Instructions Lixarit tablets 100mg No. 30
Composition
active ingredient: flecainide acetate;
1 tablet contains 100 mg of flecainide acetate;
Excipients: pregelatinized corn starch, croscarmellose sodium, microcrystalline cellulose, hydrogenated vegetable oil, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white or almost white, round, biconvex tablets with a score line and embossed with the letter "F" and the number "100".
Pharmacotherapeutic group
Class IS antiarrhythmics. Flecainide.
ATX code C01B C04.
Pharmacological properties
Pharmacodynamics.
Flecainide acetate is a class IA antiarrhythmic agent indicated for the treatment of life-threatening symptomatic ventricular arrhythmia and severe supraventricular arrhythmia.
Flecainide is a local anesthetic (class IC) with antiarrhythmic properties. It is an amide-type local anesthetic, structurally similar to procainamide and encainide, as these substances are also benzamide derivatives.
Flecainide, as a class IC compound, has three main properties: pronounced inhibition of fast sodium channels of the heart; slow onset of action and shifted kinetic characteristics of sodium channel inhibition (which is a consequence of slow binding and dissociation from sodium channels); differentiated effect of the drug on the duration of change of the bioelectric potential of ventricular muscles and Purkinje fibers, namely: no effect on the former and a significant reduction in the duration of change for the latter. This combination of properties provides a significant decrease in the conductivity of fibers, the depolarization of which depends on fast sodium channels, with a moderate increase in the effective refractory period, as evidenced by the results of studies using isolated heart tissues. The indicated electrophysiological properties of flecainide acetate are due to the possibility of increasing the PR and QRS intervals on the ECG. At very high concentrations, flecainide causes weak inhibition of slow myocardial channels. This effect is associated with a negative inotropic effect.
Pharmacokinetics.
Flecainide is almost completely absorbed after oral administration and does not undergo active first-pass metabolism. The bioavailability of flecainide acetate is reported to be approximately 90%. The therapeutic plasma concentration range is 200 to 100 ng/mL. The mean time to peak serum concentration is 0.67 hours after intravenous administration and the mean bioavailability is 98%, compared with 1 hour and 78% for the oral solution and 4 hours and 81% for the tablet formulation. Approximately 40% of flecainide is bound to plasma proteins.
Flecainide crosses the placenta and is excreted in breast milk.
Flecainide undergoes active metabolic transformation (dependent on genetic polymorphism), the two main metabolites are meta-O-dealkylated flecainide and meta-O-dealkylated flecainide lactam, both metabolites are relatively active. Metabolic transformation occurs with the participation of an isoenzyme of the cytochrome P450 system, namely the isoenzyme CYP2D6, and is associated with genetic polymorphism.
Flecainide is excreted mainly in the urine, with approximately 30% of the dose excreted unchanged, the remainder as metabolites. Approximately 5% is excreted in the feces. The excretion rate of flecainide is reduced in renal failure, liver disease, heart failure, and alkaline urine. Only 1% of flecainide is excreted unchanged during hemodialysis. The half-life of flecainide is approximately 20 hours.
Indication
AV nodal sustained tachycardia; arrhythmias associated with Wolff-Parkinson-White syndrome and similar disorders caused by the presence of additional conduction pathways (in case of ineffectiveness of other treatments).
Symptomatic paroxysmal ventricular arrhythmia of severe severity, threatening the patient's life, in the absence of response to other types of therapy. Also used when other forms of therapy are intolerable or impossible to carry out.
Paroxysmal atrial arrhythmia (atrial fibrillation, atrial flutter, atrial tachycardia) in patients with adverse symptoms after conversion, provided there is a clear need for therapy, as confirmed by the severity of clinical symptoms, if other treatments are ineffective.
Before starting use, the presence of organic heart disease and/or impaired left ventricular ejection fraction should be excluded, as this increases the risk of unwanted exacerbation of arrhythmia.
Contraindication
Hypersensitivity reaction to flecainide or to any of the excipients of the drug.
Heart failure, history of myocardial infarction with asymptomatic ventricular ectopy or asymptomatic unstable ventricular tachycardia.
Long-term atrial fibrillation, in the treatment of which no attempt was made to convert sinus rhythm, as well as valvular heart disease with significant violations of hemodynamic parameters.
Reduced or impaired ventricular function, in the presence of cardiogenic shock, severe bradycardia (less than 50 beats per minute), severe hypotension.
Use in combination with class I antiarrhythmics (sodium channel blockers).
Brugada syndrome.
If pacing is not possible, flecainide should not be used in the treatment of patients with sinus node dysfunction, atrial conduction disorders, second-degree atrioventricular block, bundle branch block, or distal block.
Asymptomatic ventricular arrhythmia or mild symptoms of ventricular arrhythmia.
Interaction with other medicinal products and other types of interactions
Class I antiarrhythmics. Flecainide should not be used concomitantly with class I antiarrhythmics (see section "Contraindications").
Class II antiarrhythmics: The possibility of an increase in the undesirable inotropic effects of class II antiarrhythmics, such as beta-blockers, should be considered when used concomitantly with flecainide.
Class III antiarrhythmics. When flecainide is used concomitantly with amiodarone, the usual dose of flecainide should be halved and the patient should be closely monitored for adverse events. Monitoring of plasma concentrations is also recommended.
Class IV antiarrhythmics: Concomitant use of flecainide with calcium channel blockers, such as verapamil, should be undertaken with caution.
Possible adverse events that threaten the patient's life are associated with drug interactions that cause an increase in the concentration of the substance in the blood plasma. The metabolic transformation of flecainide is provided mainly by CYP2D6 isoenzymes, with simultaneous use with drugs that inhibit the activity of this isoenzyme (for example, antidepressants, neuroleptics, propranolol, ritonavir, some antihistamines) or increase the activity of this isoenzyme (for example, phenytoin, phenobarbital, carbamazepine), an increase or decrease in the concentration of flecainide in the blood plasma is observed, respectively.
An increase in the concentration of flecainide in blood plasma may also be due to impaired renal function due to a decrease in flecainide clearance.
Hypokalemia, as well as hyperkalemia or other electrolyte disturbances, should be corrected before starting flecainide. Hypokalemia may result from concomitant use of diuretics, corticosteroids, or laxatives.
Antihistamines: The risk of ventricular arrhythmia is increased when used with mizolastine and terfenadine. Concomitant use should be avoided.
Antiviral agents: Plasma concentrations of the substance increase with concomitant use with ritonavir, lopinavir and indinavir (increased risk of ventricular arrhythmia), therefore concomitant use should be avoided.
Antidepressants: Fluoxetine, paroxetine and other antidepressants increase plasma concentrations of flecainide; concomitant use with tricyclic antidepressants increases the risk of ventricular arrhythmia.
Antiepileptics: Some data obtained when patients took the drug together with enzyme activators (phenytoin, phenobarbital, carbamazepine) indicate a 30% increase in the rate of excretion of flecainide.
Neuroleptics. Clozapine – increased risk of arrhythmia.
Antimalarials: Quinine increases plasma concentrations of flecainide.
Antifungal agents: Terbinafine may increase plasma concentrations of flecainide due to inhibition of CYP2D6 isoenzyme activity.
Diuretics: class effect of drugs, hypokalemia, resulting in increased cardiotoxic effects.
H2 antihistamines (for the treatment of gastric ulcers). The H2 receptor antagonist cimetidine inhibits the metabolic transformation of flecainide. In healthy volunteers treated with cimetidine (1 g daily) for 1 week, the AUC of flecainide increased by approximately 30% and the half-life increased by approximately 10%.
Smoking cessation aids: Concomitant administration of bupropion (metabolized by CYP2D6) and flecainide should be undertaken with caution and treatment should be initiated at the lowest dose in the recommended range. If bupropion is prescribed while the patient is receiving flecainide, a reduction in the dose of the latter should be considered.
Cardiac glycosides. Flecainide may increase plasma digoxin levels by 15%, which is unlikely to be clinically significant when plasma concentrations are within the therapeutic range. It is recommended that digoxin plasma levels be measured in patients receiving digitalis at least 6 hours after digoxin administration, regardless of dose, before or after flecainide administration.
Anticoagulants: Flecainide can be used concomitantly with oral anticoagulants.
Application features
Flecainide for oral administration should only be used in a hospital setting or under the direct supervision of a specialist for patients with:
AV nodal sustained tachycardia, arrhythmia associated with Wolff-Parkinson-White syndrome and similar disorders associated with the presence of additional conduction pathways.
Paroxysmal atrial fibrillation, in the presence of adverse symptoms.
The use of the drug for other indications should be initiated in a hospital setting.
Flecainide has been shown to increase the risk of death in patients with asymptomatic ventricular arrhythmia after myocardial infarction.
Flecainide, like other antiarrhythmic agents, may potentiate arrhythmias, i.e. may cause more severe arrhythmias, increase the frequency of arrhythmia episodes, or increase the intensity of undesirable symptoms.
The use of flecainide should be avoided in the treatment of patients with organic heart disease or left ventricular ejection fraction disorders.
Flecainide should be used with caution in patients with acute development of atrial fibrillation after cardiac surgery.
Flecainide causes an increase in the QT interval and a broadening of the QRS complex by 12-20%. The effect on the QT interval is insignificant.
Brugada syndrome may occur when a patient is taking flecainide. If ECG changes suggestive of Brugada syndrome are detected during flecainide therapy, discontinuation of therapy should be considered.
Since the elimination of flecainide from the plasma of patients with severe hepatic impairment may be significantly slower, flecainide should not be used in the treatment of such patients unless the potential benefit outweighs the potential risks. Monitoring of plasma concentrations is recommended.
Flecainide should be used with caution in patients with renal impairment (creatinine clearance 35 mL/min/1.73 m2 or less); therapeutic monitoring is recommended.
The rate of elimination of flecainide from the blood plasma of elderly patients may be reduced, which should be taken into account when adjusting the dosage regimen.
Electrolyte imbalances (e.g. hypokalemia and hyperkalemia) should be corrected before initiating therapy with flecainide.
Severe bradycardia or significant hypotension should be corrected before initiating therapy with flecainide.
Flecainide is known to increase the threshold of endocardial sensitivity to pacemaker signals, i.e., the sensitivity of the endocardium to pacing is reduced. This effect is reversible and affects the threshold of acute sensitivity more than chronic sensitivity. Therefore, flecainide should be used with caution in patients with permanent or temporary pacemakers and should not be used in patients with a high threshold of sensitivity to pacing or in the case of an unprogrammed pacemaker in the absence of adequate resuscitation equipment.
Usually, doubling the frequency or amplitude of the stimulating pulse (voltage) is sufficient to normalize the heart's function, but in the initial stages after implantation, if the patient receives flecainide, it is very difficult to ensure a ventricular sensitivity threshold below 1 volt.
Difficulties with defibrillation have been observed. In most of these cases, patients had a history of heart disease with increased heart size, myocardial infarction, arteriosclerotic heart disease, and heart failure.
There are reports of cases of an increase in the rate of ventricular contraction in atrial fibrillation in the absence of a therapeutic effect. Flecainide has a selective effect, increasing the refractory period of anterograde and, especially, retrograde conduction from the sinus node to the ventricles of the heart. This effect is manifested on the ECG of most patients as an increase in the corrected QT interval, so the effect on the QT interval is insignificant. However, there are reports of cases of an increase in the QT interval by 4%, but this effect is less pronounced than with the use of class 1a antiarrhythmic drugs.
Application in pediatric practice.
Flecainide is not recommended for use in children under 13 years of age due to a lack of adequate data on its safety and effectiveness.
Dairy products (milk, baby food and yoghurts) may reduce the absorption of flecainide in children and neonates. Toxicity has been reported with flecainide administered to children who were given reduced milk intake and to neonates who were switched from milk-based infant formula to glucose-based formula.
Use during pregnancy or breastfeeding
Flecainide crosses the placenta and reaches the fetus when taken during pregnancy. Therefore, the drug should be used during pregnancy only if the expected benefit outweighs the potential risk.
Use during breastfeeding
Flecainide passes into breast milk. The concentration in the blood plasma of a breastfed child is 5-10 times lower than the therapeutic level. If treatment is necessary, breastfeeding should be discontinued.
Ability to influence reaction speed when driving vehicles or other mechanisms
It is recommended to refrain from driving vehicles or working with other mechanisms, given the possibility of dizziness and visual disturbances.
Method of administration and doses
The drug is administered orally. To eliminate the effect of food on the absorption of the drug, Lixarit should be taken on an empty stomach or one hour after eating. A Lixarit 100 mg tablet can be divided into two equal parts.
Initiation of therapy with flecainide acetate and changes in the dosage regimen should be carried out under medical supervision with ECG monitoring and control of the concentration of the substance in the blood plasma. Some patients require hospitalization at this time, in particular patients with life-threatening ventricular arrhythmia. The decision on the need for hospitalization is made by a specialist. For patients with organic heart disease, especially with a history of myocardial infarction, therapy with flecainide can be prescribed only in cases where other antiarrhythmic drugs, with the exception of class IC drugs (especially amiodarone), are ineffective or intolerable and provided that non-drug treatment (surgery, amputation, implantation of a defibrillator) is not indicated. During therapy, constant ECG monitoring and control of the concentration of the substance in the blood plasma are necessary.
Adults and children aged 13 and over
Supraventricular arrhythmia. The recommended starting dose is 50 mg twice daily. For most patients, this dose provides control of undesirable symptoms. If necessary, the dose may be increased to a maximum of 300 mg daily.
Ventricular arrhythmia. The recommended initial dose is 100 mg 2 times a day. The maximum daily dose is 400 mg, but this dose is used only in the treatment of patients with a large physique or when it is necessary to quickly ensure control of the arrhythmia. After 3-5 days, a gradual adjustment of the dose to the minimum sufficient level that ensures control of the arrhythmia is recommended. With prolonged use of the drug, a further reduction in the dose of the drug is possible.
Elderly patients
Elderly patients should be given an initial daily dose not exceeding 100 mg (50 mg twice daily) as the rate of elimination of flecainide from the blood plasma of elderly patients may be reduced. This should also be taken into account when adjusting the dose. The maximum dose for elderly patients should not exceed 300 mg (150 mg twice daily).
Plasma level
According to the indicators of elimination of ventricular extrasystoles, to ensure the maximum therapeutic effect, the content of the substance in the blood plasma should be 200–1000 ng/ml. The concentration in the blood plasma above 700–1000 ng/ml is associated with an increased likelihood of adverse events.
Kidney dysfunction
In patients with severe renal impairment (creatinine clearance 35 ml/min/1.73 m2 or less), the initial dose of the drug should not exceed 100 mg per day (or 50 mg 2 times a day). For such patients, monitoring of the concentration of the substance in the blood plasma is strongly recommended. Depending on the effect and tolerability, the dose can be gradually and carefully increased. After 6-7 days, the dosage regimen should be adjusted taking into account the effectiveness and tolerability of therapy. In some patients with severe renal impairment, the clearance of flecainide is very slow, resulting in an increase in the half-life (60-70 hours).
Liver dysfunction
When using the drug in patients with impaired liver function, careful monitoring is necessary; the initial dose should not exceed 100 mg per day (50 mg 2 times a day).
The drug should be used with caution in patients with an implanted pacemaker; the daily dose should not exceed 100 mg, divided into 2 doses.
When using the drug simultaneously with cimetidine or amiodarone, careful monitoring is necessary. In the treatment of some patients, the dose should be reduced, the daily dose should not exceed 100 mg, which is divided into 2 doses. It is necessary to monitor the condition of patients during both initial and maintenance therapy.
Monitoring of the concentration of the substance in the blood plasma and ECG monitoring (control ECGs once a month) is recommended. During the initial stage of therapy and when the dose is increased, ECG examinations should be performed every 2-4 days.
When using Lixarit in patients requiring dose limitation, frequent ECG monitoring (in addition to monitoring of flecainide plasma concentrations) should be performed. Dose adjustments should be made at intervals of 6-8 days. To monitor individual dosing regimen, ECG monitoring of such patients should be performed 2 and 3 weeks after initiation of therapy.
Children
Flecainide is not recommended for children under 13 years of age due to a lack of adequate data on its safety and effectiveness.
Overdose
Overdose with flecainide is life-threatening and requires immediate medical attention. Hypersensitivity to the drug and an increase in plasma concentrations above therapeutic levels may also occur due to interactions with other drugs. There is no specific antidote. There is no known method for rapidly removing flecainide from the body. Dialysis or hemoperfusion is ineffective.
Supportive therapy is necessary, preferably to remove unabsorbed material from the gastrointestinal tract. Inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol may be used in the future, as well as mechanical ventilation and measures to support the circulation (e.g. pump for auxiliary circulation). The use of a temporary transvenous pacemaker should be considered in case of conduction block. Since the plasma half-life is approximately 20 hours, these supportive measures should be continued for a long time.
Forced diuresis with urine oxidation theoretically promotes the excretion of the substance.
Side effects
As with other antiarrhythmic agents, flecainide may cause exacerbation of arrhythmias. Symptoms of pre-existing arrhythmias may be exacerbated or a new episode may develop. The risk of proarrhythmic effects is greatest in patients with organic heart disease and/or significant left ventricular dysfunction.
The most common adverse events are second- or third-degree AV block, bradycardia, heart failure, chest pain, myocardial infarction, hypotension, sinus node arrest, tachycardia (atrial and ventricular), and palpitations.
Common adverse reactions such as dizziness and visual disturbances are observed in approximately 15% of patients when using the drug. These adverse reactions usually disappear with continued therapy or dose reduction. The list of adverse reactions is based on clinical trial data and data obtained during post-marketing surveillance.
Adverse reactions are classified by system organ class and frequency. The frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
From the side of the hematopoietic and lymphatic system: infrequent - decrease in the number of erythrocytes, decrease in the number of leukocytes and decrease in the number of platelets.
On the part of the immune system: very rare - an increase in the number of antinuclear antibodies, associated or not associated with systemic inflammation.
On the part of the psyche: rare - hallucinations, depression, confusion, anxiety, amnesia, insomnia.
Nervous system: very common - dizziness, which usually resolves quickly; rare - paresthesia, ataxia, hypoesthesia, hyperhidrosis, fainting, tremor, hot flashes, drowsiness, headache, peripheral neuropathy, convulsions, dyskinesia.
On the part of the organs of vision: very common - visual disturbances, such as diplopia and blurred vision; very rare - corneal precipitate.
On the part of the organs of hearing and balance: rare - tinnitus, dizziness of the vertigo type.
From the side of the cardiac system: frequent - proarrhythmic effect (most likely in patients with heart diseases of organic origin); infrequent - in patients with atrial fibrillation, the development of 1:1 AV conduction with an increase in heart rate is possible; frequency unknown - a dose-dependent increase in PR and QRS intervals is possible.
Changing the sensitivity threshold to the pacemaker signal.
Second or third degree atrioventricular (AV) block, cardiac arrest, bradycardia, heart failure/congestive heart failure, chest pain, hypotension, myocardial infarction, palpitations, sinus node arrest, tachycardia (atrial and ventricular), atrial fibrillation. Manifestation of symptoms of existing Brugada syndrome.
From the respiratory system: frequent - shortness of breath; rare - pneumonitis; frequency unknown - pulmonary fibrosis, interstitial lung disease.
On the part of the digestive system: infrequent - nausea, vomiting, constipation, abdominal pain, decreased appetite, diarrhea, dyspepsia, flatulence.
On the part of the hepatobiliary system: rare - increased activity of liver enzymes, with or without jaundice; frequency unknown - impaired liver function.
Skin and subcutaneous tissue disorders: uncommon - allergic dermatitis, including rash, alopecia; rare - severe urticaria; very rare - photosensitivity reaction.
Systemic disorders and disorders at the injection site: common - asthenia, fatigue, fever, edema.
Expiration date
2 years.
Storage conditions
Store in the original packaging out of the reach of children. No special storage conditions required.
Packaging
15 tablets in a blister; 2 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Laboratorios Norman, S.A.
Address
In case of side effects and questions regarding the safety of the drug, please contact the pharmacovigilance department of ASINO UKRAINE LLC at:
Vaclav Havel Boulevard, building 8, Kyiv, 03124,
phone/fax: +38 044 281 2333.
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