Flecainide sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLECAINIDE SANDOZ® (FLECAINIDE SANDOZ®)

Composition:

Active substance: flecainide acetate;

1 tablet contains 50 mg or 100 mg of flecainide acetate;

Excipients: pregelatinized corn starch, microcrystalline cellulose, corn starch, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

50 mg tablets: white, round, biconvex, uncoated tablets with an imprint "C" on one side and identifying letters "FI" on the other side;

100 mg tablets: white, round, biconvex, uncoated tablets with a breakline, and identifying imprints "C" above the line and "FJ" below the line on one side, and a breakline on the other side.

Pharmacotherapeutic group.

Class IC antiarrhythmic agents. Flecainide. ATC code C01BC04.

Pharmacological properties.

Pharmacodynamics.

Flecainide acetate is a class IС antiarrhythmic agent indicated for the treatment of life-threatening symptomatic ventricular arrhythmias and high-grade supraventricular arrhythmias.

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

As a class IС agent, flecainide has three main properties: pronounced inhibition of cardiac fast sodium channels; slow onset of action and altered kinetics of sodium channel blockade (resulting from slow binding and dissociation from sodium channels); and differential effects of the drug on the duration of the action potential in ventricular muscle and Purkinje fibers—specifically, no effect on the former and significant shortening of the latter. This combination of properties leads to a marked reduction in conduction velocity in fibers whose depolarization depends on fast sodium channels, with a moderate increase in effective refractory period, as demonstrated in studies using isolated cardiac tissues. These electrophysiological characteristics of flecainide acetate account for the potential prolongation of the PR interval and QRS complex on ECG. At very high concentrations, flecainide causes weak inhibition of slow myocardial channels. This effect is associated with a negative inotropic effect.

Pharmacokinetics.

Flecainide Sandos® is almost completely absorbed after oral administration and undergoes negligible first-pass metabolic transformation. According to available data, the bioavailability of flecainide in the acetate form is approximately 90%. The accepted therapeutic plasma concentration range is from 200 to 1000 ng/mL. After intravenous administration, the mean time to reach maximum serum concentration is 0.67 hours, with a mean bioavailability of 98%, compared to 1 hour and 78%, respectively, when administered as an oral solution, and 4 hours and 81%, respectively, in tablet form. Approximately 40% of flecainide is protein-bound in plasma.

The drug crosses the placenta and is excreted in breast milk.

Flecainide Sandos® undergoes active metabolism (subject to genetic polymorphism), with two main metabolites being meta-O-dealkylated flecainide and meta-O-dealkylated flecainide lactam; both metabolites are relatively active. Metabolism is mediated by the cytochrome P450 enzyme system, specifically the CYP2D6 isoenzyme, and is associated with genetic polymorphism.

The drug is primarily excreted in urine, with approximately 30% of the administered dose excreted unchanged and the remainder as metabolites. About 5% is excreted in feces. Flecainide elimination is reduced in renal insufficiency, hepatic disease, heart failure, and with alkaline urine. Only 1% of flecainide is eliminated unchanged during hemodialysis. The elimination half-life of flecainide is approximately 20 hours.

Clinical characteristics.

Indications.

• AV nodal reentrant tachycardia; arrhythmias associated with Wolff-Parkinson-White syndrome and similar disorders due to the presence of accessory conduction pathways, when other treatment options have proven ineffective.
• Symptomatic, high-grade paroxysmal ventricular arrhythmia that is life-threatening and unresponsive to other therapies. Also indicated when other forms of therapy are contraindicated due to intolerance or unfeasibility.
• Paroxysmal atrial arrhythmias (atrial fibrillation, atrial flutter, atrial tachycardia) in patients with unfavorable symptomatology following conversion, provided there is clear evidence of a definite need for therapy confirmed by the severity of clinical symptoms, when other treatment options are ineffective.

Prior to initiating treatment, organic heart disease and/or impaired left ventricular ejection fraction should be ruled out, as these conditions increase the risk of undesirable arrhythmia aggravation.

Contraindications.

• Hypersensitivity to flecainide or to any of the excipients of the medicinal product.
• Heart failure, history of myocardial infarction with asymptomatic ventricular ectopy or asymptomatic unstable ventricular tachycardia.
• Cardiogenic shock.
• Long-standing atrial fibrillation for which no attempt to convert to sinus rhythm has been made, as well as valvular heart disease with significant hemodynamic impairment.
• Impaired or reduced ventricular function in the presence of cardiogenic shock, severe bradycardia (less than 50 beats per minute), or severe hypotension.
• Concomitant use with Class I antiarrhythmic agents (sodium channel blockers).
• Brugada syndrome.
• Flecainide should not be used in patients with sinus node dysfunction, atrial conduction disturbances, second- or higher-degree atrioventricular block, bundle branch block, or distal conduction system block, unless cardiac pacing is available.
• Asymptomatic ventricular arrhythmia or ventricular arrhythmia with minimal symptoms.

Interaction with other medicinal products and other forms of interaction.

Class I antiarrhythmic agents. Flecainide SANDOZ® should not be used concomitantly with Class I antiarrhythmic agents.

Class II antiarrhythmic agents. The potential for enhanced adverse inotropic effects should be considered when Class II antiarrhythmics, such as beta-blockers, are used concomitantly with flecainide.

Class III antiarrhythmic agents. When flecainide is used concomitantly with amiodarone, the usual dose of flecainide should be halved, and close monitoring of the patient is required to detect adverse effects promptly. Therapeutic drug monitoring of plasma flecainide concentration is also recommended.

Class IV antiarrhythmic agents. Concomitant use of flecainide with calcium channel blockers, such as verapamil, should be performed with caution.

Potentially life-threatening adverse effects associated with drug interactions leading to increased plasma concentrations of flecainide may occur. Flecainide metabolism is primarily mediated by the CYP2D6 isoenzyme. Concomitant administration with medicinal products that inhibit (e.g., antidepressants, neuroleptics, propranolol, ritonavir, certain antihistamines) or induce (e.g., phenytoin, phenobarbital, carbamazepine) this isoenzyme results in increased or decreased plasma flecainide concentrations, respectively.

Increased plasma flecainide concentrations may also result from impaired renal function due to reduced flecainide clearance.

Hypokalemia, as well as hyperkalemia or other electrolyte imbalances, should be corrected prior to initiating flecainide therapy. Hypokalemia may result from concomitant use of diuretics, corticosteroids, or laxatives.

Antihistamines. The risk of ventricular arrhythmia increases when flecainide is used concomitantly with mizolastine and terfenadine. Concomitant use should be avoided.

Antiviral agents. Plasma concentrations of flecainide increase when used concomitantly with ritonavir, lopinavir, and indinavir (increasing the risk of ventricular arrhythmia); therefore, concomitant use should be avoided.

Antidepressants. Fluoxetine, paroxetine, and other antidepressants may increase plasma flecainide concentrations; concomitant use with tricyclic antidepressants increases the risk of ventricular arrhythmia.

Antiepileptic agents. Limited data from patients taking the drug concomitantly with enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate a 30% increase in flecainide clearance.

Neuroleptic agents. Concomitant use of flecainide with clozapine is associated with an increased risk of arrhythmia.

Antimalarial agents. Quinine may increase plasma flecainide concentrations.

Antifungal agents. Terbinafine may increase plasma flecainide concentrations due to inhibition of CYP2D6 isoenzyme activity.

Diuretics. A class effect of these agents is hypokalemia, which may enhance cardiotoxic effects.

H2-antihistamines (for treatment of gastric ulcers). The H2-receptor antagonist cimetidine inhibits the metabolic transformation of flecainide. In healthy volunteers receiving cimetidine (1 g daily) for one week, the AUC of flecainide increased by approximately 30%, and the elimination half-life increased by approximately 10%.

Smoking cessation aids. Concomitant use of bupropion (whose metabolism involves CYP2D6) with flecainide should be performed cautiously, initiating treatment at the lowest dose within the recommended range. If bupropion is prescribed to a patient already receiving flecainide, consideration should be given to reducing the flecainide dose.

Cardiac glycosides. Flecainide may increase digoxin plasma levels by approximately 15%, which is unlikely to be clinically significant when plasma concentrations are within the therapeutic range. It is recommended to measure digoxin plasma levels in patients receiving digitalis preparations, at least 6 hours after digoxin administration, regardless of dose, and independently of flecainide administration.

Anticoagulants. Flecainide may be used concomitantly with oral anticoagulants.

Special precautions for use

Flecainide SANDOZ® for oral use should be prescribed exclusively in hospital settings or under the direct supervision of a specialist for treatment of patients with:

• AV nodal reentrant tachycardia, arrhythmias associated with Wolff-Parkinson-White syndrome and similar disorders associated with the presence of accessory conduction pathways.
• Paroxysmal atrial fibrillation in the presence of unfavorable symptoms.

Initiation of treatment with this drug for other indications should begin under hospital conditions.

It has been demonstrated that flecainide increases mortality risk in patients after myocardial infarction who have asymptomatic ventricular arrhythmia.

Flecainide SANDOZ®, like other antiarrhythmic agents, may cause aggravation of arrhythmia; that is, it may induce more severe arrhythmias, increase the frequency of arrhythmia episodes, or intensify adverse symptoms.

Flecainide should be avoided in patients with organic heart disease or impaired left ventricular ejection fraction.

Flecainide should be used with caution in patients with acute onset of atrial fibrillation following cardiac surgery.

Flecainide causes QT interval prolongation and increases QRS complex width by 12–20%. The effect on the QT interval is minimal.

Brugada syndrome-type ECG changes may occur during flecainide therapy. If ECG findings suggestive of Brugada syndrome are observed during flecainide treatment, discontinuation of further therapy should be considered.

Since plasma elimination of flecainide in patients with severe hepatic impairment may be significantly slower, flecainide should not be used in such patients unless the expected benefit outweighs the potential risk. Therapeutic drug monitoring is recommended.

Flecainide SANDOZ® should be used with caution in patients with renal dysfunction (creatinine clearance ≤35 mL/min/1.73 m²); therapeutic monitoring is recommended.

Plasma elimination of flecainide may be reduced in elderly patients, which should be taken into account when adjusting the dosage regimen.

Electrolyte imbalances (e.g., hypokalemia and hyperkalemia) should be corrected prior to initiating flecainide therapy.

Severe bradycardia or significant hypotension should be corrected before starting flecainide treatment.

It is known that Flecainide SANDOZ® increases the endocardial threshold for pacemaker signals, i.e., endocardial sensitivity to pacing is reduced. This effect is reversible and affects the threshold for acute rather than chronic sensitivity more significantly. Therefore, flecainide should be used with caution in patients with permanent or temporary pacemakers and should not be used in patients with a high pacing threshold or when a non-programmable pacemaker is used without appropriate resuscitation equipment available.

Doubled stimulation frequency or amplitude (voltage) is usually sufficient to restore normal cardiac function. However, in the early period after pacemaker implantation, when the patient is receiving flecainide, it may be very difficult to achieve a ventricular sensing threshold below 1 volt.

Difficulties during defibrillation have been reported. In most such cases, patients had a history of cardiac disease with cardiac enlargement, myocardial infarction, arteriosclerotic heart disease, and heart failure.

There have been reports of increased ventricular rate during atrial fibrillation in the absence of therapeutic effect. Flecainide SANDOZ® exerts a selective effect that increases the refractory period of anterograde, especially retrograde, conduction from the sinus node to the ventricles. This effect is manifested on ECG in most patients as corrected QT interval prolongation; however, the effect on QT interval is generally minimal. Nevertheless, there are reports of QT interval prolongation by up to 4%. This effect is less pronounced than with class Ia antiarrhythmic agents.

Use in pediatric practice

Flecainide SANDOZ® is not recommended for use in children under 12 years of age due to lack of adequate safety and efficacy data.

Dairy products (milk, infant formula, and possibly yogurt) may reduce flecainide absorption in children, including newborns. Cases of flecainide toxicity have been reported in children when milk intake was reduced, as well as in newborns when milk-based infant formula was replaced with glucose-containing feeds.

Use during pregnancy or breastfeeding

Flecainide SANDOZ® crosses the placenta and reaches the fetus when administered during pregnancy. Therefore, it should not be used during pregnancy unless the expected benefit outweighs the potential risk to the fetus.

Use during lactation

Flecainide is excreted in breast milk. The plasma concentration in a breastfed infant is 5–10 times lower than the therapeutic level. If treatment is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

Patients should refrain from driving or operating machinery due to the potential for dizziness and visual disturbances.

Method of Administration and Dosage

The drug is administered orally. To eliminate the influence of food on the absorption of the active substance, Flecainide SANDOZ® should be taken on an empty stomach or one hour before meals. The 100 mg tablet of Flecainide SANDOZ® can be divided into two equal parts.

Initiation of therapy with flecainide acetate and any changes in dosage regimen must be performed under medical supervision with ECG monitoring and control of plasma drug concentration. Hospitalization may be required for some patients during this period, particularly those with life-threatening ventricular arrhythmias. The decision on hospitalization is made by a specialist. In patients with organic heart disease, especially those with a history of myocardial infarction, flecainide therapy should be initiated only if other antiarrhythmic drugs (except Class IC agents, particularly amiodarone) are ineffective or not tolerated, and if non-pharmacological treatments (surgical intervention, ablation, defibrillator implantation) are not indicated. Continuous ECG monitoring and control of plasma drug concentration are required throughout the treatment period.

Adults and children aged 13 years and older

Supraventricular arrhythmia. The recommended initial dose of flecainide is 50 mg twice daily. For most patients, this dose provides adequate control of arrhythmia symptoms. If necessary, the dose may be increased up to a maximum of 300 mg per day.

Ventricular arrhythmia. The recommended initial dose is 100 mg twice daily. The maximum daily dose is 400 mg, but this dose should be reserved only for patients with large body size or when rapid arrhythmia control is required. After 3–5 days, the dose should be gradually adjusted to the minimum effective level required to control arrhythmia. With long-term treatment, further dose reduction may be possible.

Elderly patients

In elderly patients, the initial daily dose should not exceed 100 mg (50 mg tablet twice daily), as the elimination rate of flecainide from plasma may be reduced in this population. This should also be considered when adjusting the dose. The maximum dose for elderly patients should not exceed 300 mg (150 mg twice daily).

Plasma concentration

Based on suppression of ventricular extrasystoles, the plasma concentration required for optimal therapeutic effect should be maintained between 200 and 1000 ng/mL. Plasma concentrations above 700–1000 ng/mL are associated with an increased risk of adverse effects.

Renal impairment

In patients with severe renal impairment (creatinine clearance ≤35 mL/min/1.73 m²), the initial dose should not exceed 100 mg per day (or 50 mg twice daily). Close monitoring of plasma drug concentration is strongly recommended in these patients. The dose may be gradually and cautiously increased based on efficacy and tolerability. After 6–7 days, the dosage regimen should be adjusted according to therapeutic response and tolerability. In some patients with severe renal impairment, flecainide clearance is markedly reduced, resulting in prolonged elimination half-life (60–70 hours).

Hepatic impairment

Careful monitoring is required when administering the drug to patients with hepatic impairment. The initial dose should not exceed 100 mg per day (50 mg twice daily).

The drug should be used with caution in patients with implanted pacemakers. The daily dose should not exceed 100 mg, divided into two doses.

Careful monitoring is required when flecainide is used concomitantly with cimetidine or amiodarone. In some patients, the dose should be reduced, and the daily dose should not exceed 100 mg, divided into two doses. Monitoring of patients is necessary during both initiation and maintenance therapy.

Recommended monitoring includes plasma drug concentration and ECG monitoring (monthly ECG checks). During initial therapy and dose escalation, ECGs should be performed every 2–4 days.

When Flecainide SANDOZ® is administered to patients requiring dose adjustments, frequent ECG monitoring should be performed (in addition to monitoring of plasma flecainide concentration). Dose adjustments should be made at intervals of 6–8 days. To monitor individual dosing regimens, ECGs should be performed 2 and 3 weeks after initiation of therapy.

Children

Flecainide SANDOZ® is not recommended for children under 13 years of age due to insufficient data on safety and efficacy.

Overdose

Overdose with Flecainide SANDOZ® is life-threatening and requires immediate medical intervention. Increased sensitivity to the drug and elevated plasma concentrations above the therapeutic range may also result from interactions with other medicinal products. There is no specific antidote. There is no known method to rapidly eliminate Flecainide SANDOZ® from the body. Dialysis or hemoperfusion are ineffective.

Supportive therapy is required, including removal of unabsorbed drug from the gastrointestinal tract. Subsequently, inotropic agents or cardiac stimulants such as dopamine, dobutamine, or isoproterenol may be used, along with mechanical ventilation and circulatory support measures (e.g., ventricular assist device). Temporary transvenous cardiac pacing should be considered in cases of conduction block. Because the elimination half-life from plasma is approximately 20 hours, supportive therapy must be maintained for a prolonged period.

Forced diuresis with urine alkalinization may theoretically enhance flecainide elimination.

Intravenous administration of 8.4% sodium bicarbonate reduces flecainide activity.

Intravenous lipid emulsion and extracorporeal membrane oxygenation (ECMO) may be considered on a case-by-case basis.

Adverse Reactions

Like other antiarrhythmic agents, flecainide may provoke exacerbation of arrhythmia. This may manifest as increased intensity of symptoms of existing arrhythmia or development of a new episode. The risk of proarrhythmic effects is highest in patients with organic heart disease and/or significant impairment of left ventricular function.

The most common adverse effects include second- or third-degree AV block, bradycardia, heart failure, chest pain, myocardial infarction, hypotension, sinus node arrest, tachycardia (atrial and ventricular tachycardia), and palpitations.

Common adverse reactions such as dizziness and visual disturbances occur in approximately 15% of patients receiving this therapy. These adverse reactions are usually transient and resolve with continued treatment or upon dose reduction. The list of adverse reactions provided below is based on experience from clinical trials and post-marketing pharmacovigilance data.

Adverse reactions are classified by system organ classes and frequency. Frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

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

Immune system disorders

Rare: increased number of antinuclear antibodies, associated or not associated with systemic inflammation.

Psychiatric disorders

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

Nervous system disorders

Very common: dizziness, usually transient.

Rare: paresthesia, ataxia, hyposthesia, hyperhidrosis, syncope, tremor, flushing, somnolence, headache, peripheral neuropathy, seizures, dyskinesia.

Eye disorders

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

Rare: corneal precipitates.

Ear and labyrinth disorders

Rare: tinnitus, vertigo-type dizziness.

Cardiac disorders

Common: proarrhythmic effect (most likely in patients with organic heart disease).

Uncommon: in patients with atrial flutter, development of 1:1 AV conduction with increased heart rate is possible.

Frequency not known: dose-dependent prolongation of PR and QRS intervals is possible.

Change in pacemaker signal sensitivity threshold.

Second- or third-degree atrioventricular block, cardiac arrest, bradycardia, heart failure/congestive heart failure, chest pain, hypotension, myocardial infarction, palpitations, sinus node arrest, tachycardia (atrial and ventricular) or atrial fibrillation. Manifestation 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 enzyme activity, with or without jaundice.

Frequency not known: liver function abnormalities.

Skin and subcutaneous tissue disorders

Uncommon: allergic dermatitis, including rash, alopecia.

Rare: severe urticaria.

Very rare: photosensitivity reaction.

General disorders and administration site conditions

Common: asthenia, fatigue, fever, edema.

Musculoskeletal and connective tissue disorders

Frequency not known: arthralgia, myalgia.

Shelf life

2 years.

Storage conditions

Store at temperatures not exceeding 25°C in the original packaging.

Keep out of reach of children.

Packaging

10 tablets in a blister; 3, 6, or 12 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

SALUTAS Pharma GmbH

Manufacturer's address and place of business

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany