Amariton

INSTRUCTIONS for medical use of the medicinal product AMARHYTON (AMARHYTON)

Composition:

Active substance: flecainide acetate;

One prolonged-release hard capsule contains 50 mg or 100 mg of flecainide acetate;

Excipients: povidone (Kollidon 25), microcrystalline cellulose (PH 101), crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Capsule shell containing: Eudragit S-100 (copolymer of methacrylic acid and methyl methacrylate; 1:2), macrogol 400 (polyethylene glycol), talc.

Pharmaceutical form. Prolonged-release hard capsules.

Main physicochemical properties:

for dosage (50 mg): opaque gelatin capsules №4 with white body and white cap, containing white or almost white round microtablets;

for dosage (100 mg): opaque gelatin capsules №3 with grey body and white cap, containing white or almost white round microtablets.

Pharmacotherapeutic group.

Class IC antiarrhythmic agents. Flecainide. ATC code C01BC04.

Pharmacological properties

Pharmacodynamics

Flecainide acetate is a class IC antiarrhythmic agent used for the treatment of severe symptomatic, life-threatening ventricular and supraventricular arrhythmias.

Electrophysiologically, flecainide is a local anesthetic (class IC) antiarrhythmic compound. It is an amide-type local anesthetic structurally related to procainamide and encainide, as these agents are also benzamide derivatives.

The classification of flecainide as a class IC agent is based on a triad of characteristics: marked depression of the fast sodium channel in the heart; slow onset and offset kinetics of sodium channel blockade (reflecting slow association with and dissociation from sodium channels); and differential effect of the drug on action potential duration in ventricular muscle compared to Purkinje fibers, having little effect on the former while significantly shortening it in the latter. This combination of properties results in a marked reduction in conduction velocity in fibers dependent on fast channels for depolarization, with only a moderate increase in effective refractory period when tested in isolated cardiac tissues. These electrophysiological properties of flecainide acetate may lead to prolongation of the PR interval and QRS duration on the electrocardiogram (ECG). At very high concentrations, flecainide exerts a weak depressive effect on the slow calcium channel in the myocardium, which is associated with a negative inotropic effect.

Pharmacokinetics

Absorption

Flecainide is almost completely absorbed after oral administration and does not undergo extensive first-pass metabolism. The bioavailability of flecainide acetate capsules is approximately 90%.

The therapeutic plasma concentration range is typically between 200 ng and 1000 ng per milliliter.

After intravenous administration, the mean time to reach maximum serum concentration was 0.67 hours, with a mean bioavailability of 98%, compared to 1 hour and 78% for the oral solution and 4 hours and 81% for the capsules.

Distribution

Flecainide is approximately 40% bound to plasma proteins. Flecainide crosses the placenta and is excreted in breast milk.

Biotransformation

Flecainide is extensively metabolized (depending on genetic polymorphism), with two major metabolites being m-O-dealkylated flecainide and m-O-dealkylated flecainide lactam, both of which may possess some pharmacological activity. Its metabolism appears to involve the cytochrome P450 isoenzyme CYP2D6, which exhibits genetic polymorphism.

Elimination

Flecainide is primarily excreted in the urine, with approximately 30% eliminated unchanged and the remainder as metabolites. About 5% is excreted in feces. Flecainide elimination is reduced in renal impairment, hepatic disease, heart failure, and in alkaline urine. Hemodialysis removes only about 1% of unchanged flecainide.

The elimination half-life of flecainide is approximately 20 hours.

Clinical characteristics.

Indications.

• Treatment and prevention of recurrences of documented symptomatic and disabling ventricular arrhythmias in the absence of confirmed left ventricular function impairment and/or confirmed coronary artery disease. Treatment should be initiated with low doses and ECG monitoring should be performed.
• Prevention of recurrences of documented supraventricular tachycardia when treatment is deemed necessary and in the absence of left ventricular function deterioration.
• Prevention of electrical shock in certain patients with implanted defibrillators.

Contraindications.

• Hypersensitivity reaction to flecainide or to any of the excipients of the medicinal product.
• Myocardial infarction (acute or old), except in cases of life-threatening ventricular tachycardia.
• Heart failure, regardless of the presence of arrhythmia.
• Complete left bundle branch block, bifascicular block, second- or third-degree atrioventricular block, sinus node dysfunction, and atrial disease, in the absence of a pacemaker.
• Cardiogenic shock.
• Brugada syndrome.

Interaction with other medicinal products and other forms of interaction.

Many antiarrhythmic agents are depressants of cardiac automaticity, conduction, and contractility. Combining antiarrhythmic agents from different classes may produce a beneficial therapeutic effect, but is usually very delicate and requires careful clinical observation and ECG monitoring. Combination of antiarrhythmic agents from the same class is not recommended (used only in exceptional cases) due to an increased risk of cardiac adverse reactions.

Combination with medicinal products having bradycardic, negative inotropic properties and/or those slowing atrioventricular conduction is delicate and requires clinical monitoring and ECG control.

Combinations not recommended

• Class I antiarrhythmic agents (quinidine, hydroquinidine, disopyramide, mexiletine, lidocaine, propafenone, cibenzoline).

Flecainide acetate should not be combined with other Class I antiarrhythmic agents, except in individual cases, due to an increased risk of cardiac adverse effects.

Special precautions for use.

Warning

Flecainide acetate was evaluated in a randomized, multicenter, double-blind study (the CAST study) in patients with asymptomatic and life-threatening ventricular arrhythmias following myocardial infarction occurring more than 6 days and up to 2 years previously. The incidence of death and non-fatal cardiac arrest was higher with flecainide than in the placebo control group.

As with other Class I antiarrhythmic agents, there is no controlled study demonstrating a beneficial effect of flecainide acetate on survival or sudden cardiac death.

Flecainide therapy should be initiated by a physician experienced in managing patients with cardiac disorders.

Any initiation or change in dosing requires clinical and electrocardiographic monitoring to assess treatment response.

Due to risks associated with Class I antiarrhythmic agents, particularly the proarrhythmic risk, strict adherence to the conditions for use of flecainide—including indications, dosage, contraindications, warnings, and precautions—is essential.

When switching from a flecainide-containing product to another, careful monitoring is recommended for patients at risk.

Special safety precautions

Proarrhythmic effects

Flecainide acetate, like other antiarrhythmic agents, may induce more severe arrhythmias, increase the frequency of previously diagnosed arrhythmias, or worsen symptom severity (see section "Side effects"). Spontaneous variation in the patient's underlying arrhythmia may be difficult to distinguish from worsening secondary to drug administration.

The emergence of increased ventricular or polymorphic extrasystoles should prompt discontinuation of treatment.

History of heart failure

Due to the negative inotropic effect of flecainide acetate, it should be administered under strict monitoring of cardiac function in patients with a history of heart failure or symptoms suggestive of developing heart failure.

Electrocardiographic changes

• Flecainide acetate should be used cautiously in patients with pre-existing conduction disturbances.
• Development of atrioventricular block, persistent complete bundle branch block of the His bundle, or sinoatrial block during treatment should lead to discontinuation of flecainide acetate.
• An increase in QRS complex duration by more than 25% from baseline values should lead to dose reduction.

When changing the dosage of flecainide acetate or initiating concomitant therapy that may affect cardiac conduction, patients—especially those with conduction disturbances—should be under close ECG monitoring.

Flecainide prolongs the QT interval and widens the QRS complex by 12–20%. No significant effect on the JT interval is observed.

Brugada syndrome may be unmasked following flecainide administration. If ECG changes suggestive of Brugada syndrome occur during flecainide treatment, discontinuation of therapy should be considered.

Electrolyte imbalance

Hypokalemia, hyperkalemia, or hypomagnesemia may enhance the proarrhythmic effects of Class I antiarrhythmic agents; therefore, these imbalances should be corrected prior to initiating flecainide acetate.

Use in atrial flutter

Due to the risk of 1:1 conduction, concomitant use of an AV nodal blocking agent with flecainide acetate is recommended.

Patients with renal impairment, elderly patients

In patients with renal impairment and/or elderly patients, the elimination rate of flecainide acetate may be reduced. This may lead to an increased risk of drug accumulation in plasma and tissues, potentially causing adverse reactions. This risk justifies dose adjustment in severe renal dysfunction (see section 4.2) and necessitates treatment monitoring.

Children under 12 years of age

Flecainide is not recommended for use in children under 12 years of age due to lack of data on safety and efficacy in this patient group.

Pulmonary manifestations

Very rarely, interstitial lung disease may occur during chronic flecainide therapy, likely due to an immune-allergic mechanism. If symptoms suggestive of interstitial pneumonitis appear (such as onset of dyspnea or dry cough, isolated or associated with changes in general condition), diagnosis should be pursued with radiological evaluation. If diagnosis is confirmed, discontinuation of therapy should be considered, and short-term corticosteroid therapy may be beneficial (see section 4.8).

Milk products (milk, infant formulas, and possibly yogurts) may reduce flecainide absorption in children and infants. Although flecainide is not approved for use in children under 12 years of age, flecainide toxicity has been reported in children who reduced milk intake and in infants switched from milk-based formulas to dextrose-based feeds.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have yielded conflicting results and do not allow conclusions regarding embryotoxic or teratogenic potential (see section "Pharmacological properties"). From a clinical standpoint, there are insufficient relevant data to assess the potential malformative or fetotoxic effects of flecainide acetate when used during pregnancy.

Therefore, the use of flecainide acetate is not recommended during pregnancy.

Breastfeeding period

Flecainide is excreted in breast milk. Plasma concentrations in breastfed infants are 5–10 times lower than therapeutic levels. Although the risk of adverse reactions is very low, flecainide should be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery.

Based on its pharmacodynamic properties and pharmacovigilance data, flecainide acetate may worsen pre-existing cardiac rhythm disturbances or induce new arrhythmias.

It may also cause side effects such as dizziness, tremor, and visual disturbances, which may have a minor impact on the ability to drive or operate machinery. Therefore, patients should be informed of these risks.

Furthermore, arrhythmias that may lead to cardiovascular collapse require specialized assessment regarding the ability to drive vehicles.

Method of Administration and Dosage

For Adults Only

In documented supraventricular tachycardias

The usual initial dose is 100 mg per day.

Dose escalation may only be considered after a period of 4 to 5 days.

The average maintenance dose is 200 mg per day.

The maximum dose is 300 mg per day.

In documented ventricular tachycardias

The usual dose is 200 mg per day.

Dose escalation may only be considered after a period of 4 to 5 days.

The maximum dose is 300 mg per day.

In frail patients:

• elderly patients;
• history or symptoms suggestive of heart failure;
• severe renal impairment (creatinine clearance ≤ 20 mL/min/m²).

The initial dose should not exceed 100 mg every 24 hours: it ranges from 50 to 100 mg/24 hours depending on the patient's condition. The dosage may be increased or decreased in increments of 50 mg per day, bearing in mind that a minimum of 4 to 5 days is required to reach a new steady-state plasma concentration after each adjustment. Clinical and electrocardiographic monitoring is required.

Administration method

Administer once daily.

Children.

The medicinal product Amriton is not recommended for use in children under 12 years of age due to lack of data on safety and efficacy.

Overdose.

Flecainide overdose is potentially fatal and requires monitoring in a specialized hospital setting. Increased sensitivity to the drug and plasma concentrations above the therapeutic range may also result from interactions with other medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). There is no antidote. There is no known method for rapid elimination of flecainide, and dialysis or hemoperfusion are ineffective.

Treatment is primarily symptomatic and may include removal of the unabsorbed fraction of the drug from the gastrointestinal tract. Intravenous administration of 8.4% sodium bicarbonate solution reduces flecainide activity. Other measures may include administration of inotropic agents or cardiac stimulants such as dopamine, dobutamine, or isoproterenol, or mechanical ventilation and circulatory support (e.g., using an intra-aortic balloon pump). In case of conduction disturbances, temporary cardiac pacing may be considered. Given the plasma half-life of approximately 20 hours, these treatment measures should be maintained for a prolonged period. Forced diuresis with acidification of urine may theoretically enhance drug elimination. Extracorporeal circulation may be considered on a case-by-case basis.

Adverse Reactions

Adverse reactions are listed below by organ class and frequency (the number of patients in whom the reaction is expected to occur), according to the following categories:

• Very common (≥ 1/10);
• Common (≥ 1/100 and <1/10);
• Uncommon (≥ 1/1,000 and <1/100);
• Rare (≥ 1/10,000 and <1/1,000);
• Very rare (< 1/10,000);
• Frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: decreased number of erythrocytes, decreased number of leukocytes, and decreased number of thrombocytes.

Immune system disorders

Very rare: increased levels of antinuclear antibodies with or without systemic inflammation.

Psychiatric disorders

Rare: hallucinations, depression, confusion, anxiety, amnesia, insomnia.

Nervous system disorders

Very common: dizziness, usually transient.

Rare: paresthesia, coordination disturbances, decreased sensation, hyperhidrosis, syncope, tremor, hot flushes, somnolence, headache, peripheral neuropathy, seizures, dyskinesia.

Eye disorders

Very common: visual disturbances such as diplopia and blurred vision.

Very rare: corneal deposits.

Ear and labyrinth disorders

Rare: tinnitus, vertigo.

Cardiac disorders

Common: proarrhythmic effects (mainly in patients with structural heart disease).

Frequency not known: dose-dependent prolongation of PR and QRS intervals and electrical changes may occur (see section "Special precautions for use").

Uncommon: in patients with atrial flutter, 1:1 flutter may develop with increased heart rate.

Frequency not known: second- and third-degree atrioventricular block, cardiac arrest, bradycardia, heart failure/congestive heart failure, chest pain, arterial hypotension, myocardial infarction, palpitations, sinus arrest, tachycardia (atrial and ventricular), or ventricular fibrillation. Unmasking of pre-existing Brugada syndrome.

Respiratory, thoracic and mediastinal disorders

Common: dyspnea.

Rare: pneumonitis.

Frequency not known: pulmonary fibrosis, interstitial lung disease.

Gastrointestinal disorders

Uncommon: nausea, vomiting, constipation, abdominal pain, decreased appetite, diarrhea, dyspepsia, flatulence.

Hepatobiliary disorders

Rare: increased liver enzymes with or without jaundice.

Frequency not known: hepatic dysfunction.

Skin and subcutaneous tissue disorders

Uncommon: allergic dermatitis, including rash, alopecia.

Rare: severe urticaria.

Very rare: photosensitivity reaction.

Musculoskeletal and connective tissue disorders

Frequency not known: arthralgia and myalgia.

General disorders and administration site conditions

Common: asthenia, fatigue, fever, edema.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging. 10 capsules in a blister pack. 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

JSC "Chaikapharma High-Quality Medicines".

Manufacturer's address and place of business.

1172, Sofia, bul. G.M. Dimitrov, No. 1, Bulgaria.