Instructions for Ritmonorm film-coated tablets 150 mg No. 50
Composition
active ingredient: propafenone hydrochloride;
1 tablet contains propafenone hydrochloride 150 mg;
Excipients: microcrystalline cellulose, croscarmellose sodium, corn starch, hypromellose, magnesium stearate, purified water, macrogol 400, macrogol 6000, titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, white to off-white, biconvex, embossed with "150" on one side. Diameter – 9.0-9.4 mm, thickness – 3.7-4.6 mm.
Pharmacotherapeutic group
Drugs for the treatment of heart diseases. Class IS antiarrhythmic drugs. ATC code C01B C03.
Pharmacological properties
Pharmacodynamics.
Propafenone is a class IA antiarrhythmic drug.
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 through the His-Purkinje conduction system.
Impulse conduction through accessory pathways, as in WPW syndrome (Wolf-Parkinson-White syndrome), is inhibited due to 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 susceptibility 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 continue to 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 amounts. 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 interindividual variability, largely due to the first-pass effect and nonlinear pharmacokinetics in extensive metabolizers. The significant variability in blood concentrations of the drug in patients requires careful dose selection, during which it is necessary to closely monitor clinical and electrocardiographic manifestations of toxicity.
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 listed in the "Composition" section.
Brugada syndrome has been identified (see "Special instructions").
A history of myocardial infarction within the last 3 months. Significant organic heart disease, such as:
uncontrolled chronic heart failure (left ventricular ejection fraction
ventricle < 35%);
cardiogenic shock (unless caused by arrhythmia).
Severe symptomatic bradycardia. Uncontrolled electrolyte disturbances (e.g. potassium metabolism disorders). Severe obstructive pulmonary disease. Severe arterial hypotension. Sinus node dysfunction, atrial conduction disorders, second or higher degree AV block, bundle branch block or distal block in the absence of an artificial pacemaker. Concomitant use with ritonavir. Myasthenia gravis. Severe hepatic insufficiency.
Interaction with other medicinal products and other types of interactions
The side effects of Ritmonorm® 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 with an increase in 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 used concomitantly with Ritmonorm®. 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 Ritmonorm® to determine the clinical effectiveness of treatment and the need for its continuation.
The weak negative inotropic effect of Ritmonorm® may be of importance in patients at risk of developing heart failure.
Propafenone may unmask Brugada syndrome or induce Brugada-like 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.
There is a potential for paroxysmal atrial fibrillation to transition to atrial flutter, accompanied by 2:1 conduction block or 1:1 conduction (see Adverse Reactions).
As with other class IC antiarrhythmics, patients with significant organic heart disease may be more likely to develop serious adverse reactions, and 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 Ritmonorm®, the dose should be reduced or the drug should be discontinued.
Blood system. Infrequently, during the first 4-6 weeks of treatment with Ritmonorm®, 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 Ritmonorm® 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 selected under ECG control and clinical supervision. Increased levels of liver enzymes in the blood, hepatitis and cholestasis have also been observed (see section "Adverse reactions"). Cumulation of the drug may occur in cases of 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 Ritmonorm®. 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 standard therapeutic doses are administered, therefore, Ritmonorm® 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 Ritmonorm® 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. Limited data suggest 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
It is recommended that Ritmonorm® therapy 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 dose 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 with an increase in dose at least at three-day intervals 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 daily doses smaller than usual, 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, and such patients should be closely monitored. The same applies to the maintenance dose. Any necessary 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 in such patients should be selected under ECG control and clinical supervision.
Children.
Ritmonorm® 150 mg tablets are not for use 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 protein binding (>95%) and large volume of distribution, hemodialysis is ineffective; 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 cardiopulmonary resuscitation may be necessary.
Adverse reactions
The following adverse reactions have been reported in at least one of 885 patients treated with propafenone hydrochloride extended-release in five phase II and two phase III clinical trials. The adverse reactions and their frequency for the immediate-release formulations are expected to be similar. The following reactions also include adverse reactions from post-marketing experience with propafenone.
Adverse reactions at least possibly related to propafenone are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100) and not known (adverse reactions from post-marketing surveillance; frequency cannot be estimated from the available data).
From the blood and lymphatic system.
Uncommon: thrombocytopenia; unknown frequency: agranulocytosis, leukopenia, granulocytopenia, anemia, hematomas, purpura, increased bleeding time.
From the immune system.
Uncommon: allergic reactions, positive ANA titer; unknown frequency: 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 an increase in heart rate (tachycardia) or ventricular fibrillation; some of these arrhythmias may be life-threatening and require resuscitation measures to prevent a possible fatal outcome), AV dissociation, cardiac arrest, flushing, feeling of heat, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia, torsades de pointes; with an unknown frequency - ventricular fibrillation, heart failure (pre-existing heart failure may worsen), decreased heart rate.
From the side of the vessels.
Uncommon: hypotension; unknown frequency: orthostatic hypotension.
On the part of the respiratory system, chest organs and mediastinum.
Often – dyspnoea.
From the gastrointestinal tract.
Often - abdominal pain, vomiting, nausea, diarrhea, constipation, dry mouth, taste disturbance, dyspepsia, anorexia; infrequently - bloating, flatulence, gastroenteritis; with an unknown frequency - vomiting, gastrointestinal disorders.
On the part of the hepatobiliary system.
Common: Liver dysfunction (this term includes increased AST, ALT, GGT and alkaline phosphatase in the blood); 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; not known: 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.
Often - chest pain, weakness, fatigue, fever, increased sweating; infrequently - alopecia; increased blood glucose levels, pain; with an unknown frequency - 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
10 tablets in a blister, 5 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
AbbVie Deutschland GmbH & Co. KG, Germany.
Location of the manufacturer and address of its place of business
Knollstrasse, 67061 Ludwigshafen, Germany.
You can report an adverse event or a complaint about the quality of a medicinal product to Abbott by phone (24/7) or at:
Ukraine, 01032, Kyiv, 110 Zhylyanska St., 2nd floor, tel. +380 44 498 6080 (for Ukraine and other CIS countries); Republic of Belarus, 220035, Minsk, 1-Zagorodny Ave., building 20, office 1503, tel. +375 17 256 7920; Republic of Uzbekistan, 100015, Tashkent, 38a Oybek St., tel. +998 71 129 0550.
