Ritmonorm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RYTHMONORM® (RYTMONORM®)

Composition:

Active substance: propafenone hydrochloride;

1 tablet contains propafenone hydrochloride 150 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, corn starch, hypromellose, magnesium stearate, purified water, polyethylene glycol 400, polyethylene glycol 6000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white to almost white, biconvex, with "150" embossed on one side.

Pharmacotherapeutic group. Drugs for the treatment of heart diseases. Antiarrhythmic agents of class IC. Propafenone. ATC code C01BC03.

Pharmacological properties.

Pharmacodynamics.

Propafenone is a class IC antiarrhythmic agent.

It exerts a stabilizing effect on myocardial membranes, reduces the fast inward current carried by sodium ions, decreases the rate of depolarization, and prolongs impulse conduction through the atria, AV node, and primarily through the His–Purkinje conduction system.

Conduction through accessory pathways, as seen in WPW syndrome (Wolff–Parkinson–White syndrome), is suppressed due to prolongation of the refractory period or blockage of the conducting pathway in both anterograde and predominantly retrograde directions.

Additionally, spontaneous excitability is reduced due to an increased threshold of myocardial sensitivity, while electrical excitability of the myocardium is decreased by raising the ventricular fibrillation threshold.

Antiarrhythmic effects include slowing of the rate of rise of the action potential, reduced excitability, homogenization of the conduction coefficient, suppression of ectopic automaticity, and decreased myocardial susceptibility to fibrillation.

Propafenone has mild beta-sympatholytic activity without clinical significance. However, high daily doses (900–1200 mg) may potentially cause a sympatholytic (antiadrenergic) effect.

On the ECG, propafenone causes slight prolongation of the P, PR, and QRS intervals, while the QTc interval usually remains unchanged.

In digitalized patients with a left ventricular ejection fraction of 35–50%, left ventricular contractility is slightly reduced. In patients with acute transmural myocardial infarction and heart failure, intravenous administration of propafenone may significantly reduce the left ventricular ejection fraction, although this effect is considerably less pronounced in patients with acute myocardial infarction not associated with heart failure. In both cases, pulmonary artery pressure increases minimally. Peripheral arterial pressure shows no significant changes. This demonstrates that propafenone does not cause clinically significant negative effects on left ventricular function. Clinically significant reduction in left ventricular function is expected only in patients with pre-existing impaired ventricular function.

Therefore, untreated heart failure may progressively worsen, potentially leading to decompensation.

Pharmacokinetics.

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

Absorption

Maximum plasma concentration is reached within 2–3 hours after administration of propafenone hydrochloride. Propafenone undergoes extensive, dose- and formulation-dependent presystemic biotransformation (CYP2D6-dependent first-pass hepatic effect), resulting in dose- and formulation-dependent absolute bioavailability. Although in a single-dose study food intake increased the maximum plasma concentration and bioavailability of the drug, repeated dosing in healthy volunteers showed that food intake did not cause significant changes in bioavailability.

Distribution

Propafenone is rapidly distributed. The steady-state volume of distribution ranges from 1.9 to 3.0 L/kg. The extent of propafenone binding to plasma proteins depends on its concentration and decreases from 97.3% at a concentration of 0.25 µg/mL to 81.3% at 100 µg/mL.

Biotransformation and elimination

There are two genetically determined metabolic pathways for propafenone. In more than 90% of patients, the drug undergoes rapid and extensive metabolism, with a half-life ranging from 2 to 10 hours (extensive metabolizers). In these patients, metabolic transformation 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), propafenone metabolism is slower, with little or no formation of the 5-hydroxy metabolite. The calculated elimination half-life of propafenone is 2–10 hours in extensive metabolizers and 10–32 hours in poor metabolizers. Propafenone clearance ranges from 0.67 to 0.81 L/h/kg.

Since steady-state concentration of propafenone hydrochloride is achieved within 3–4 days of treatment, the recommended dosing regimen for propafenone is the same for all patients, regardless of metabolic type (i.e., both poor and extensive metabolizers).

Linearity/non-linearity

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

Inter- and intra-individual variability

Propafenone hydrochloride pharmacokinetics are characterized by considerable individual variability, largely due to the first-pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. The wide variability in drug plasma concentrations among patients necessitates careful dose titration, with close monitoring of clinical and electrocardiographic signs of toxicity.

Elderly patients

Propafenone exposure levels in elderly patients with normal renal function were highly variable but did not significantly differ from those observed in healthy young volunteers. Exposure to 5-hydroxypropafenone was similar in elderly patients, but exposure to propafenone glucuronides doubled.

Renal impairment

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

Hepatic impairment

In patients with impaired liver function, oral bioavailability of propafenone is increased and the drug's elimination half-life is prolonged. Therefore, dose adjustment is required in patients with hepatic disease.

Clinical characteristics.

Indications.

Prevention and treatment of:

• ventricular arrhythmias;
• paroxysmal supraventricular tachyarrhythmias, including paroxysmal atrial flutter/fibrillation and paroxysmal re-entry tachycardias involving the AV node or accessory conduction pathways, when standard therapy is ineffective or contraindicated.

Contraindications.

• Hypersensitivity to propafenone hydrochloride or to any other component of the medicinal product listed in the section "Composition".

• Diagnosed Brugada syndrome (see "Special precautions").

• Myocardial infarction within the last 3 months.

• Significant organic heart disease, such as:

• uncontrolled congestive heart failure (left ventricular ejection fraction < 35%);

• cardiogenic shock (if not caused by arrhythmia);

• severe symptomatic bradycardia;

• sinus node dysfunction, atrial conduction disturbances, second-degree or higher AV block, bundle branch block or distal block in the absence of a pacemaker;

• severe arterial hypotension.

• Manifest electrolyte disturbances (e.g. disturbances in potassium metabolism).

• Severe obstructive lung diseases.

• Concomitant use with ritonavir.

• Myasthenia gravis.

• Severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Adverse effects of propafenone hydrochloride may be potentiated when used concomitantly with local anesthetics (e.g. during pacemaker implantation, surgery, or dental procedures) or with other agents that suppress heart rate and/or myocardial contractility (e.g. beta-blockers, tricyclic antidepressants).

In a study involving 8 healthy volunteers who received propafenone and warfarin concomitantly, mean steady-state plasma concentrations of warfarin increased by 39%, with a corresponding 25% increase in prothrombin time. When propafenone is used concomitantly with oral anticoagulants (e.g. phenprocoumon, warfarin, acenocoumarol), blood coagulation parameters must be closely monitored, as propafenone may enhance the effects of these agents, increasing prothrombin time. Anticoagulant doses should be appropriately reduced if signs of overdose occur.

Concomitant use of propafenone hydrochloride with medicinal products metabolized by CYP2D6 (such as venlafaxine) may lead to increased concentrations of these agents. Increased plasma or blood concentrations of propranolol, metoprolol, desipramine, cyclosporine, theophylline (with development of theophylline toxicity), and digoxin have been reported when administered concomitantly with propafenone hydrochloride. Doses of these medicinal products should be appropriately reduced if signs of overdose occur.

Medicinal products that inhibit CYP2D6, CYP1A2, and CYP3A4, such as ketoconazole, cimetidine, quinidine, erythromycin, and grapefruit juice, may lead to increased blood levels of propafenone hydrochloride. Patients receiving propafenone hydrochloride with inhibitors of these enzymes should be closely monitored and the dose adjusted accordingly.

Combined therapy with amiodarone and propafenone hydrochloride may impair conduction and repolarization and lead to disturbances that are potentially proarrhythmic. Depending on the therapeutic effect, dose adjustment of both agents may be required.

No significant effect on the pharmacokinetics of propafenone or lidocaine has been observed after their concomitant administration to patients. However, concomitant use of propafenone hydrochloride and lidocaine has been reported to increase the risk of lidocaine-related central nervous system adverse effects.

Phenobarbital is a known inducer of CYP3A4. During prolonged concomitant use of phenobarbital, clinical response to propafenone therapy should be monitored.

Concomitant use of propafenone hydrochloride and rifampicin may reduce the antiarrhythmic effect of propafenone due to decreased plasma concentrations (risk of sudden arrhythmias).

Increased plasma levels of propafenone may occur when used concomitantly with selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and paroxetine. Concomitant use of propafenone hydrochloride and fluoxetine in extensive metabolizers increased Cmax (maximum plasma concentration) and AUC (area under the pharmacokinetic curve) of S-propafenone by 39% and 50%, respectively, and Cmax and AUC of R-propafenone by 71% and 50%, respectively. Lower doses of propafenone may be sufficient to achieve the desired therapeutic effect.

Propafenone should be used with caution concomitantly with herbal products that modulate cytochrome P450, such as St. John's wort.

Special precautions for use.

Cardiovascular system. Propafenone, like other antiarrhythmic agents, may cause proarrhythmic effects; that is, it may induce new arrhythmias or worsen existing ones (see "Side effects"). It is important that each patient undergoes electrocardiographic and clinical evaluation before and during therapy with propafenone hydrochloride to determine the clinical efficacy of treatment and the need for its continuation.

The weak negative inotropic effect of propafenone hydrochloride may be significant in patients at risk of developing heart failure.

Propafenone may unmask Brugada syndrome or induce Brugada-type ECG changes in individuals with asymptomatic manifestations of this syndrome. An ECG should be performed after initiation of propafenone therapy to exclude changes indicative of Brugada syndrome.

Propafenone hydrochloride may alter the stimulation threshold and sensing function of implanted cardiac pacemakers. In patients with pacemakers, device function should be checked and, if necessary, reprogrammed.

There is a potential risk of conversion of paroxysmal atrial fibrillation into atrial flutter with 2:1 block or 1:1 conduction (see "Side effects").

As with other class IC antiarrhythmic agents, patients with significant organic heart disease may be predisposed to serious adverse reactions. Therefore, propafenone hydrochloride is contraindicated in such patients (see "Contraindications").

Propafenone slows cardiac conduction, which may cause dose-dependent prolongation of the PR interval and QRS complex, development of first-degree or higher atrioventricular block, bundle branch block, or intraventricular conduction delay (see section "Side effects"). Therefore, if signs of increased depression of cardiac conduction occur during treatment with propafenone, the dose should be reduced or the drug discontinued.

Blood system. Rarely, during the first 4–6 weeks of treatment with propafenone, agranulocytosis has been reported, presenting with symptoms such as fever, weakness, malaise, and signs of infection. If leukopenia occurs or symptoms and signs of agranulocytosis or granulocytopenia appear, propafenone treatment must be stopped immediately. Recovery of blood cells usually occurs within the following two weeks after discontinuation of the drug.

Hepatobiliary system. Propafenone hydrochloride should be used with caution in patients with hepatic impairment. Dose adjustment should be performed under ECG monitoring and clinical observation. Elevations in liver enzymes, hepatitis, and cholestasis have also been observed (see section "Side effects"). Drug accumulation is possible in patients with impaired liver function.

Immune system. During long-term studies, positive titers of antinuclear antibodies (ANA) have been observed in some patients receiving propafenone, and one case of lupus-like syndrome has been reported. Therefore, patients who test positive for ANA or show increased ANA titers should discontinue therapy with the drug.

Kidneys. In patients with impaired renal function, drug accumulation may occur when standard therapeutic doses are administered; therefore, propafenone should be used with caution in patients with renal insufficiency.

Reproductive system. In some patients during clinical evaluation, decreased sperm count, and reduced levels of follicle-stimulating hormone and testosterone have been observed.

Other. Due to the beta-blocking effect of propafenone, caution should be exercised when treating patients with obstructive respiratory diseases, such as asthma.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown teratogenic effects. Adequate and well-controlled studies on the use of this medicinal product during pregnancy are lacking; therefore, Rythmonorm**®** should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is known that propafenone hydrochloride crosses the human placental barrier. Propafenone concentrations in umbilical cord blood have been reported to be 30% of maternal plasma concentrations.

Breastfeeding. Studies on the excretion of propafenone hydrochloride into human breast milk have not been conducted. Limited data indicate that propafenone may pass into human breast milk. Propafenone hydrochloride should be used with caution in breastfeeding women.

Ability to affect reaction speed when driving or operating machinery.

It should be considered that in sensitive patients, side effects (blurred vision, dizziness, weakness, postural hypotension) may occur during treatment, which could affect the patient's reaction speed and impair the ability to drive vehicles or operate machinery, as well as perform tasks requiring concentration.

Administration and Dosage

Initiation of therapy with Rhythmonorm**®** is recommended under hospital conditions and should be managed by a physician experienced in the treatment of arrhythmias. The individual maintenance dose should be determined under continuous cardiac monitoring, including ECG surveillance and blood pressure control. If the QRS complex prolongs by more than 20%, the dose should be reduced or administration temporarily discontinued until ECG parameters return to normal.

Due to the bitter taste and local anesthetic effect of propafenone, tablets should be swallowed whole (without chewing) with liquid.

Administer orally to adults. At the beginning of treatment: 150 mg three times daily, increasing the dose with intervals of at least three days to 300 mg twice daily, and, if necessary, up to the maximum dose of 300 mg three times daily. Dose escalation should not occur earlier than 3–4 days after initiation of treatment. For patients with body weight less than 70 kg, lower than usual daily doses are recommended, individualized according to clinical response.

Geriatric Patients

Higher plasma concentrations of propafenone have been observed in elderly patients. Therefore, a clinical response may be achieved at lower doses in this population.

Overall, no significant differences in safety or efficacy have been observed in elderly patients; however, increased sensitivity in some individuals cannot be excluded. Thus, these patients should be closely monitored, including during maintenance therapy. Any necessary dose increase should be performed after 5–8 days of treatment.

Renal and/or Hepatic Impairment

In patients with impaired renal and/or hepatic function, accumulation of the drug may occur when standard therapeutic doses are administered. Therefore, propafenone dosage in such patients should be adjusted under ECG monitoring and clinical supervision.

Children

Rhythmonorm**®** 150 mg tablets are not recommended for use in children.

Overdose

Cardiac symptoms of overdose

The effects of propafenone hydrochloride overdose on the myocardium may manifest as disturbances in impulse generation and conduction, including PQ prolongation, widening of the QRS complex, suppression of sinus node automaticity, AV block, ventricular tachycardia, ventricular flutter/fibrillation, and cardiac arrest. Decreased myocardial contractility (negative inotropic effect) may lead to arterial hypotension, which in severe cases may result in cardiogenic shock.

Non-cardiac signs and symptoms of overdose

Metabolic acidosis, headache, dizziness, blurred vision, paresthesia, tremor, nausea, constipation, dry mouth, and seizures have been reported in cases of overdose. A fatal case has also been reported.

In cases of severe poisoning, clonic-tonic seizures, paresthesia, somnolence, coma, and respiratory arrest may develop.

Treatment

Due to the high degree of plasma protein binding (>95%) and large volume of distribution, hemodialysis is ineffective; attempts at elimination via hemoperfusion are poorly effective.

In addition to general supportive measures, vital functions should be monitored and, if necessary, corrected in an intensive care setting.

Effective interventions for controlling rhythm and blood pressure include defibrillation and infusion of dopamine and isoproterenol. Intravenous diazepam may be administered to control seizures.

General supportive measures such as mechanical ventilation and external cardiac massage may also be required.

Adverse Reactions

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

Listed below are adverse reactions observed in at least one of 885 patients who received sustained-release propafenone hydrochloride in five Phase II and two Phase III clinical studies. Adverse reactions and their frequencies for immediate-release formulations are expected to be similar. The reactions listed below also include those reported from post-marketing experience with propafenone. Adverse reactions considered at least possibly related to propafenone are listed by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and frequency not known (reactions from post-marketing surveillance; frequency cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon – thrombocytopenia; frequency not known – agranulocytosis, leukopenia, granulocytopenia, anemia, hematomas, purpura, prolonged bleeding time.

Immune system disorders

Uncommon – allergic reactions, positive ANA titer; frequency not known – hypersensitivity (which 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, insomnia, somnolence; uncommon – syncope, ataxia, paresthesia, speech disorder, depression, memory impairment, numbness, paresthesias, psychosis, mania, tinnitus, abnormal sense of smell; frequency not known – seizures, extrapyramidal symptoms, restlessness, apnea, coma.

Eye disorders

Common – blurred vision; uncommon – eye irritation.

Ear and labyrinth disorders

Uncommon – vertigo.

Cardiac disorders

Very common – disturbances in cardiac conduction (including sinoatrial, atrioventricular, and intraventricular block), palpitations; common – sinus bradycardia, bradycardia, tachycardia, atrial flutter, angina, increased QRS duration, premature ventricular contractions, edema, interventricular block; uncommon – ventricular tachycardia, arrhythmia (propafenone may be associated with proarrhythmic effects, manifesting as increased heart rate (tachycardia) or ventricular fibrillation; some of these arrhythmias may be life-threatening and require resuscitation to prevent possible fatal outcome), AV dissociation, cardiac arrest, flushing, hot sensation, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia, torsades de pointes; frequency not known – ventricular fibrillation, heart failure (existing heart failure may worsen), 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, taste disturbances, dyspepsia, anorexia; uncommon – abdominal distension, flatulence, gastroenteritis; frequency not known – urge to vomit, gastrointestinal disorders.

Hepatobiliary disorders

Common – liver function abnormalities (this term includes elevated levels of AST, ALT, GGT, and alkaline phosphatase in blood); 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 (AGEP).

Musculoskeletal and connective tissue disorders

Common – arthralgia; uncommon – muscle cramps, muscle weakness; frequency not known – lupus-like syndrome.

Reproductive system and breast disorders

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

Renal and urinary disorders

Uncommon – nephrotic syndrome; frequency not known – renal failure.

General disorders

Common – chest pain, weakness, fatigue, fever, increased sweating; uncommon – alopecia, increased blood glucose, pain; frequency not known – hyponatremia, impaired ADH secretion.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister pack, 5 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. AbbVie Deutschland GmbH & Co. KG, Germany or Benta Lyon, France.

Manufacturer's address and place of business. Knollstrasse, 67061 Ludwigshafen, Germany or 29 avenue Charles de Gaulle, Saint Genis Laval, 69230, France.