient's weight and the initial level of potassium ions in the blood when the patient arrives in the operating room. Possible manifestations of the cardiac ventricular activity may require a larger volume of Normacor® to enhance the content of potassium ions in the cells of cardiomyocytes.

To do this, in accordance with the antegrade (Figure 1) or retrograde (Figure 2) scheme for the supply of cardioplegic mixture (Figure 3), perfusion of a mixture of Solution No. 1 and oxygenated blood of the patient is carried out at a ratio of 1:2.

Under both antegrade and retrograde cardioplegia during the perfusion, it is necessary to control the volume and level of potassium ions in the blood and not to add potassium ions to the perfusate. The criterion for inadequate protection of the heart at the stage of aortic cross-clamping is resumption of ventricular activity that is associated with the development of hypokalemia. The increase in the content of potassium ions and the achievement of asystole provides the remaining needs of the heart and eliminates the problem of ischemia.

In order to achieve stable asystole again, re-perfusion is carried out with a mixture of Solution No. 1 and oxygenated blood in a ratio of 1:2, without removing the aortic cross clamp.

4. Initial cardioplegia

After connecting the CPB pump, at the highest point of the ascending aorta, a purse-string or a U-shaped stitch (PDS 4-0) with a loop is applied to secure the perfusion cannula and drainage.

Normacor® is applied at room temperature under normothermic (36 °С–37 °С) or mild hypothermic (30 °С–35 °С) cardiopulmonary bypass.

While connecting the perfusion system to the container with cardioplegic solution, special attention should be paid to thorough ventilation of the tube system. The trap for air bubbles in the system must be filled with the solution up to overflowing to avoid formation of microbubbles due to the high air pressure.

Immediately before clamping the aorta, a puncture or an incision is made in the purse-string or between the legs of the U-shaped stitch and a cardioplegic cannula is inserted, after that the tourniquet is tightened and the cardioplegic cannula is secured on the general cardioplegic line.

5. Mode of administration

Depending on the pathology antegrade (through the aortic root), retrograde (through the coronary sinus), or mixed cardioplegia is performed. The solution is injected using the cardioplegic system. Cardioplegia is completely drawn into the system of the CPB pump.

Normacor. PIL

Figure 1 - Diagram of antegrade delivery of the cardioplegic mixture of Normacor® and oxygenated blood

In addition to the antegrade method, according to the indications, one can use the mixed mode of administration for cardioplegia - antegrade and retrograde - through the coronary sinus (see Figure 2).

Normacor. PIL 2

Figure 2 - Mixed (antegrade and retrograde) delivery of the cardioplegic mixture of Normacor® and oxygenated blood

A - general cardioplegic line;
1 - clip on the aorta; 2 - standard Y-shaped cardioplegic cannula;
3 - aortic root; 4 - clip on the line for the drainage of the left ventricle;
5 - clip on antegrade cardioplegic line; 6 - Luer connector;
7 - coronary sinus; 8 - standard catheter for retrograde cardioplegia;
9 - clip on the catheter line for retrograde cardioplegia.

On the general cardioplegic line (A), after the clamping of the ascending aorta (1), the cardiac arrest is conducted antegradely (see Figure 1). Cardioplegic mixture enters the aortic root (3) through the standard Y-shaped cardioplegic cannula (2). The line for the drainage of the left ventricle through the aortic root must be simultaneously clamped with a clip (4). If it is necessary to unload the left heart, the delivery of the cardioplegic mixture must be stopped, the antegrade cardioplegia line (5) must be clipped after removing the clip from the line for the drainage of the left ventricle. The tightness of the connection is provided by Luer connectors (6) included in the standard package for cardioplegia delivering cardioplegic mixture through the general cardioplegic line. After antegrade cardiac arrest, according to the indications, retrograde delivery of the cardioplegic feed mixture through the coronary sinus (7) can be started using a standard retrograde cardioplegia catheter (8). The antegrade cardioplegic line must be clamped and the total cardioplegic line must be connected to the standard catheter for retrograde cardioplegia using the Luer connector. The line for drainage of the left ventricle is unclamped simultaneously, and so the left heart is unloaded through the aortic root. If it is necessary to restart antegrade cardioplegia, the catheter for retrograde cardioplegia must be clamped (9) and antegrade cardioplegia must be performed according to the standard procedure described above.

The solution is injected using the cardioplegic system (see Figure 3).

Normacor. PIL 3

Figure 3 - Scheme of injection of cardioplegic mixture of Normacor®
(Solution No. 1 or Solution No. 2) and oxygenated blood

1 - arterial pump; 2 - fitting for arterial perfusion, 3 - oxygenator; 4 - fitting for coronary perfusion; 5 - line for coronary perfusion; 6, 9 - roller pumps of the cardioplegic attachment of the CPB pump; 7 - T-piece which connects the blood and Normacor®; 8 - vial with Solution No. 1 or Solution No. 2; 10 - line for coronary perfusion of Normacor®; A - general cardioplegic line.

Through the arterial pump (1) of the CPB pump, blood (from the oxygenator fitting for arterial perfusion (2) enters the patient’s aorta via the standard cardiopulmonary bypass circuit. Oxygenator (3) has a special fitting for coronary perfusion (4) through which the blood in the line (5) via the pump (6) of cardioplegic attachment of the CPB pump enters the coronary bed of the patient, mixing in the T-piece (7) with Normacor® from the vial (8). Normacor® enters the patient's coronary bed via another pump (9) of the cardioplegic attachment of the CPB pump and the T-piece, but via the line of the cardioplegic system (10). Separate injection of Normacor® and oxygenated blood through the pumps of the cardioplegic attachment of the CPB pump enables changing the ratio of 1:2 to 1:4 and back without removing the aortic cross clamp, as well as adjusting the volume of the administered cardioplegic solution entering the general cardioplegic line (A).

1. Posology

Achievement of asystole

Before clamping the aorta, the cardioplegic system is filled with a mixture of cardioplegic solution No. 1 and oxygenated blood. Immediately after the aortic clamping, antegrade perfusion of cardioplegic mixture of Solution No. 1 and oxygenated blood at a ratio of 1:2 is performed. The rate of the antegrade delivery of the mixture until the asystole is achieved is 300 ml/min. As a rule, asystole occurs within 1 - 2 minutes. After reaching asystole, the drug remaining in the vial (polymer container) should be injected to bring its total volume to 400 ml by decreasing the delivery rate of the mixture with blood to 250 mL/min. If asystole does not occur within 3 minutes, the delivery rate of the mixture should be increased to 350 ml/min. If necessary an additional vial (polymer container) of Solution No. 1 should be used. If asystole does not occur within 5 minutes, retrograde delivery of the cardioplegic mixture of Solution No 1 and oxygenated blood at a ratio of 1: 2 through the coronary sinus without removing the aortic cross clamp should be used (see item 5 Mode of administration) at 100 ml/min and the pressure not exceeding 50 mm Hg.

Maintaining asystole

It is necessary to maintain the asystole in one of three equivalent ways:

1) To maintain asystole of an arrested heart by perfusion of a cardioplegic mixture of Solution No. 2 and oxygenated blood at a ratio of 1:4.

Maintenance of asystole of an arrested heart in order to prevent the resumption of ventricular activity is carried out by perfusion of a cardioplegic mixture of Solution No. 2 and oxygenated blood at a ratio of 1:4 at a rate of 150 ml/min antegrade or retrograde at a rate of 100 ml/min with consistent multiple interruption of the cardioplegic mixture supply for a period of 15 minutes followed by its resumption for 2-3 minutes between intervals. Under retrograde perfusion, the pressure shouldn’t be more than 50 mm Hg. In case of resumption of ventricular activity, it’s required to switch to the perfusion of a cardioplegic mixture of Solution No. 1 and oxygenated patient’s blood at a ratio of 1:2 with a mixture flow rate of antegrade 150 ml/min or retrograde 100 ml/min until the asystole is reached. After reaching a stable asystole in 15 minutes, it’s required to switch to the asystole maintenance scheme described above.

2) To maintain asystole in case of resumption of ventricular activity by perfusion of cardioplegic mixture of Solution No. 1 and oxygenated blood at a ratio of 1:2.

Maintenance of the asystole is carried out only when the ventricles of the heart are active. It is performed in case of resumption of ventricular activity by perfusion of a cardioplegic mixture of Solution No. 1 and oxygenated blood at a ratio of 1:2 with a mixture flow rate of antegrade 150 ml/ min or retrograde 100 ml/min until stable asystole is reached. Under retrograde perfusion the pressure shouldn’t be more than 50 mm Hg.

3) If there are preconditions for the resumption of ventricular activity, maintenance of the asystole on an arrested heart is carried out by perfusion of a cardioplegic mixture of Solution No. 1 and oxygenated blood at a ratio of 1:2.

Maintenance of an asystole in case of preconditions for the resumption of ventricular activity is carried out by perfusion of a cardioplegic mixture of Solution No. 1 and oxygenated blood at a ratio of 1:2 with a mixture flow rate of antegrade 150 ml/min or retrograde 100 ml / min lasting 2-3 minutes (possibly repeatedly) in order to prevent the resumption of ventricular activity. The pressure under retrograde perfusion is not more than 50 mmHg.

2. Termination of cardioplegia

Before removing the clip from the aorta, perfusion of cardioplegic mixture of Normacor® and oxygenated blood is stopped.

Adverse effect

Allergic reactions to components of the drug are possible. No adverse or allergic reactions were identified during the clinical study of the drug.

Overdose

The consequence of Normacor® overdose can be hyperkalemia. Under administration of Normacor®, potassium is the main element responsible for the arrest and protection of the heart at the main stage of the surgery. Hyperkalemia manifests itself by the lengthening of the interval of the self-recovery of the heart rate after removal of the clamp from the aorta. Elimination of the effects of overdose (hyperkalemia) occurs by itself, as a result of potassium washing out due to the effect of one of the components of Normacor®, osmotic diuretic - mannitol.

Additional treatment is not required.

Drug interaction

No drug interaction was found. The drugs can be excreted faster due to the presence of mannitol in Normacor®.

Special precautions

Normacor® is not used for any types of injections or infusions.

Presentation

Cardioplegia solutions delivery set (250, 450 ml bottles or polymer containers) 200, 400 ml.

Solution No. 1. 200 ml or 400 ml of the product in 250 ml or 450 ml glass bottles (polymer container) respectively, sealed with rubber stoppers and crimped with aluminum caps.

Solution No. 2. 200 ml or 400 ml of the product in 250 ml or 450 ml glass bottles (polymer container) respectively, sealed with rubber stoppers and crimped with aluminum caps.

Cardioplegia solutions delivery set: Solution No. 1 and No. 2, 250 ml bottles (polymer containers), 14 pcs of each; or Solution No. 1 and No. 2, 450 ml bottles (polymer containers), 7 pcs of each, along with the package insert are placed in a cardboard box.

Storage conditions

In a dark place at a temperature of less than 25 °C. Keep out of the reach of children.

Shelf life

3 years. Do not use after the expiry date.

Prescription status

For hospitals only.

Marketing Authorization Holder:

JSC CardioSistemPharma, Russia (JSC «CSP», Russia)

office 93, floor 5, 2a-1, Rabochaya St. Khimki, Moscow Region, 141401, Russia

Tel.: +7 (495) 925-30-74,

Fax: +7 (495) 626-97-80.

Send claims to:

iFarma LLC, Russia

121205, Moscow, g vn.ter.g. Mozhaisky Municipal District, ter of the Skolkovo Innovation Center, Bolshoy b-r, 40, floor/room. 3/XXXIII, office 77.

phone: +7 (495) 276-11-43,

sae@ipharma.ru

www.ipharma.ru, www.normacor.ru

Manufacturer (full cycle):

MOSFARM LLC, Russia

Legal Address:

141342, Moscow region, Sergiev Posad district, Bogorodskoye settlement, 63, letter B, room 32, floor 2.

Manufacturing site:

Moscow region, Sergiev Posad Municipal district, Bogorodskoye settlement, 63.