Instructions for Propanorm film-coated tablets 150 mg No. 50
Composition
active ingredient: propafenone hydrochloride;
1 tablet contains propafenone hydrochloride 150 mg or 300 mg;
excipients: microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, corn starch, copovidone, magnesium stearate, opadry white 02 F 28310 (hypromellose, titanium dioxide (E 171), polyethylene glycol), simethicone emulsion.
Dosage form
Film-coated tablets.
Main physicochemical properties: almost white, film-coated, biconvex tablets, with a diameter of about 8 mm (150 mg tablets) and about 11 mm (300 mg tablets).
Pharmacotherapeutic group
Drugs for the treatment of heart diseases. Class IC antiarrhythmic drugs. ATC code C01B C03.
Pharmacological properties
Pharmacodynamics
Propafenone is a class IC antiarrhythmic agent.
It has a stabilizing effect on myocardial membranes, reduces the rapid inward current conducted by sodium ions, with a decrease in the rate of depolarization, and prolongs the impulse conduction time through the atrium, AV node, and mainly the His-Purkinje conduction system.
Impulse conduction through accessory pathways, as in WPW syndrome (Wolf-Parkinson-White syndrome), is inhibited by prolongation of the refractory period or blockade of the conduction pathway in both the antegrade and predominantly retrograde directions.
At the same time, spontaneous excitability is reduced due to an increase in the threshold of myocardial sensitivity, while electrical excitability of the myocardium is reduced due to an increase in the threshold of ventricular fibrillation.
Antiarrhythmic effects: slowing the rate of action potential growth, reducing excitability, homogenizing the conduction coefficient, suppressing ectopic automatism, reducing the tendency of the myocardium to fibrillation.
Propafenone has moderate beta-sympatholytic activity of no clinical significance. However, there is a possibility that high daily doses (900-1200 mg) may produce a sympatholytic (antiadrenergic) effect.
On the ECG, propafenone causes a slight prolongation of the P, PR, and QRS intervals, while the QTc interval generally remains unchanged.
In digitalized patients with an ejection fraction of 35-50%, left ventricular contractility is somewhat reduced. In patients with acute transmural infarction and heart failure, intravenous propafenone can markedly reduce left ventricular ejection fraction, but to a much lesser extent in patients with acute myocardial infarction without heart failure. In both cases, pulmonary artery pressure increases minimally. Peripheral arterial pressure does not show significant changes. This demonstrates that propafenone does not cause a clinically significant negative effect on left ventricular function. A clinically significant decrease in left ventricular function should be expected only in patients with pre-existing impaired ventricular function.
Therefore, untreated heart failure may further worsen with possible decompensation.
Pharmacokinetics
Propafenone is a racemic mixture of S- and R-propafenone.
Absorption
Peak plasma concentrations are reached 2–3 hours after administration of propafenone hydrochloride. Propafenone has been shown to undergo extensive saturable presystemic biotransformation (CYP2D6-dependent first-pass metabolism), as evidenced by the dose- and dosage form-dependent absolute bioavailability. Although food intake increased peak plasma concentrations and bioavailability in a single-dose study, food intake did not significantly alter bioavailability in multiple-dose studies in healthy volunteers.
Distribution
Propafenone is rapidly distributed. The volume of distribution at steady state is 1.9 to 3.0 l/kg. The extent of binding of propafenone to plasma proteins is concentration-dependent and decreases from 97.3% at a concentration of 0.25 ng/ml to 91.3% at 100 ng/ml.
Biotransformation and excretion
There are two genetically determined pathways for propafenone metabolism. In more than 90% of patients, the drug undergoes rapid and extensive metabolism with a half-life of 2 to 10 hours (extensive metabolizers). In such patients, the metabolic transformation of propafenone leads to the formation of two active metabolites: 5-hydroxypropafenone, formed by CYP2D6, and N-depropylpropafenone (norpropafenone), formed by CYP3A4 and CYP1A2. In less than 10% of patients (poor metabolizers), the metabolism of propafenone occurs more slowly, since the 5-hydroxy metabolite is not formed or is formed in minimal quantities. The estimated half-life of propafenone is
2–10 hours in extensive metabolizers and 10–32 hours in poor metabolizers. The clearance of propafenone is 0.67 to 0.81 L/h/kg.
Since the equilibrium concentration of propafenone hydrochloride is reached after 3–4 days of taking the drug, the recommended dosage regimen of propafenone is the same for all patients regardless of the type of metabolism (i.e. for both slow and fast metabolizers).
The saturable hydroxylation metabolic pathway (CYP2D6-dependent) in extensive metabolizers leads to nonlinear pharmacokinetics of the drug. In poor metabolizers, propafenone pharmacokinetics are linear.
Inter- and intra-individual variability
The pharmacokinetics of propafenone hydrochloride are characterized by a significant degree of individual variability, which is largely due to the first-pass effect through the liver and nonlinear pharmacokinetics in extensive metabolizers. Due to the significant variability in drug concentrations in the blood of patients, careful dose selection and careful monitoring of clinical and electrocardiographic indicators of toxicity are required.
Elderly patients
Propafenone exposure levels in elderly patients with normal renal function were highly variable and did not differ from those reported in healthy young volunteers. 5-hydroxypropafenone exposure in elderly patients was similar, but exposure levels of propafenone glucuronides were doubled.
Kidney dysfunction
In patients with renal impairment, exposure levels of propafenone and 5-hydroxypropafenone did not differ from those in healthy control subjects, but accumulation of the glucuronide metabolites of propafenone was observed. Propafenone hydrochloride should be administered with caution to patients with renal disease.
Liver dysfunction
In patients with impaired liver function, the oral bioavailability of propafenone is increased and the half-life of the drug is prolonged. Therefore, patients with liver disease require dose adjustment of the drug.
Indication
Prevention and treatment:
ventricular arrhythmias;
paroxysmal supraventricular tachyarrhythmias, including paroxysmal atrial flutter/fibrillation and paroxysmal torsades de pointes involving the AV node or accessory pathways, when standard therapy is ineffective or contraindicated.
Contraindication
Hypersensitivity to propafenone or to any other component of the drug.
Brugada syndrome has been identified (see "Special instructions").
A case of myocardial infarction in the last 3 months.
Significant organic heart disease, such as:
uncontrolled chronic heart failure (left ventricular ejection fraction < 35%);
cardiogenic shock (unless caused by arrhythmia).
Severe symptomatic bradycardia.
Uncontrolled electrolyte disturbances (e.g. potassium metabolism disorders).
Severe obstructive lung diseases.
Severe arterial hypotension.
Sinus node dysfunction, atrial conduction disorders, second-degree or higher AV block, bundle branch block, or distal block in the absence of an artificial pacemaker.
Concomitant use with ritonavir.
Myasthenia gravis.
Severe liver failure.
Interaction with other medicinal products and other types of interactions
The side effects of propafenone hydrochloride may be potentiated when used in combination with local anesthetics (e.g., during pacemaker implantation, surgery, or dental procedures) or with other agents that depress heart rate and/or myocardial contractility (e.g., beta-blockers, tricyclic antidepressants).
In a study of 8 healthy volunteers receiving propafenone and warfarin concomitantly, mean steady-state plasma concentrations of warfarin increased by 39% with a corresponding increase in prothrombin time of 25%. When propafenone is used concomitantly with oral anticoagulants (e.g. phenprocoumon, warfarin, acenocoumarol), blood coagulation should be closely monitored, as propafenone may enhance the efficacy of these drugs by increasing prothrombin time. The anticoagulant dose should be reduced accordingly if signs of overdose are observed.
Concomitant use of propafenone hydrochloride with drugs metabolized by CYP2D6 (such as venlafaxine) may result in increased concentrations of these drugs. Increased plasma or blood concentrations of propranolol, metoprolol, desipramine, cyclosporine, theophylline (with the development of theophylline toxicity) and digoxin have been reported when administered concomitantly with propafenone hydrochloride. The doses of these drugs should be reduced accordingly if signs of overdose are observed.
Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4, such as ketoconazole, cimetidine, quinidine, erythromycin and grapefruit juice, may increase propafenone hydrochloride blood levels. Patients should be closely monitored and the dose adjusted accordingly when propafenone hydrochloride is used with inhibitors of these enzymes.
No significant effect on the pharmacokinetics of propafenone or lidocaine was observed after their concomitant administration in patients. However, concomitant administration of propafenone hydrochloride and lidocaine has been reported to increase the risk of central nervous system adverse effects of lidocaine.
Phenobarbital is a known inducer of CYP3A4. During long-term combined use of phenobarbital, the clinical response to propafenone therapy should be monitored.
The combined use of propafenone hydrochloride and rifampicin may worsen the antiarrhythmic effect of propafenone due to a decrease in its concentration in the blood plasma (risk of sudden arrhythmias).
Increased plasma levels of propafenone may occur when it is administered concomitantly with selective serotonin reuptake inhibitors such as fluoxetine and paroxetine. Concomitant administration of propafenone hydrochloride and fluoxetine in extensive metabolisers increased the Cmax (maximum plasma concentration) and AUC (area under the pharmacokinetic curve) of S propafenone by 39% and 50%, respectively, and the Cmax and AUC of R propafenone by 71% and 50%. Lower doses of propafenone may be sufficient to achieve the desired therapeutic effect.
Propafenone should be used with caution with herbal preparations that modulate cytochrome P450, such as St. John's wort.
Application features
Cardiovascular system. It is important that each patient undergo electrocardiographic and clinical examination before starting and during therapy with PROPANORM® to determine the clinical effectiveness of treatment and the need for its continuation.
The weak negative inotropic effect of PROPANORM® may be of importance in patients at risk of developing heart failure.
Propafenone may unmask Brugada syndrome or cause ECG changes in asymptomatic individuals. An ECG should be performed after initiation of propafenone therapy to exclude changes suggestive of Brugada syndrome.
Propafenone hydrochloride may alter the excitation threshold and sensitivity of artificial pacemakers. In patients with pacemakers, the function of these devices should be checked and, if necessary, reprogrammed.
Potentially, paroxysmal atrial fibrillation may transition to atrial flutter, accompanied by 2:1 conduction block or 1:1 conduction (see Adverse Reactions).
Patients with significant organic heart disease may be predisposed to the development of serious adverse reactions, therefore propafenone hydrochloride is contraindicated in such patients (see "Contraindications").
Propafenone slows cardiac conduction, which can cause dose-dependent prolongation of the PR interval, QRS complex, development of first or higher degree atrioventricular block, bundle branch block or intraventricular conduction delay (see section "Adverse reactions").
Thus, if signs of increased cardiac conduction depression appear during treatment with PROPANORM®, the dose should be reduced or the drug should be discontinued.
Blood system. Infrequently, during the first 4-6 weeks of treatment with PROPANORM®, the development of agranulocytosis has been reported, manifested by symptoms such as fever, weakness, malaise, signs of infection. In the event of a decrease in the number of leukocytes in the blood or the appearance of signs and symptoms of agranulocytosis or granulocytopenia, treatment with PROPANORM® should be discontinued immediately. Blood cell recovery occurs within the next two weeks after discontinuation of the drug.
Hepatobiliary system.
Propafenone hydrochloride should be used with caution in patients with impaired liver function. The dose should be adjusted by monitoring the patient's condition with ECG and clinical observation. Elevated liver enzymes, hepatitis and cholestasis have also been observed (see section "Adverse reactions"). Cumulation of the drug may occur in patients with impaired liver function.
Immune system: In long-term studies, positive antinuclear antibody (ANA) titers and one case of lupus-like syndrome were reported in some patients receiving PROPANORM®. Therefore, discontinuation of therapy with the drug is recommended in patients who develop an abnormal ANA test result or an increase in ANA titer.
Kidneys. In patients with impaired renal function, cumulation of the drug may occur when prescribing standard therapeutic doses, therefore, PROPANORM® should be used with caution in patients with renal insufficiency.
Reproductive system: Some patients have experienced decreases in sperm count, follicle-stimulating hormone, and testosterone levels during clinical evaluation.
Other: Due to the beta-blocking effect of propafenone, caution should be exercised when treating patients with obstructive airway disease, such as asthma.
Use during pregnancy or breastfeeding
Animal studies have not shown teratogenic effects. There are no adequate and well-controlled studies of the use of this medicinal product during pregnancy, therefore PROPANORM® should be used during this period only if the potential benefit from use outweighs the possible risk to the fetus. Propafenone hydrochloride is known to cross the placental barrier in humans. It has been reported that the concentration of propafenone in cord blood was 30% of its concentration in maternal blood.
No studies have been conducted to investigate the excretion of propafenone hydrochloride in human milk. Some evidence suggests that propafenone may pass into human milk. Propafenone hydrochloride should be used with caution in nursing mothers.
Ability to influence reaction speed when driving vehicles or other mechanisms
It should be taken into account that sensitive patients may experience adverse reactions (blurred vision, dizziness, weakness, postural hypotension) when using the drug, which may affect the patient's reaction speed and impair his ability to drive vehicles or other mechanisms and perform work that requires concentration.
Method of administration and doses
PROPANORMOM® therapy is recommended to be initiated in a hospital setting and should be administered by a physician experienced in the treatment of arrhythmias. The individual maintenance dose should be determined under cardiological supervision, including ECG monitoring and blood pressure control.
If the QRS complex is prolonged by more than 20%, the dose should be reduced or the drug should be discontinued until the ECG returns to normal.
Due to the bitter taste and superficial anesthetic effect of propafenone, the tablets should be swallowed whole (without chewing) with liquid.
Administer to adults orally, at the beginning of treatment – 150 mg 3 times a day, increasing the dose with an interval of at least three days to 300 mg 2 times a day, and if necessary – to a maximum dose of 300 mg 3 times a day. For patients weighing less than 70 kg, it is recommended to prescribe smaller daily doses, individually.
Elderly people
Higher plasma concentrations of propafenone have been observed in elderly patients. Therefore, in these patients, a clinical response to treatment may be obtained with lower doses of the drug.
In elderly patients, no difference in safety or efficacy has been observed in general, but increased sensitivity in some individuals cannot be excluded, so such patients should be closely monitored. Any dose increase should be made after 5-8 days of treatment.
Impaired kidney and/or liver function
In patients with impaired renal and/or hepatic function, accumulation of the drug may occur at standard therapeutic doses. Therefore, the dose of propafenone should be selected in such patients, monitoring the patient's condition with ECG and clinical supervision.
Children
The drug is not used in children.
Overdose
Cardiac symptoms of overdose
The effect of propafenone hydrochloride overdose on the myocardium is manifested by disturbances in impulse generation and conduction, such as prolongation of the PQ, widening of the QRS complex, inhibition of sinus node automaticity, AV block, ventricular tachycardia, ventricular flutter/fibrillation. A decrease in cardiac contractility (negative inotropic effect) can cause arterial hypotension, which in severe cases can lead to cardiovascular shock.
Non-cardiac symptoms of overdose
Headache, dizziness, blurred vision, paresthesia, tremor, nausea, constipation and dry mouth are common. In very rare cases, convulsions have been reported in cases of overdose. There has also been a report of a fatal case.
In case of severe poisoning, clonic-tonic seizures, paresthesias, drowsiness, coma, and respiratory arrest may develop.
Treatment
Due to the high degree of binding to blood proteins (>95%) and the large volume of distribution, hemodialysis is ineffective, and attempts at elimination by hemoperfusion are ineffective.
In addition to applying general emergency measures, it is necessary to monitor the patient's vital signs in the intensive care unit, and if necessary, correct them.
Defibrillation and infusion of dopamine and isoproterenol are effective measures to control rhythm and blood pressure. Intravenous diazepam is used to relieve seizures.
General supportive measures, such as mechanical ventilation and chest compressions, may be necessary.
Adverse reactions
The most frequent and widespread adverse reactions associated with propafenone therapy are dizziness, cardiac conduction disturbances, and palpitations.
Adverse reactions at least probably related to
propafenone, listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), frequency unknown (adverse reactions from post-marketing surveillance; frequency cannot be estimated from the available data).
From the blood and lymphatic system.
Uncommon: thrombocytopenia; frequency unknown: agranulocytosis, leukopenia, granulocytopenia, anemia, hematomas, purpura, increased bleeding time.
From the immune system.
Uncommon: allergic reactions, positive ANA titer; frequency unknown: hypersensitivity (which may manifest as cholestasis, blood abnormalities and rash).
From the side of metabolism and nutrition.
Uncommon: decreased appetite.
From the psychological side.
Often - anxiety, sleep disturbances; infrequently - nightmares; with an unknown frequency - confusion.
From the nervous system.
Very common - dizziness (except vertigo); common - headache, dysgeusia, insomnia, drowsiness; uncommon - syncope, ataxia, paresthesia, speech disorder, depression, memory loss, numbness, paresthesia, psychosis, mania, tinnitus, abnormal sense of smell; frequency unknown - restlessness, extrapyramidal symptoms, convulsions, apnea, coma.
From the organs of vision.
Common: blurred vision; uncommon: eye irritation.
From the side of the organs of hearing and labyrinth.
Uncommon: vertigo.
From the heart.
Very common - cardiac conduction disorders (including sinoatrial, atrioventricular and intraventricular block), palpitations; common - sinus bradycardia, bradycardia, tachycardia, atrial flutter, angina pectoris, QRS prolongation, ventricular premature contraction, edema, interventricular block; uncommon - ventricular tachycardia, arrhythmia (propafenone may be associated with proarrhythmic effects, manifested by increased heart rate (tachycardia) or ventricular fibrillation; some of these arrhythmias may be life-threatening and require resuscitation measures), AV dissociation, cardiac arrest, flushing, feeling of heat, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia, torsades de pointes; frequency unknown - ventricular fibrillation, heart failure (pre-existing heart failure may worsen), decreased heart rate.
From the side of the vessels.
Uncommon: hypotension; frequency unknown: orthostatic hypotension.
On the part of the respiratory system, chest organs and mediastinum.
Often – dyspnoea.
From the gastrointestinal tract.
Common: abdominal pain, vomiting, nausea, diarrhea, constipation, dry mouth, taste disturbance, dyspepsia, anorexia; uncommon: abdominal distension, flatulence, gastroenteritis; frequency unknown: nausea, gastrointestinal disorders.
On the part of the hepatobiliary system.
Common: Liver dysfunction (this term includes increased AST, ALT, GGT and blood alkaline phosphatase); frequency unknown: hepatocellular damage, cholestasis, hepatitis and jaundice.
On the skin and subcutaneous tissue.
Uncommon: urticaria, itching, rash, redness of the skin.
Musculoskeletal and connective tissue.
Common: joint pain; uncommon: muscle cramps, muscle weakness; frequency unknown: lupus-like syndrome.
Disorders of the reproductive system and mammary glands.
Uncommon: erectile dysfunction; frequency unknown: decreased sperm count (this phenomenon is reversible upon discontinuation of propafenone therapy).
From the urinary system and kidneys.
Uncommon: nephrotic syndrome; unknown frequency: renal failure.
General violations.
Common: chest pain, weakness, fatigue, fever, increased sweating; uncommon: alopecia; increased blood glucose levels, pain; frequency unknown: hyponatremia, impaired ADH secretion.
Expiration date
3 years.
Storage conditions
Store out of the reach of children at a temperature not exceeding 25 °C.
Packaging
150 mg tablets: 10 tablets in a blister, 5 blisters in a cardboard box.
300 mg tablets: 10 tablets in a blister, 5 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
PRO.MED.CS Praha a.t. / PRO.MED.CS Prahа as
Location of the manufacturer and address of its place of business
Telčska 1, 140 00 Prague 4, Czech Republic.
