INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROPRANORM® (PROPANORM®)

Composition:

Active substance: propafenone;

1 ml of solution contains 3.5 mg of propafenone hydrochloride;

Excipients: glucose monohydrate, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution, practically free of particles.

Pharmacotherapeutic group.

Medicinal products for the treatment of heart diseases. Class IC antiarrhythmic agents. Propafenone.

ATC code C01B C03.

Pharmacological properties.

Pharmacodynamics.

Propafenone hydrochloride is an antiarrhythmic agent with membrane-stabilizing and sodium channel-blocking effects (Class IС according to the Vaughan-Williams classification). The drug also exerts a weak inhibitory effect on beta-receptors (Class II according to the Vaughan-Williams classification). Propafenone hydrochloride slows the upstroke of the action potential, thereby reducing the conduction velocity (negative dromotropic effect); the refractory period in the atria, atrioventricular node, and ventricles is prolonged under the influence of this substance.

Propafenone hydrochloride prolongs the refractory period of accessory pathways in patients with Wolff-Parkinson-White (WPW) syndrome.

Pharmacokinetics.

Propafenone is a racemic mixture of S- and R-propafenone.

Absorption

Propafenone hydrochloride undergoes extensive presystemic metabolism (via the CYP2D6 isoenzyme during first-pass hepatic metabolism), so its absolute bioavailability depends on the dose and route of administration. Although food increased the maximum plasma concentration and bioavailability in single-dose studies, food did not have a significant effect on bioavailability when multiple doses of propafenone hydrochloride were administered to healthy volunteers.

Distribution

Propafenone hydrochloride is rapidly distributed. The volume of distribution at steady state ranges from 1.9 to 3.0 L/kg. Protein binding to plasma proteins is independent of concentration in the range of 0.25 to 1.5 µg/mL and decreases from 97.3% at a concentration of 0.25 ng/mL to 81.3% at a concentration of 100 ng/mL. Propafenone binding is concentration-dependent at concentrations of 1.5 µg/mL and above.

Biotransformation and elimination

There are two genetically determined pathways of propafenone metabolism. In more than 90% of patients, the drug undergoes rapid metabolism with a half-life (T_1/2) ranging from 2 to 10 hours (extensive metabolizers). In these patients, metabolic conversion of propafenone leads to the formation of two active metabolites: 5-hydroxypropafenone, formed via CYP2D6, and N-depropylpropafenone (norpropafenone), formed via CYP3A4 and CYP1A2. In less than 10% of patients (poor metabolizers), metabolism of propafenone hydrochloride is slower, as 5-hydroxypropafenone is either not formed or formed only in minimal amounts. The expected half-life of propafenone hydrochloride in these patients ranges from 10 to 32 hours.

The clearance of propafenone hydrochloride ranges from 0.67 to 0.81 L/h/kg.

Since steady-state concentrations of propafenone hydrochloride are achieved within 3–4 days of drug administration, the recommended dosing regimen for oral administration of propafenone hydrochloride is the same for all patients, regardless of metabolic phenotype (i.e., both for poor and extensive metabolizers).

Linearity/non-linearity

The saturated metabolic pathway of hydroxylation (CYP2D6-dependent) in extensive metabolizers leads to non-linear pharmacokinetics of the drug. In poor metabolizers, the pharmacokinetics of propafenone are linear.

Inter- and intra-individual variability

The pharmacokinetics of propafenone hydrochloride are characterized by a high degree of individual variability, largely due to the first-pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. Due to the significant variability in drug plasma concentrations, doses should be carefully titrated, and clinical and electrocardiographic signs of toxicity should be closely monitored.

The therapeutic plasma concentration range is 100–1000 ng/mL.

Pregnancy and breastfeeding

It has been established that propafenone hydrochloride crosses the human placental barrier and is also excreted into breast milk.

Transfer to the fetus: two cases have been described in which the concentration of propafenone and its active metabolite 5-hydroxypropafenone in breast milk did not exceed 0.03–0.1% of the mother's daily oral dose after ingestion by the infant. Propafenone and 5-hydroxypropafenone were not detectable in breast milk 12 hours after a single oral dose of 150 mg propafenone. After intravenous administration, 5-hydroxypropafenone is often undetectable; therefore, it is highly unlikely that the propafenone metabolite enters breast milk in significant amounts after short-term propafenone infusion.

Elderly patients

The exposure level of propafenone hydrochloride in elderly patients with normal renal function was highly variable but did not differ from that observed in healthy young volunteers. Exposure to 5-hydroxypropafenone in elderly patients was similar, but exposure to propafenone glucuronides doubled.

Renal impairment

In patients with impaired renal function, exposure levels of propafenone hydrochloride and 5-hydroxypropafenone did not differ from those in healthy control volunteers, but accumulation of glucuronide metabolites was observed.

Propafenone hydrochloride should be administered with caution to patients with kidney disease.

Hepatic impairment

In patients with impaired liver function, the bioavailability of propafenone hydrochloride increases after oral administration, and the drug's T_1/2 is prolonged. Therefore, patients with liver disease require dose adjustment.

Pediatric population

The apparent clearance of propafenone hydrochloride after intravenous and oral administration in 13 infants and children aged 3 days to 7.5 years ranged from 0.13 to 2.98 L/h/kg, without a clear correlation with age. Steady-state concentrations of propafenone hydrochloride after oral administration of standard doses in 47 children aged 1 day to 10.3 years (median 2.2 months) were 45% higher in children over one year of age compared to children under one year of age. Despite significant inter-individual differences, ECG monitoring is more appropriate for dose adjustment than monitoring plasma concentrations of propafenone hydrochloride.

Clinical characteristics.

Indications.

Symptomatic conditions of tachycardia-related supraventricular arrhythmia requiring therapy, i.e. atrioventricular nodal tachycardia, supraventricular tachycardia in Wolff-Parkinson-White (WPW) syndrome, or paroxysmal atrial fibrillation.
Severe symptomatic ventricular tachyarrhythmia when the physician considers the condition life-threatening.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
History of Brugada syndrome (see section "Special precautions").
Severe structural heart diseases:
Myocardial infarction within the last 3 months;
Uncontrolled chronic heart failure with left ventricular ejection fraction less than 35%;
Cardiogenic shock, except shock caused by arrhythmia;
Severe symptomatic bradycardia;
Sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block, bundle branch block or intraventricular block in the absence of a cardiac pacemaker.
Severe arterial hypotension.
Manifest electrolyte imbalance (e.g. disturbances in potassium metabolism).
Severe obstructive bronchopulmonary disease.
Myasthenia gravis.
Concomitant use with ritonavir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Adverse reactions of propafenone hydrochloride may be potentiated when used in combination with local anesthetics (e.g. during pacemaker implantation, surgical procedures or dental interventions) or with other medicinal products that suppress heart rate and/or myocardial contractility (e.g. beta-blockers, tricyclic antidepressants).

Concomitant administration of propafenone hydrochloride and intravenous lidocaine has been associated with an increased risk of central nervous system adverse reactions due to lidocaine.

Concomitant use of propafenone hydrochloride with medicinal products metabolized by CYP2D6 (such as venlafaxine) may lead to increased concentrations of these drugs.

Increased plasma or blood concentrations of propranolol, metoprolol, desipramine, cyclosporine, theophylline, and digoxin have been reported when administered concomitantly with propafenone hydrochloride. If symptoms of overdose with these medicinal products occur, their plasma concentrations should be measured and doses adjusted accordingly.

Medicinal products that inhibit the activity of CYP2D6, CYP1A2, and CYP3A4 isoenzymes, such as ketoconazole, cimetidine, quinidine, erythromycin, and grapefruit juice, may lead to increased blood levels of propafenone hydrochloride. Careful monitoring of patients and appropriate dose adjustments are required when propafenone hydrochloride is used with inhibitors of these enzymes.

Concomitant administration of ritonavir at doses of 800–1200 mg/day and propafenone hydrochloride is contraindicated due to the risk of increased plasma concentrations (see section "Contraindications").

Combined therapy with amiodarone and propafenone hydrochloride may impair conduction, repolarization, and potentially cause proarrhythmic effects. Depending on the therapeutic response, dose adjustments of both medicinal products may be necessary.

Concomitant use of propafenone hydrochloride with phenobarbital and/or rifampicin (CYP3A4 inducers) may reduce the antiarrhythmic efficacy of propafenone hydrochloride due to decreased plasma concentration. Therefore, the therapeutic effect of propafenone hydrochloride should be monitored during long-term concomitant use with phenobarbital and/or rifampicin.

When propafenone hydrochloride is used concomitantly with oral anticoagulants (e.g. phenprocoumon, warfarin), blood coagulation should be closely monitored, as propafenone hydrochloride may increase the plasma concentration of these agents, thereby prolonging prothrombin time. Doses of these medicinal products should be adjusted as necessary.

Concomitant use of propafenone hydrochloride with selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and paroxetine, may result in increased plasma levels of propafenone hydrochloride. Concomitant administration of propafenone hydrochloride and fluoxetine in patients who are "rapid metabolizers" of S-propafenone increases the maximum concentration (Cmax) by 39% and the area under the concentration-time curve (AUC) by 50%, while in R-propafenone it increases Cmax by 71% and AUC by 50%. Lower doses of propafenone hydrochloride may be sufficient to achieve the desired therapeutic effect.

Pediatric population

Interaction studies have been conducted only in adults. It is unknown whether the range of interactions in pediatric patients is similar to that in adults.

Special precautions for use

Like other antiarrhythmic agents, propafenone hydrochloride may cause proarrhythmic effects; that is, it may induce a new arrhythmia or worsen an existing arrhythmia (see section "Adverse reactions").

Electrocardiographic (ECG) monitoring and regular clinical evaluations are required both before and during treatment to assess therapeutic response and to determine whether continued therapy is appropriate.

Particular caution and gradual dose escalation are required when initiating treatment in elderly patients and in patients with severe myocardial damage.

Propafenone hydrochloride may affect both the rhythm and the frequency threshold of pacemakers. Therefore, pacemaker function should be checked and, if necessary, the device reprogrammed.

There is a potential risk of conversion of paroxysmal atrial fibrillation into atrial flutter with 2:1 or 1:1 conduction, which may lead to an increase in ventricular rate (e.g., > 180 beats/min) (see section "Adverse reactions").

As with other class IС antiarrhythmic agents, patients with significant structural heart disease are at increased risk of serious adverse reactions. Propafenone hydrochloride is contraindicated in such patients (see section "Contraindications").

In previously asymptomatic carriers of Brugada syndrome genes, Brugada syndrome may be unmasked or ECG changes resembling Brugada syndrome may be provoked following administration of propafenone hydrochloride. An ECG should be performed after initiation of propafenone hydrochloride therapy to exclude ECG changes suggestive of Brugada syndrome.

Due to the beta-blocking effect of propafenone hydrochloride, caution should be exercised when treating patients with asthma.

Pediatric population

The injectable solution is not suitable for use in children due to its pharmaceutical form and high concentration.

Use during pregnancy or breastfeeding

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted. In a few limited cases, pregnancies and breastfeeding periods have proceeded without complications, and no clinical signs of abnormalities have been reported in newborns. Experimental animal studies have not revealed any prenatal or perinatal damage to offspring at clinically relevant doses. Propafenone hydrochloride crosses the placental barrier (see section "Pharmacokinetics"), and its concentration in umbilical cord blood is approximately 30% of the maternal plasma concentration. Therefore, propafenone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding

Limited data indicate that propafenone is excreted in breast milk in very low amounts following oral administration. Data on parenteral administration during breastfeeding are lacking. Therefore, caution should be exercised when prescribing propafenone to breastfeeding mothers, and the infant's heart rate should be monitored. During short-term parenteral administration, it is recommended, whenever possible, to maintain an interval between the last dose and the next breastfeeding (approximately 24 hours).

Ability to affect reaction speed when driving or operating machinery

Blurred vision, dizziness, fatigue, and postural hypotension may impair a patient's reaction speed. Even at the recommended dose, the drug Propafenone**®** may alter reaction times such that the ability to drive a car, operate machinery, or perform tasks requiring safe balance and coordination may be compromised. This is particularly relevant during the initial phase of treatment, during dose escalation, when switching to another medication, and when alcohol is consumed concurrently.

Dosage and Administration

Initiation of propafenone hydrochloride therapy in patients with ventricular rhythm disorders must be performed under strict cardiological supervision and only in the presence of equipment for emergency cardiac care and reliable monitoring. During treatment, regular monitoring examinations must be conducted (e.g., standard ECG once a month, or Holter monitoring every three months, or stress ECG if permissible). If any parameters deteriorate—for example, if the QRS complex or QT interval prolongs by more than 25%, the PR interval by more than 50%, or if the QT interval exceeds 500 ms—or if the frequency or severity of rhythm disturbances increases, therapy must be re-evaluated.

Dosage must be individually adjusted for each patient based on ECG and blood pressure monitoring. When infusions are used, careful monitoring of ECG (QRS complex, PR and QTc intervals) and cardiovascular parameters is required.

Single dose – 1 mg/kg body weight. The desired therapeutic effect is often achieved with a dose of 0.5 mg/kg. If necessary, the single dose may be increased to 2 mg/kg. Treatment should begin with the lowest dose, with careful patient observation and continuous ECG and blood pressure monitoring.

The drug must be administered immediately after dilution.

Elderly patients

In elderly patients, no significant differences in safety or efficacy have generally been observed, but increased sensitivity in some individuals cannot be ruled out; therefore, these patients should be under close supervision. This also applies to maintenance dosing. Any necessary dose increase should occur after 5–8 days of treatment.

Renal and/or hepatic impairment

In patients with impaired renal and/or hepatic function, accumulation of the active substance may occur when standard therapeutic doses are administered. In such patients, the initiation phase of propafenone hydrochloride titration may be started, but only under strict ECG and plasma level monitoring.

Propafenone hydrochloride should be administered to patients with renal impairment with particular caution.

Dosage in patients with hepatic impairment must be adjusted.

Administration method

Intravenous injections

Intravenous injections should be administered slowly over 3–5 minutes. The interval between individual injections should not be less than 90–120 minutes. If QRS complex widening or QT interval prolongation dependent on heart rate changes exceeding 20% is observed, intravenous administration of the drug must be immediately discontinued.

Short-term infusion

When administering propafenone hydrochloride via short-term infusion over 1–3 hours, the infusion rate should be 0.5–1 mg/min.

Slow intravenous infusion

When administering propafenone hydrochloride as a slow intravenous infusion, a maximum daily dose of 560 mg (corresponding to 160 mL of Propafenone®) is usually sufficient.

For infusion preparation, glucose 5% solution must be used. Due to the potential for precipitate formation, physiological saline is not suitable for preparing infusions.

The duration of intravenous treatment with Propafenone® in male patients should not exceed 7 days.

Children

The drug must not be used in children.

Overdose

Symptoms

Cardiac symptoms of overdose

Toxic effects of propafenone hydrochloride on the myocardium manifest as excitation and conduction disturbances, such as PQ interval prolongation, QRS widening, sinus node automaticity suppression, atrioventricular block, ventricular tachycardia, ventricular flutter, and ventricular fibrillation. Arterial hypotension may develop, which in severe cases may lead to cardiogenic shock.

Other signs of overdose

Overdose may present with headache, dizziness, visual disturbances, paresthesia, tremor, nausea, constipation, and dry mouth.

In severe poisoning, tonic-clonic seizures, paresthesia, somnolence, coma, respiratory arrest, and death may occur.

Treatment

In addition to general supportive measures, vital signs must be continuously monitored and appropriately managed in an intensive care unit.

Specific measures

Bradycardia: reduce the dose or discontinue the drug; if necessary, administer atropine.

SA block of grade II or III and AV block: atropine; orciprenaline; if necessary, cardiac pacing.

Intraventricular block (bundle branch block): reduce or discontinue the drug; if necessary, electrical therapy, as there is no safe antidote for class I antiarrhythmic-induced bundle branch block. If electrical pacing is not possible, attempts should be made to shorten the QRS duration by administering high doses of orciprenaline.

Heart failure with reduced blood pressure: discontinue the drug; administer cardiac glycosides; in case of pulmonary edema, high-dose nitroglycerin, diuretics, and if necessary, catecholamines (e.g., adrenaline and/or dopamine and dobutamine).

Measures required in severe poisoning (e.g., in suicide attempts): in cases of severe arterial hypotension and bradycardia (patients are usually unconscious): intravenous atropine 0.5–1 mg, intravenous adrenaline 0.5–1 mg, or if necessary, continuous intravenous infusion of adrenaline. The infusion rate depends on the clinical response.

In case of seizures: intravenous diazepam; ensure airway patency. Intubation if necessary and controlled ventilation with a muscle relaxant (e.g., 2–6 mg pancuronium).

Cardiac arrest due to asystole or ventricular fibrillation

General measures to restore cardiovascular and respiratory function (ABC protocol):
- Airway must be open or intubation must be performed.
- Breathing, preferably with supplemental oxygen.
- Circulation, e.g., cardiac massage (if necessary, for several hours).
- Adrenaline 0.5–1 mg intravenously or 1.5 mg diluted in 10 mL of physiological saline via endotracheal tube. Repeat as needed depending on clinical response.
- Intravenous 8.4% sodium bicarbonate solution at 1 mL/kg body weight. Repeat after 15 minutes. Defibrillation in case of ventricular fibrillation.

If therapy is ineffective, repeat after prior intravenous administration of 5–15 mval of potassium chloride solution.

Intravenous infusion of catecholamines (adrenaline and/or dopamine/dobutamine).
If indicated, intravenous infusion of concentrated (80–100 mval) sodium chloride solution until plasma sodium levels reach 145–150 mval/L.
- Intravenous dexamethasone 25–50 mg.
- Intravenous 40% sorbitol solution at 1 mL/kg body weight.
- Cardiac pacing.

Symptomatic intensive therapy.

Due to the high degree of propafenone hydrochloride binding to plasma proteins (>95%) and its large volume of distribution, hemodialysis is ineffective, and attempts to eliminate the drug from the body via hemoperfusion have limited efficacy.

Adverse Reactions

The most common and frequent adverse reactions associated with propafenone hydrochloride therapy are dizziness, cardiac conduction disturbances, and palpitations.

The following adverse reactions have been observed in clinical trials and following the post-marketing use of propafenone hydrochloride.

Adverse reactions associated with the use of propafenone hydrochloride are listed below by organ system class and frequency of occurrence:

Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon – thrombocytopenia; frequency not known – agranulocytosis, leukopenia, granulocytopenia.

Immune system disorders

Frequency not known – hypersensitivity (may manifest as cholestasis, blood dyscrasias, and rash).

Metabolism and nutrition disorders

Uncommon – decreased appetite.

Psychiatric disorders

Common – anxiety, sleep disturbances; uncommon – nightmares; frequency not known – confusion.

Nervous system disorders

Very common – dizziness (excluding vertigo); common – headache, dysgeusia; uncommon – syncope, ataxia, paraesthesia; frequency not known – seizure, extrapyramidal symptoms, restlessness.

Eye disorders

Common – blurred vision.

Ear and labyrinth disorders

Uncommon – vertigo.

Cardiac disorders

Very common – cardiac conduction disturbances (including sinoatrial, atrioventricular, and intraventricular block, most commonly manifesting as first-degree AV block, which is usually asymptomatic but may require monitoring and dose reduction to prevent higher-grade conduction block), palpitations; common – sinus bradycardia, bradycardia, tachycardia, atrial flutter; uncommon – ventricular tachycardia, arrhythmia (propafenone hydrochloride may be associated with proarrhythmic effects, presenting as increased heart rate (tachycardia) or ventricular fibrillation; some of these arrhythmias may be life-threatening and require resuscitation to prevent fatal outcomes); frequency not known – ventricular fibrillation, heart failure (pre-existing heart failure may be exacerbated), decreased heart rate.

Vascular disorders

Uncommon – arterial hypotension; frequency not known – orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders

Common – dyspnea.

Gastrointestinal disorders

Common – abdominal pain, vomiting, nausea, diarrhea, constipation, dry mouth; uncommon – abdominal distension, flatulence; frequency not known – belching, gastrointestinal disturbances.

Hepatobiliary disorders

Common – liver function abnormalities (this term includes abnormal liver function tests such as increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP)); frequency not known – hepatocellular injury, cholestasis, hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Uncommon – urticaria, pruritus, rash, erythema.

Frequency not known – acute generalized exanthematous pustulosis.

Musculoskeletal and connective tissue disorders

Frequency not known – syndrome resembling systemic lupus erythematosus.

Reproductive system and breast disorders

Uncommon – erectile dysfunction; frequency not known – decreased sperm count (this effect is reversible upon discontinuation of propafenone hydrochloride therapy).

General disorders and administration site conditions

Common – chest pain, asthenia, fatigue, fever.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging, out of reach of children. No special storage conditions required.

Incompatibilities.

The medicinal product Propamorm®, injection solution 3.5 mg/mL, should not be diluted with 0.9% sodium chloride solution (physiological saline) due to the potential for precipitate formation.

Packaging.

10 mL in a glass ampoule. 5 ampoules in transparent PVC blisters, 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder.

PRO.MED.CS Prague a.s. / PRO.MED.CS Prague a.s.

Manufacturer's address and place of business.

Telčská 377/1, Michle, Prague 4, 140 00, Czech Republic / Telčská 377/1, Michle, Prague 4, 140 00, Czech Republic.