Refralon (Concentrate) Instructions for Use

Marketing Authorization Holder

Russian Cardiology Research and Production Complex of the Federal State Institution Rosmedtechnologies – Experimental Production of Medical and Biological Preparations (Russia)

ATC Code

C01BD (Class III antiarrhythmic agents)

Dosage Form

Refralon

Concentrate for solution for intravenous administration 1 mg/ml: 2 ml amp. 3, 5, 10 or 15 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for intravenous administration as a clear, slightly colored liquid.

Excipients: citric acid monohydrate 0.33 mg, sodium citrate dihydrate 6.49 mg, polysorbate 80 2 mg, water for injections up to 1 ml.

2 ml – ampoules (3) – contour cell packs (1) – cardboard cartons.
2 ml – ampoules (5) – contour cell packs (1) – cardboard cartons.
2 ml – ampoules (5) – contour cell packs (2) – cardboard cartons.
2 ml – ampoules (5) – contour cell packs (5) – cardboard cartons.

Clinical-Pharmacological Group

Antiarrhythmic drug

Pharmacotherapeutic Group

Antiarrhythmic agent

Pharmacological Action

The main mechanism of action of Refralon is the suppression of the delayed rectifier potassium outward current, which leads to the prolongation of the action potential repolarization phase and to the lengthening of the refractory periods of the heart fibers. It is the lengthening of the myocardial refractory periods that is the mechanism of the antiarrhythmic action of class III drugs. Refralon does not have a significant effect on sinus node automaticity, does not slow down the speed of impulse conduction through the cardiac conduction system, including in the atrioventricular node. The drug does not affect the PQ and QRS intervals in sinus-origin complexes. However, the drug’s action may be accompanied by a frequency-dependent impairment of intraventricular conduction in the form of aberrant ventricular complexes in response to premature atrial impulses. The main electrocardiographic manifestation of the drug’s action is the prolongation of the QT and QTc intervals. In some cases, the appearance of a U wave may be observed.

The antiarrhythmic effect (termination of arrhythmia) may develop immediately after the administration of the first dose of the drug, but it may be delayed relative to the time of administration of repeated doses. The duration of the QT(QTc) interval – the main indicator of the severity of the pharmacological effect of the drug and the control of its safety, begins to increase already during the solution infusion, and after its cessation reaches a maximum by 15 minutes from the start of infusion. After that, it changes little for a period from 1 hour to 6-7 hours depending on the total dose of the administered drug. Subsequently, the duration of the QT (QTc) interval gradually decreases, reaching normal values within a period of 3 to 24 hours depending on the dose and the individual patient’s response. In therapeutic doses, the drug does not affect blood pressure, does not have an adverse effect on the main systems and functions of the body. It does not cause allergic reactions, does not have mutagenic or teratogenic properties, is not carcinogenic and does not have embryotoxic effects.

Pharmacokinetics

Upon intravenous administration, Refralon rapidly disappears from the bloodstream with a distribution half-life of 5.13 min. The elimination half-life from the blood was 23.3 min. The drug very quickly penetrates into organs such as the liver, kidneys, and heart. No accumulation was observed in these organs. The elimination half-life of the drug from the organs was about 1 hour. The drug was not detected in brain tissues. When administered intravenously, the drug is excreted in the urine both unchanged and in the form of metabolites. The drug is absent in feces.

Data from the study of the drug’s metabolism show that its biotransformation proceeds via deethylation, reduction of the NO2 group to NH2 with subsequent acetylation.

Indications

• Termination of atrial fibrillation and flutter, including for pharmacological cardioversion of persistent (lasting more than 7 days) forms of these arrhythmias.

ICD codes

Dosage Regimen

For intravenous use only.

The administration of Refralon should be carried out in an intensive care unit setting with subsequent observation for 24 hours under continuous ECG monitoring for the timely detection of possible adverse events. Before the drug administration and after the administration of each of the sequential doses of the drug, it is necessary to record a 12-lead ECG to monitor heart rate, QRS, QT, QTc interval durations. Before use, Refralon must be diluted in 20 ml of 0.9% sodium chloride solution.

The drug administration is carried out in three consecutive stages

• administration at a dose of 10 mcg per 1 kg of body weight, intravenously over 2-3 minutes;

• if there is no effect (sinus rhythm has not been restored) after 15 minutes, repeated intravenous administration at a dose of 10 mcg per 1 kg of body weight (total drug dose 20 mcg/kg body weight);

• if there is no effect (sinus rhythm has not been restored) after 15 minutes, repeated intravenous administration at a dose of 10 mcg per 1 kg of body weight (maximum total drug dose 30 mcg/kg body weight).

Drug administration is stopped at any of the stages in case of

• restoration of sinus rhythm;

• decrease in heart rate < 50 beats/min;

• increase in QT interval duration > 500 ms;

• development of proarrhythmic effects.

Adverse Reactions

Cardiovascular system decrease in heart rate against the background of sinus rhythm less than 50 beats/min, increase in QT interval duration > 500 ms, appearance of ventricular heart rhythm disorders.

Laboratory parameters increased activity of aspartate aminotransferase and ALT.

During the drug administration, a “feeling of heat” may occur.

The patient should be warned to inform the doctor about any unusual sensations during the drug administration.

Contraindications

• Congenital or acquired prolongation of the QT interval on the surface ECG of more than 440 ms;
• Bradycardic form of atrial fibrillation or flutter with heart rate < 50 beats per minute or pauses > 3 sec, recorded on ECG or identified by the results of 24-hour Holter ECG monitoring;
• Sick sinus syndrome (sinus bradycardia, sinoatrial block), previously recorded against the background of sinus rhythm, except for cases of their correction by an artificial pacemaker;
• Atrioventricular block of II-III degree, bifascicular and trifascicular blocks in the absence of an artificial pacemaker;
• Hypokalemia, hypomagnesemia;
• Age under 18 years (efficacy and safety have not been studied);
• Acute coronary syndrome (efficacy and safety have not been studied);
• Decompensated or severe chronic heart failure (III-IV functional class according to NYHA classification) (efficacy and safety have not been studied);
• Bronchial asthma, severe respiratory failure (efficacy and safety have not been studied).

With caution

• In case of impaired liver function;
• In case of impaired renal function;
• In elderly patients.

Use in Pregnancy and Lactation

Due to the lack of necessary clinical data, the use of Refralon is not recommended during pregnancy.

Information on the excretion of the drug into breast milk is not available. If it is necessary to prescribe the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in case of impaired liver function.

Use in Renal Impairment

Use with caution in case of impaired renal function.

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Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

The administration of Refralon should be carried out in an intensive care unit setting with subsequent stay there for continuous ECG monitoring in order to timely detect possible ventricular arrhythmias and for dynamic measurement of the QT, QTc interval until these parameters normalize or for up to 24 hours. Before each administration and after the administration of each of the sequential doses of the drug, it is necessary to record a 12-lead ECG to monitor heart rate, QRS, QT, QTc interval durations.

It must be taken into account that in elderly individuals, patients with impaired renal and/or liver function, the risk of developing side effects and the likelihood of drug overdose are higher.

Effect on ability to drive vehicles and operate machinery

Information on the effect of the drug on the ability to drive vehicles and perform other potentially hazardous activities requiring increased attention and speed of psychomotor reactions is not available.

Overdose

Symptoms severe bradycardia (heart rate less than 50 beats/min), increase in QT interval duration > 500 ms, appearance of ventricular heart rhythm disorders may occur. The incidence of polymorphic ventricular tachycardia of the “torsades de pointes” type is 1.5%.

Treatment in case of a sustained paroxysm of “torsades de pointes” ventricular tachycardia, intravenous administration of magnesium salts or overdrive pacing is recommended; if necessary, electrical cardioversion should be performed. In case of severe bradycardia developing against the background of restored sinus rhythm, atropine administration is possible.

There is no specific antidote.

Drug Interactions

The combination of Refralon with drugs potentially capable of causing polymorphic ventricular tachycardia of the “torsades de pointes” type is contraindicated, including

• Antiarrhythmic drugs: Class IA (quinidine, hydroquinidine, disopyramide, procainamide), Class III (dofetilide, amiodarone, dronedarone, ibutilide, bretylium tosilate), sotalol;
• Other (non-antiarrhythmic) drugs such as bepridil, vincamine; some antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride, veralipride), butyrophenones (droperidol, haloperidol), sertindole, pimozide; tricyclic antidepressants; cisapride; macrolide antibiotics (erythromycin for intravenous administration, spiramycin); azoles; antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine); pentamidine for parenteral administration; difemanil methyl sulfate; mizolastine; astemizole; terfenadine; fluoroquinolones (e.g., moxifloxacin);

Due to the risk of developing bradycardia and conduction disorders, the administration of the drug is not recommended while taking beta-blockers, heart rate-lowering “slow” calcium channel blockers (verapamil, diltiazem), digoxin.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

Dispensed only for cardiology departments of medical and preventive institutions.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.