Almarytm - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Flecainide (Flecainide acetate)

ALMARYTM 100 mg tablets

Almarytm package inserts are available for pack sizes:
  • ALMARYTM 100 mg tablets
  • ALMARYTM 150 mg / 15 ml solution for injection

Indications Why is Almarytm used? What is it for?

  • Almarytm is indicated in patients without organic heart disease for paroxysmal supraventricular tachycardias including atrioventricular nodal reentry tachycardia, atrioventricular reentry tachycardia, other unspecified mechanism supraventricular tachycardias associated with disabling symptoms and associated paroxysmal atrial fibrillation / flutter. to disabling symptoms.
  • Almarytm is also indicated for the treatment of documented and life-threatening ventricular hyperkinetic arrhythmias such as sustained ventricular tachycardia.

In patients with sustained ventricular tachycardia, treatment with Almarytm must be initiated in the hospital and followed by a specialist doctor who will periodically evaluate the efficacy of the long-term treatment using specific methods.

Contraindications When Almarytm should not be used

  • Hypersensitivity to flecainide or to any of the excipients listed in the "Composition" section.
  • Heart failure and patients with a history of myocardial infarction with asymptomatic ventricular ectopias or asymptomatic non-sustained ventricular tachycardia.
  • Cardiogenic shock.
  • Patients with long-standing atrial fibrillation in whom there has been no attempt to convert to sinus rhythm, and patients with haemodynamically significant valvular heart disease.
  • Established Brugada syndrome.
  • Unless a pacemaker is available for emergency cardiac stimulation, Almarytm should not be given to patients with sinus node dysfunction, atrial conduction disturbances, second degree or greater atrioventricular block, bundle bundle block or distal block. .
  • In the case of a pre-existing myocardial infarction the use of Almarytm is contraindicated except in the treatment of life-threatening ventricular arrhythmias.
  • Finally, it should be borne in mind that in consideration of the proarrhythmic effect of flecainide, Almarytm should not be administered in arrhythmias not included among the indications and, in particular, it is contraindicated in asymptomatic ventricular arrhythmias and less severe symptomatic ones.

Precautions for use What you need to know before taking Almarytm

Chronic atrial fibrillation.

THE USE OF FLECAINIDE IN CHRONIC ATRIAL FIBRILLATION MUST BE AVOIDED, AS IT IS NOT SUFFICIENTLY DOCUMENTED.

Proarrhythmic effects (see also "Special warnings").

Treatment with oral Almarytm should take place in hospital or under the supervision of a specialist for patients with:

  • Reciprocating nodal AV tachycardia; arrhythmias associated with Wolff-Parkinson-White syndrome and in similar conditions with accessory conduction pathways.
  • Paroxysmal atrial fibrillation in patients with disabling symptoms.

Heart failure.

Almarytm should be avoided in patients with structural heart disease or abnormal left ventricular function (see section "Undesirable effects"). Almarytm has a negative inotropic effect that can cause or aggravate congestive heart failure, especially in patients with cardiomyopathy, pre-existing severe heart failure (NYHA functional class III or IV) or reduced ejection fraction (less than 30%). In patients with supraventricular arrhythmias, occurrence or worsening of heart failure is observed in 0.4% of cases during treatment with flecainide. The onset or worsening of congestive heart failure attributable to flecainide therapy in patients with sustained ventricular tachycardia occurred in approximately 6.3% of cases. Particular attention should be paid to maintaining cardiac function, including optimization of digitalis, diuretic or other therapy. In cases where the insufficiency had developed or worsened during treatment with flecainide, the time to onset varied from a few hours to several months after initiation of therapy. Almarytm treatment may continue therapy with digitalis or diuretic dose adjustments; others may require dose reduction or discontinuation of Almarytm therapy. If possible, it is recommended that plasma levels of flecainide be monitored and should be kept below 0.7-1.0 µg / ml.

Sinus node disease (bradycardia-tachycardia syndrome).

Almarytm should be used with extreme caution in patients with sinus node disease as it can induce sinus bradycardia, sinus pause or arrest.

Almarytm should be used with caution in patients with acute onset of atrial fibrillation after cardiac surgery.

Electrolyte changes.

Any electrolyte disturbances (eg hypo- and hyperkalaemia) must be corrected before using Almarytm (see "Interactions" section). Severe bradycardia or marked hypotension must be corrected before using Almarytm.

Brugada syndrome.

A Brugada syndrome can be unmasked thanks to Almarytm therapy. If ECG changes which may indicate Brugada syndrome develop during treatment with Almarytm, treatment discontinuation should be considered.

Since flecainide is a drug with a low therapeutic index, caution and careful monitoring are required when the patient switches from one formulation to another.

Treatment of patients with other indications should always be initiated in the hospital.

Effects on stimulation thresholds.

Flecainide is known to raise endocardial pacing thresholds, i.e. it can decrease endocardial pacing sensitivity and suppress ventricular escape rhythms. These effects are more pronounced on the acute than chronic stimulation threshold and are reversible with drug withdrawal. Almarytm should therefore be used with caution in all patients with permanent pacemakers or temporary pacing electrodes, and should not be administered to patients with low-threshold pacemakers or non-programmable pacemakers, unless a pacemaker is available to an emergency cardiac stimulation. In patients with pacemakers the pacing threshold should be determined before starting Almarytm therapy, again after one week of dosing and at regular intervals thereafter. Generally, changes in thresholds fall within the range of pluri-programmable pacemakers and, when they occur, doubling either the voltage or the intensity of the stimulus is usually sufficient to regain capture.

Defibrillation has been difficult for some patients. In most of the reported cases, patients suffered from a pre-existing heart disorder with heart enlargement, a history of myocardial infarction, arteriosclerotic heart disease, and heart failure.

Hepatic impairment.

Since elimination of flecainide from plasma may be significantly slower in patients with significant hepatic impairment, Almarytm should not be used in such patients unless the potential benefits outweigh the risks. Any dose increases should be made with great caution, bearing in mind that it takes more than 4 days to reach plateau in such patients Monitoring of plasma levels is recommended.

Renal impairment.

Almarytm should be used with caution in patients with renal impairment (creatinine clearance ≤ 35 ml / min / 1.73 m2) and therapeutic monitoring is recommended.

Elderly patients

The elimination rate of Almarytm from plasma may be reduced in the elderly. This should be taken into consideration when making dose adjustments.

Pediatric population

Almarytm is not recommended in children below 12 years of age, as there is insufficient evidence of its use in this age group.

Interactions Which drugs or foods may change the effect of Almarytm

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.

Class I antiarrhythmics: Almarytm should not be administered concomitantly with other class I antiarrhythmics.

Class II antiarrhythmics: The possibility of additional negative inotropic effects of class II antiarrhythmics, i.e. beta-blockers with Almarytm, should be considered. In a study of healthy subjects treated simultaneously with flecainide and propranolol, the blood levels of one were increased by about 20% and those of the other by about 30% compared to the control values. In this formal interaction study it was shown that the negative inotropic effects characteristic of flecainide and propranolol were additive. The effects on the PR interval were less than additive.

Class III antiarrhythmics: If Almarytm is administered in the presence of amiodarone, the normal dose of Almarytm should be reduced by 50% and the patient should be closely monitored for adverse events. In these circumstances, monitoring of plasma levels is strongly recommended.

Class IV antiarrhythmics: The use of Almarytm with calcium channel blockers, eg verapamil, should be considered with caution. Life-threatening or even lethal adverse events may occur due to interactions causing increased plasma concentrations ( see paragraph "Overdose").

Almarytm is metabolised to a large extent by CYP2D6 and concomitant use of inhibitory drugs (eg antidepressants, neuroleptics, propranolol, ritonavir and some antihistamines) or inducers of this iso-enzyme (eg phenytoin, phenobarbital, carbamazepine) may increase or decrease, respectively. Almarytm plasma concentrations.

An increase in plasma levels may also result from renal insufficiency due to a reduction in the clearance of Almarytm. Hypokalaemia, but also hyperkalaemia or other electrolyte disturbances must be corrected prior to administration of Almarytm. Hypokalaemia may result from concomitant use of diuretics, corticosteroids or laxatives.

Antihistamines: increased risk of ventricular arrhythmias with mizolastine and terfenadine (avoid concomitant use).

Antivirals: Almarytm plasma concentrations are increased by ritonavir, lopinavir, and indinavir (increased risk of ventricular arrhythmias, avoid concomitant use).

Antidepressants: fluoxetine and other antidepressants increase the plasma concentration of Almarytm; increased risk of arrhythmias with tricyclic antidepressants.

Antiepileptics: Limited data in patients treated with known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the elimination rate of Almarytm. Antipsychotics: clozapine: increases the risk of arrhythmias.

Antimalarials: Quinine increases the plasma concentrations of Almarytm.

Antifungals: Terbinafine may increase the plasma concentrations of Almarytm resulting from its inhibition of CYP2D6 activity.

Diuretics: Hypokalaemia, a class effect, can lead to cardiotoxicity.

H2 antihistamines (for the treatment of gastric ulcers): the H2 antagonist cimetidine inhibits the metabolism of Almarytm. In healthy subjects treated with cimetidine (1 g per day) for 1 week, the AUC of Almarytm increased by approximately 30% and the half-life increased by approximately 10%.

Drugs for smoking cessation: Co-administration of bupropion (metabolised by CYP2D6) with Almarytm should be approached with caution and initiated with the lowest recommended dose for the concomitant drug. If bupropion is added to the treatment of a patient already on Almarytm, the need to decrease the Almarytm dosage should be considered.

Cardiac Glucosides: Almarytm may cause an elevation of the plasma digoxin concentration level of approximately 15%, which is unlikely to be of clinical relevance for patients with plasma levels within the therapeutic range. In patients being treated with digitalis, it is recommended that plasma digoxin levels be measured no less than 6 hours after each dose of digoxin, before or after administration of Almarytm.

Anticoagulants: Almarytm treatment is compatible with the use of oral anticoagulants.

Warnings It is important to know that:

Almarytm has been shown to increase the risk of post-myocardial infarction mortality in patients with asymptomatic ventricular arrhythmia.

Almarytm, like other antiarrhythmics, can cause pro-arrhythmic effects, ie it can cause the appearance of a more severe type of arrhythmia, increase the frequency of an existing arrhythmia or the severity of symptoms (see "Side Effects"). In studies with flecainide used to treat ventricular arrhythmias, 75% of proarrhythmic events were new or aggravated ventricular tachyarrhythmias, the remainder being increases in the rate of ventricular ectopic beats or new supraventricular arrhythmias.

Considering patients treated with flecainide for sustained ventricular tachycardia, 80% of proarrhythmic events occurred within 14 days of initiation of therapy. In patients treated for supraventricular arrhythmia, proarrhythmic events were found in 4% of cases and consisted of "worsening" of the supraventricular arrhythmia, or the occurrence (in patients with myocardial ischaemia) of ventricular arrhythmia.

In patients with complex arrhythmias it is often difficult to distinguish a spontaneous change in pre-existing individual rhythm disorder from drug-induced worsening; therefore the consequent percentages are to be considered approximate. Proarrhythmic effects were reported in 7% of patients treated with flecainide. Their frequency was related to dose and pre-existing cardiac disease.

Among patients treated for sustained ventricular tachycardia (who also frequently presented with heart failure, reduced ejection fraction, previous myocardial infarction and / or episodes of cardiac arrest), the incidence of proarrhythmic events was 13% when dosing was started. to 200 mg / day with gradual increases not exceeding 300 mg / day in most patients. In preliminary studies on patients with sustained ventricular tachycardia undergoing a higher starting dose (400 mg / day) the incidence of proarrhythmic events was 26% with fatal evolution in about 10% of treated patients; with lower starting doses, the "incidence of proarrhythmic events with fatal evolution decreased to 0.5%. It is therefore extremely important to follow the recommended dosage schedule (see "Dose, method and time of administration").

Effects on cardiac conduction.

Almarytm slows cardiac conduction prolongs the QT interval and widens the QRS complex by 12-20%. The effect on the JT interval is insignificant.

The PR interval increases on average by approximately 25% (0.04 seconds) and up to 118% in some patients. Approximately one third of patients may develop new first degree AV heart block (PR interval> 0, 20 seconds).

The QRS complex increases on average by about 25% (0.02 seconds) and up to 150% in some patients. In many patients, QRS complexes lasting 0.12 seconds or longer develop.

In one study, a new branch block developed in 4% of patients during treatment with flecainide. The degree of lengthening of the PR and QRS intervals is neither predictive of efficacy nor of the occurrence of adverse cardiac reactions. In clinical studies, an increase in PR intervals of 0.30 seconds or greater or QRS intervals of 0.18 seconds or more was unusual. Should such increases occur, caution should be exercised and possible dose reductions considered.

One case of "Torsade de Pointes" arrhythmia associated with flecainide therapy has been reported.

Clinically significant conduction changes were observed with the following frequencies: sinus node dysfunction such as sinus pause, sinus arrest and sinus bradycardia (1.2%), second degree AV block (0.5%) and third degree AV block grade (0.4%). To minimize this effect (see "Dose, method and time of administration"), the patient should be treated with the lowest effective dose.

In case of second degree or third degree AV block or right bundle bundle block associated with left hemiblock, Almarytm therapy should be discontinued unless there is an implanted or temporary ventricular pacemaker to ensure adequate ventricular rhythm.

As with other Class I drugs, there have been reports of 1: 1 atrioventricular conduction in patients treated for atrial flutter, referable to a slowing of the atrial rate.

Patients with atrial fibrillation treated with Almarytm may also experience a paradoxical increase in ventricular rate. The risk of this complication can be decreased by concomitant negative chronotropic therapy with digoxin or beta blockers.

Dairy products (milk, infant formula and possibly yogurt) may reduce the absorption of flecainide in children and infants. The use of flecainide is not authorized in children under the age of 12, however toxicity from flecainide has been reported during Almarytm treatment in infants who have reduced milk intake and in infants who have switched from formula feeding to dextrose feeding.

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy

There are no adequate data on the safety of flecainide in pregnancy. Data showed that flecainide crosses the placenta to the fetus in patients treated with flecainide during pregnancy. Flecainide should only be used in pregnancy if the benefits outweigh the risks. Labor and delivery It is not known whether the use of flecainide during labor or delivery has immediate or late secondary effects on the mother or fetus, affects the duration of labor or delivery, or increases the possibility of delivery with forceps or other obstetric interventions. .

Feeding time

Flecainide is excreted in breast milk. The plasma concentrations obtained in an infant are 5-10 times lower than the therapeutic drug concentrations. Assuming a maternal plasma level at the peak of the therapeutic range (1 µg / ml), the calculated dose per infant who takes about 700 ml of breast milk at day should be less than 3 mg. Although the risk of harmful effects to the infant is small, flecainide should only be used during breastfeeding if the benefits outweigh the risks.

Effects on ability to drive and use machines

Almarytm moderately affects the ability to drive and use machines. The ability to drive, use machines or work unsafe may be affected by the onset of adverse reactions such as dizziness and visual disturbances.

Dosage and method of use How to use Almarytm: Dosage

In patients with sustained ventricular tachycardia, regardless of their cardiac status, Almarytm therapy, as with other antiarrhythmics, should be initiated in hospital with heart rhythm monitoring.

Flecainide has a long half-life (12 to 27 hours in patients). Stable blood levels in patients with normal renal and hepatic function are reached no earlier than 3 to 5 days of therapy at a given dose. Therefore, dose adjustments should be made no more frequently than once every four days, as the optimal effect of a given dose may not have been achieved during the first 2 or 3 days of therapy.

For patients with sustained ventricular tachycardia the recommended starting dose is 100 mg every 12 hours. This dose can be increased in increments of 50 mg twice daily every four days until the effective dose is achieved. Most such patients do not require more than 150 mg every 12 hours (300 mg / day), and the dose maximum recommended is 400 mg / day.

For patients with supraventricular arrhythmia the recommended starting dose is 50 mg every 12 hours. This dose can be increased in 50 mg increments twice a day every 4 days until the effective dose is reached.

In patients with paroxysmal atrial fibrillation, a substantial increase in efficacy can be achieved without a significant increase in adverse events by increasing the dose of Almarytm from 50 to 100 mg twice daily.

The maximum recommended dose for patients with paroxysmal supraventricular arrhythmia is 300 mg / day.

The use of higher starting doses and faster dose adjustments resulted in an increased incidence of proarrhythmic events and congestive failure, especially during the first days of treatment (see "Special warnings"). Therefore a loading dose is not recommended.

Following administration of Almarytm tablets, in anticipation of the therapeutic effect of flecainide, the drug has occasionally been associated with intravenous administration of lidocaine. No interaction effects appeared; on the other hand, no formal studies have yet been conducted to demonstrate the usefulness of this therapeutic regimen.

Occasionally patients inadequately controlled by (or intolerant to) a 12 hour dose interval may take doses at 8 hour intervals.

Once adequate control of the arrhythmia has been achieved, it may be possible, in some patients, to reduce the dose as necessary to minimize unwanted or conduction effects. In such patients, efficacy at the lower dose should be evaluated.

Almarytm should be used with caution in patients with a history of congestive heart failure or myocardial dysfunction (see "Precautions for use") and in patients with renal and / or hepatic dysfunction.

Renal impairment

In patients with severe renal impairment (creatinine clearance equal to or less than 35 ml / min / 1.73 m2) the starting dose should be 100 mg once daily (or 50 mg twice daily); Dosage adjustment should be guided by plasma level monitoring (see below: "Plasma Level Monitoring").

In patients with less severe renal impairment, the starting dose should be 100 mg every 12 hours; Plasma monitoring during dose adjustment is always useful. In both groups of patients, this adjustment should be made with great caution; once the plateau has been reached (after more than 4 days), it should be carefully considered that in such patients, after the dose change, it may take more than 4 days to reach the new plateau.

Elderly patients

The rate of elimination of flecainide from plasma may be reduced in the elderly. A starting dose of 100 mg twice daily is generally adequate and may be reduced after the first week in maintenance therapy.

Switching to Almarytm from another antiarrhythmic drug

On the basis of theoretical considerations rather than experimental results, the following is suggested: in the case of switching from a therapy with another antiarrhythmic drug to Almarytm, allow two to four plasma half-lives of the drug that is discontinued to pass before starting Almarytm at the usual dosage . In patients in whom discontinuation of a previous antiarrhythmic agent is likely to induce even very severe arrhythmias, the physician should consider hospitalization for the patient.

When flecainide is administered with amiodarone, the usual dose of flecainide should be reduced by 50% and the patient closely monitored, including with monitoring of plasma levels.

Monitoring of plasma levels

It was observed that the vast majority of patients successfully treated with Almarytm had plasma drug levels between 0.2 and 1.0 µg / ml.

The likelihood of undesirable effects, especially cardiac effects, may increase with higher plasma concentrations, especially when these exceed 1.0 µg / ml. Periodic monitoring of plasma levels may be helpful during therapy. Monitoring of plasma levels is important in patients with severe hepatic or renal impairment, in whom elimination may be slowed. It is also recommended in patients with associated amiodarone and may also be useful in patients with congestive heart failure and renal impairment although of modest entity.

Overdose What to do if you have taken too much Almarytm

Overdose with flecainide is a "potentially life-threatening medical emergency." Increased sensitivity to the drug and plasma concentrations above therapeutic levels may also result from drug interactions (see "Interactions").

Animal investigations suggest that the following events may occur following overdose: prolongation of the PR interval, increase in QRS duration, QT interval and T wave amplitude; reduction in the rhythm and contractility of the myocardium; conduction disturbances; hypotension and death from respiratory failure or asystole.

No specific antidote is known. There are no known methods of rapidly removing flecainide from the body. Neither dialysis nor hemoperfusion are effective. Treatment should therefore be supportive and may include removal of unabsorbed drug from the gastrointestinal tract.

Additional measures may include inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol as well as mechanical ventilation and circulatory assistance (eg balloon dilation). Temporary insertion of a transvenous pacemaker should be considered in the event of blockade. conduction. Due to flecainide's long plasma half-life of approximately 20h, these supportive measures may need to be continued for an extended period of time. Forced diuresis with acidification of the urine theoretically promotes urinary excretion of flecainide.

Side Effects What are the side effects of Almarytm

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and <1/10), uncommon (≥ 1/1000 and <1/100), rare (≥1 / 10,000 and < 1/1000) and very rare (<1 / 10,000), not known (cannot be estimated from the available data).

Alterations of the blood and lymphatic system:

uncommon: red blood cell count decreased, white blood cell count decreased, platelet count decreased.

Immune system disorders:

very rare: antinuclear antibody increase with or without systemic inflammation.

Psychiatric disorders:

uncommon: impotence, decreased libido, depersonalization, euphoria, increased dream activity, apathy, stupor;

rare: hallucinations, depression, confusional state, anxiety, amnesia, insomnia.

Nervous system disorders:

very common: dizziness, usually transient;

rare: paraesthesia, ataxia, hypoesthesia, hyperhidrosis, syncope, tremor, involuntary contractions, flushing, somnolence, headache, peripheral neuropathy, convulsions, dyskinesia, paresis, speech disturbances.

Eye disorders:

very common: visual impairment, such as diplopia and blurred vision;

uncommon: eye irritation, photophobia, nystagmus;

very rare: corneal deposits

Ear and labyrinth disorders:

rare: tinnitus, dizziness;

Cardiac disorders:

common: proarrhythmia (more likely in patients with structural heart disease);

uncommon: hypertension. Patients with atrial flutter may develop 1: 1 AV conduction with increased heart rate;

not known: dose-related increases in PR and QRS intervals; pacing threshold alteration, second and third degree atrioventricular block, cardiac arrest, bradycardia, heart failure / congestive heart failure, chest pain, hypotension, myocardial infarction, palpitations, sinus arrest and tachycardia (AT or VT) or ventricular fibrillation. Exposing a pre-existing Brugada syndrome.

Respiratory, thoracic and mediastinal disorders:

common: dyspnoea;

uncommon: bronchospasm;

rare: pneumonia;

not known: pulmonary fibrosis, interstitial lung disease.

Gastrointestinal disorders:

uncommon: nausea, vomiting, constipation, abdominal pain, decreased appetite, diarrhea, dyspepsia, flatulence, dry mouth, altered taste.

Hepatobiliary disorders:

rare: increased liver enzymes with or without jaundice;

not known: hepatic dysfunction.

Skin and subcutaneous tissue disorders:

uncommon: pruritus, exfoliative dermatitis, allergic dermatitis, including rash, alopecia;

rare: severe urticaria;

very rare: photosensitivity reactions;

Musculoskeletal and connective tissue disorders:

uncommon: arthralgia, myalgia;

Renal and urinary disorders:

uncommon: polyuria, urinary retention;

General disorders and administration site conditions:

common: asthenia, fatigue, fever, edema, malaise;

uncommon: swollen lips, tongue and mouth.

Although no cause and effect relationship has been established, it is advisable to discontinue the administration of Almarytm in patients with unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate flecainide as a possible cause.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Do not use the medicine after the expiry date indicated on the package. The expiry date refers to the last day of the month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

KEEP THE MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN.

Other_information "> Other information

Composition

Each tablet contains:

Active ingredient: flecainide acetate 100 mg.

Excipients: gelatinized maize starch; cross-caramellose sodium; microcrystalline cellulose; hydrogenated vegetable oil; magnesium stearate.

Pharmaceutical form

20 tablets for oral use dosed at 100 mg of flecainide acetate.

60 tablets for oral use dosed at 100 mg of flecainide acetate.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Almarytm can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

ALMARYTM 100 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Flecainide acetate is a benzamide N- (2-piperidinmethyl) 2,5 bis (2,2,2 trifluoroethoxy) monoacetate.

It occurs as a white powder (pKa = 9.3) soluble in water in 48.4 mg / ml at 37 ° C.

Each tablet contains :

Active principle

Flecainide acetate 100 mg.

03.0 PHARMACEUTICAL FORM -

Tablets.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

ALMARYTM is indicated in patients without organic heart disease in paroxysmal supraventricular tachycardias including atrioventricular nodal reentry tachycardia, atrioventricular reentry tachycardia, other unspecified supraventricular tachycardias associated with disabling symptoms, and paroxysmal atrial fibrillation / flutter associated with disabling symptoms.

ALMARYTM is also indicated for the treatment of documented and life-threatening ventricular hyperkinetic arrhythmias such as sustained ventricular tachycardia.

In patients with sustained ventricular tachycardia, treatment with ALMARYTM should be initiated in the hospital and followed by the specialist doctor who will periodically evaluate the efficacy of the long-term treatment with specific methods.

04.2 Posology and method of administration -

In patients with sustained ventricular tachycardia, regardless of their cardiac status, ALMARYTM therapy, as with other antiarrhythmics, should be initiated in hospital with rhythm monitoring.

Flecainide has a long half-life (12 to 27 hours in patients). Stable blood levels in patients with normal renal and hepatic function are reached no earlier than 3-5 days of therapy at a given dose. Therefore, dose adjustments should be made no more frequently than once every 4 days, as the optimal effect of a given dose may not have been achieved during the first 2 or 3 days of therapy.

For patients with sustained ventricular tachycardia, the recommended starting dose is 100 mg every 12 hours.This dose can be increased in increments of 50 mg twice daily every four days until the effective dose is achieved. Most such patients do not require more than 150 mg every 12 hours (300 mg / day), and the dose maximum recommended is 400 mg / day.

For patients with supraventricular arrhythmia the recommended starting dose is 50 mg every 12 hours. This dose can be increased in 50 mg increments twice daily every 4 days until the effective dose is reached.

In patients with paroxysmal atrial fibrillation, a substantial increase in efficacy can be achieved, without a significant increase in adverse events, by increasing the dose of ALMARYTM from 50 to 100 mg twice a day.

The maximum recommended dose for patients with paroxysmal supraventricular arrhythmia is 300 mg / day.

The use of higher starting doses and more rapid dose adjustments resulted in an increased incidence of proarrhythmic events and congestive failure, especially during the first days of treatment (see Warnings). Therefore a "loading" dose is not recommended.

After administration of ALMARYTM tablets, in anticipation of the therapeutic effect of flecainide, the drug was occasionally associated with intravenous administration of lidocaine. No interaction effects appeared; on the other hand, no formal studies have yet been conducted to demonstrate the usefulness of this therapeutic regimen.

Occasionally patients inadequately controlled by (or intolerant to) a 12 hour dose interval may take doses at 8 hour intervals.

Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize unwanted or conduction effects. In such patients efficacy should be evaluated at the lower dose.

ALMARYTM should be used with caution in patients with a history of congestive heart failure or myocardial dysfunction (see Warnings).

In patients with severe renal impairment (creatinine clearance 35 ml / min / 1.73 m² or less) the starting dose should be 100 mg once daily (or 50 mg twice daily); dosage adjustment should be guided by plasma level monitoring (see plasma level monitoring).

In patients with less severe renal impairment, the starting dose should be 100 mg every 12 hours; Plasma monitoring during dosage adjustment is always useful. In both groups of patients, this adjustment should be made with great caution; once the plateau has been reached (after more than 4 days) it should be carefully considered that in these patients, after change of dose, it may take more than 4 days to reach the new plateau.

Elderly patients: The rate of elimination of flecainide from plasma may be reduced in the elderly. A starting dose of 100 mg twice daily is generally adequate and may be reduced after the first week in maintenance therapy.

On the basis of theoretical considerations rather than experimental results, the following is suggested: in the case of switching from a therapy with another antiarrhythmic drug to ALMARYTM, allow two to four plasma half-lives of the drug that is discontinued before starting ALMARYTM at the usual dosage . In patients in whom discontinuation of a previous antiarrhythmic agent is likely to induce even very severe arrhythmias, the physician should consider hospitalization for the patient.

When flecainide is administered with amiodarone, the usual dose of flecainide should be reduced by 50% and the patient closely monitored, including with monitoring of plasma levels.

Monitoring of plasma levels: It was observed that the vast majority of patients successfully treated with ALMARYTM had plasma drug levels between 0.2 and 1.0 mcg / mL.

The likelihood of undesirable effects, especially cardiac effects, may increase with higher plasma concentrations, especially when these exceed 1.0 mcg / ml. Periodic monitoring of plasma levels may be helpful during therapy. Monitoring of plasma levels is important in patients with severe hepatic or renal impairment, in whom elimination may be slowed. It is also recommended in patients with associated amiodarone and may also be useful in patients with congestive heart failure and renal impairment although of modest entity.

04.3 Contraindications -

Hypersensitivity to flecainide or to any of the excipients

ALMARYTM is contraindicated in heart failure and in patients with a history of myocardial infarction suffering from asymptomatic ventricular ectopias or asymptomatic non-sustained ventricular tachycardia.

ALMARYTM is contraindicated in the presence of cardiogenic shock.

It is also contraindicated in patients with long-standing atrial fibrillation in whom there has been no attempt to convert to sinus rhythm, and in patients with haemodynamically significant valvular heart disease.

Established Brugada syndrome.

Unless a pacemaker is available for emergency cardiac pacing, ALMARYTM should not be administered to patients with sinus node dysfunction, atrial conduction disturbances, second degree or greater atrioventricular block, bundle bundle block or distal block .

In the case of a pre-existing myocardial infarction the use of ALMARYTM is contraindicated except in the treatment of ventricular arrhythmias which are life-threatening.

It should also be borne in mind that in consideration of the proarrhythmic effect of flecainide, the use of ALMARYTM is not recommended in arrhythmias not included among the indications and, in particular, it is contraindicated in asymptomatic ventricular arrhythmias and less severe symptomatic ones.

04.4 Special warnings and appropriate precautions for use -

THE USE OF FLECAINIDE IN CHRONIC ATRIAL FIBRILLATION IS NOT RECOMMENDED AS IT IS NOT SUFFICIENTLY DOCUMENTED.

Treatment with oral ALMARYTM should take place in hospital or under the supervision of a specialist for patients with:

- Reciprocating nodal AV tachycardia; arrhythmias associated with Wolff-Parkinson-White syndrome and similar conditions with accessory conduction pathways.

- Paroxysmal atrial fibrillation in patients with disabling symptoms.

ALMARYTM has been shown to increase the risk of post-myocardial infarction mortality in patients with asymptomatic ventricular arrhythmia.

ALMARYTM, like other antiarrhythmics, can cause pro-arrhythmic effects, i.e. it can cause the appearance of a more severe type of arrhythmia, increase the frequency of an existing arrhythmia or the severity of symptoms (see section 4.8).

In studies with flecainide used to treat ventricular arrhythmias, 75% of the proarrhythmic events were new or aggravated ventricular tachyarrhythmias, the remainder were increases in the rate of ventricular ectopic beats or new supraventricular arrhythmias.

Considering patients treated with flecainide for sustained ventricular tachycardia, 80% of proarrhythmic events occurred within 14 days of initiation of therapy.

In patients treated for supraventricular arrhythmia, proarrhythmic events were found in 4% and consisted of "worsening" of the supraventricular arrhythmia, or the occurrence (in patients with myocardial ischaemia) of ventricular arrhythmia.

In patients with complex arrhythmias it is often difficult to distinguish a spontaneous change in pre-existing individual rhythm disorder from drug-induced worsening; therefore the consequent percentages are to be considered approximate. Proarrhythmic effects were reported in 7% of patients treated with flecainide. Their frequency was related to dose and pre-existing cardiac disease.

Among patients treated with flecainide for sustained ventricular tachycardia (who also frequently presented with heart failure, reduced ejection fraction, previous myocardial infarction and / or episodes of cardiac arrest), the incidence of proarrhythmic events was 13% when the posology it was started at 200 mg / day with gradual increases without exceeding 300 mg / day in most patients. In preliminary studies on patients with sustained ventricular tachycardia undergoing a higher starting dose (400 mg / day) the incidence of proarrhythmic events was 26% with fatal evolution in about 10% of treated patients; with lower starting doses, the "incidence of proarrhythmic events with fatal evolution decreased to 0.5%. It is therefore extremely important to follow the recommended dosing schedule (see Posology).

ALMARYTM should be avoided in patients with structural heart disease or abnormal left ventricular function (see section 4.8). ALMARYTM has a negative inotropic effect that can cause or aggravate congestive heart failure, especially in patients with cardiomyopathy, pre-existing severe heart failure (NYHA functional class III or IV) or reduced ejection fraction (less than 30%). In patients with supraventricular arrhythmias, occurrence or worsening of heart failure is observed in 0.4% during treatment with flecainide. The onset or aggravation of congestive heart failure attributable to flecainide therapy in patients with sustained ventricular tachycardia occurred in approximately 6.3%.

Particular attention should be paid to the maintenance of cardiac function, including the optimization of digitalis, diuretic or other therapy. In cases where the insufficiency had developed or worsened during treatment with flecainide, the time to onset varied from a few hours to several months after starting therapy. Some patients who have developed decreased myocardial function during treatment with ALMARYTM may continue therapy with digitalis or diuretic dose adjustments; others may require dose reduction or discontinuation of ALMARYTM therapy. If possible, it is recommended that plasma levels of flecainide be monitored and should be kept below 0.7-1.0 μg / mL.

ALMARYTM should be used with caution in patients with acute onset of atrial fibrillation after cardiac surgery.

Treatment of patients with other indications should continue to be initiated in the hospital.

ALMARYTM slows cardiac conduction, prolongs the QT interval and widens the QRS complex by 12-20%. The effect on the JT interval is insignificant. The PR interval increases on average by approximately 25% (0.04 seconds) and up to 118% in some patients. Approximately one third of patients may develop new first degree AV heart block (PR interval ≥ 0, 20 seconds).

In many patients, QRS complexes lasting 0.12 seconds or longer develop.

In one study, a new branch block developed in 4% of patients during treatment with flecainide. The degree of lengthening of the PR and QRS intervals is neither predictive of efficacy nor of the occurrence of adverse cardiac reactions. In clinical studies, an increase in PR intervals of 0.30 seconds or greater or QRS intervals of 0.18 seconds or more was unusual. Should such increases occur, caution should be exercised and possible dose reductions considered.

One case of "Torsade de Pointes" arrhythmia associated with flecainide therapy has been reported.

Clinically significant conduction changes were observed with the following frequencies: sinus node dysfunction such as sinus pause, sinus arrest and sinus bradycardia (1.2%), second degree AV block (0.5%) and third degree AV block grade (0.4%). To minimize these effects (see "Posology"), the patient should be treated with the lowest effective dose.

In the event of second degree or third degree AV block or right bundle bundle block associated with left hemiblock, ALMARYTM therapy should be discontinued unless there is an implanted or temporary ventricular pacemaker to ensure adequate ventricular rhythm.

As with other Class 1 drugs, there have been reports of 1: 1 atrioventricular conduction in patients treated for atrial flutter, referable to a slowing of the atrial rate.

Patients with atrial fibrillation treated with ALMARYTM may also experience a periodoxical increase in the ventricular rate. The risk of this complication can be decreased by concomitant negative chronotropic therapy with digoxin or beta blockers.

ALMARYTM should be used with extreme caution in patients with sinus node disease as it can induce sinus bradycardia, sinus pause or arrest.

A Brugada syndrome can be unmasked thanks to ALMARYTM therapy. In case of development of ECG changes during treatment with ALMARYTM that may indicate Brugada syndrome, treatment discontinuation should be considered.

Since elimination of ALMARYTM from plasma may be significantly slower in patients with significant hepatic impairment, ALMARYTM should not be used in such patients unless the potential benefits outweigh the risks. Any dose increases should be made with great caution, bearing in mind that, in such patients, reaching the plateau takes more than 4 days.

Plasma level monitoring is recommended.

ALMARYTM should be used with caution in patients with renal impairment (creatinine clearance ≤ 35 ml / min / 1.73 m²) and therapeutic monitoring is recommended.

The rate of elimination of ALMARYTM from plasma may be reduced in the elderly. This should be taken into consideration when making dose adjustments.

ALMARYTM is not recommended for children under 12 years of age, as there is insufficient evidence of its use in this age group.

Electrolyte disturbances (e.g. hypo and hyperkalaemia) must be corrected before using ALMARYTM (see section 4.5).

Severe bradycardia or marked hypotension must be corrected before using ALMARYTM.

ALMARYTM is known to increase endocardial pacing thresholds, i.e. to decrease endocardial pacing sensitivity. This effect is reversible and is more marked on the acute than chronic stimulation threshold. ALMARYTM should therefore be used with caution in all patients with permanent pacemakers or temporary pacing electrodes, and should not be administered to patients with low-threshold pacemakers or non-programmable pacemakers, unless a pacemaker is available to an emergency cardiac stimulation.

Defibrillation has been difficult for some patients. In most of the reported cases, patients suffered from a pre-existing heart disorder with heart enlargement, a history of myocardial infarction, arteriosclerotic heart disease, and heart failure. In patients with pace-makers the stimulation threshold should be determined before starting ALMARYTM therapy, again after one week of administration and at regular intervals thereafter. Generally the variations of the thresholds fall within the range of multi-programmable "pace-makers" and, when they intervene, the doubling of either the voltage or the intensity of the stimulus is usually sufficient to regain capture.

For further warnings and precautions please refer to section 4.5.

04.5 Interactions with other medicinal products and other forms of interaction -

Class I antiarrhythmics: Almarytm should not be administered concomitantly with other class I antiarrhythmics.

Class II antiarrhythmics: The possibility of additional negative inotropic effects of class II antiarrhythmics, i.e. beta-blockers with Almarytm, should be considered. In a study of healthy subjects receiving flecainide and propanolol simultaneously, the blood levels of one were increased by about 20% and those of the other by about 30% compared to the control values. In this formal interaction study it was shown that the negative inotropic effects characteristic of flecainide and propanolol were additive. The effects on the PR interval were less than additive.

Class III antiarrhythmics: If Almarytm is administered in the presence of amiodarone, the normal dose of Almarytm should be reduced by 50% and the patient should be closely monitored for adverse events. In these circumstances, monitoring of plasma levels is strongly recommended.

Class IV antiarrhythmics: The use of Almarytm with calcium channel blockers, eg verapamil, should be considered with caution.

Life-threatening or even fatal adverse events may occur due to interactions causing increased plasma concentrations (see section 4.9).

Almarytm is metabolised to a large extent by CYP2D6 and concomitant use of drugs that inhibit or induce this iso-enzyme may increase or decrease the plasma concentrations of Almarytm, respectively.

An increase in plasma levels may also result from renal insufficiency due to decreased clearance of Almarytm (see section 4.4).

Hypokalaemia, but also hyperkalaemia or other electrolyte disturbances must be corrected prior to administration of Almarytm. Hypokalaemia may result from concomitant use of diuretics, corticosteroids or laxatives.

Antihistamines: increased risk of ventricular arrhythmias with mizolastine and terfenadine (avoid concomitant use).

Antivirals: Almarytm plasma concentrations are increased by ritonavir, lopinavir, and indinavir (increased risk of ventricular arrhythmias, avoid concomitant use).

Antidepressants: fluoxetine and other antidepressants increase the plasma concentration of Almarytm; increased risk of arrhythmias with tricyclic antidepressants.

Antiepileptics: Limited data in patients treated with known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the elimination rate of Almarytm.

Antipsychotics: clozapine - increased risk of arrhythmias.

Antimalarials: Quinine increases the plasma concentrations of Almarytm.

Antifungals: Terbinafine may increase the plasma concentrations of Almarytm resulting from its inhibition of CYP2D6 activity.

Diuretics: Hypokalaemia, a class effect, can lead to cardiotoxicity.

Class H2 antihistamines (for the treatment of gastric ulcers): The H2 antagonist cimetidine inhibits the metabolism of Almarytm. In healthy subjects treated with cimetidine (1 g daily) for 1 week, the AUC of Almarytm increased by approximately 30% and the half-life increased by approximately 10%.

Drugs for smoking cessation: Co-administration of bupropion (metabolised by CYP2D6) with Almarytm should be approached with caution and initiated with the lowest recommended dose for the concomitant drug.

If bupropion is added to the treatment of a patient already on Almarytm, the need to decrease the Almarytm dosage should be considered.

Cardiac Glucosides: Almarytm may cause an elevation of the plasma digoxin concentration level of approximately 15%, which is unlikely to be of clinical relevance for patients with plasma levels within the therapeutic range.

In patients being treated with digitalis, it is recommended that plasma digoxin levels be measured no less than 6 hours after each dose of digoxin, before or after administration of Almarytm.

Anticoagulants: Almarytm treatment is compatible with the use of oral anticoagulants.

04.6 Pregnancy and breastfeeding -

Pregnancy

There are no adequate data on the safety of flecainide in pregnancy. In White New Zeland rabbits, high doses of flecainide caused some fetal abnormalities, but these effects were not observed in Duch Belted rabbits or rats (see section 5.3). The relevance of these findings to humans has not been established. Data showed that flecainide crosses the placenta to the fetus in patients treated with flecainide during pregnancy. Flecainide should only be used in pregnancy if the benefits outweigh the risks.

Labor and childbirth

It is not known whether the use of flecainide during labor or delivery has immediate or late secondary effects on the mother or fetus, affects the duration of labor or delivery, or increases the possibility of delivery with forceps or other obstetric interventions.

Feeding time

Flecainide is excreted in breast milk. The plasma concentrations obtained in an infant are 5-10 times lower than the therapeutic drug concentrations (see section 5.2). Assuming a maternal plasma level at the peak of the therapeutic range (1 mcg / ml), the calculated dose per infant taking approximately 700 ml of breast milk per day should be less than 3 mg. Although the risk of harmful effects to the infant is reduced, flecainide should only be used during breastfeeding if the benefits outweigh the risks.

04.7 Effects on ability to drive and use machines -

Almarytm moderately affects the ability to drive and use machines. The ability to drive and use machines can be affected by the onset of adverse reactions such as dizziness and visual disturbances.

04.8 Undesirable effects -

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and

Alterations of the blood and lymphatic system:

uncommon: red blood cell count decreased, white blood cell count decreased, platelet count decreased.

Immune system disorders:

very rare: antinuclear antibody increase with or without systemic inflammation.

Psychiatric disorders:

uncommon: impotence, decreased libido, depersonalization, euphoria, increased dream activity, apathy, stupor

rare: hallucinations, depression, confusional state, anxiety, amnesia, insomnia

Nervous system disorders:

very common: vertigo, usually transient, dizziness

rare: paraesthesia, ataxia, hypoesthesia, hyperhidrosis, syncope, tremor, involuntary contractions, flushing, somnolence, headache, peripheral neuropathy, seizures, dyskinesia, paresis, speech disorders

Eye disorders:

very common: visual impairment, such as diplopia and blurred vision

uncommon: eye irritation, photophobia, nystagmus

very rare: corneal deposits

Ear and labyrinth disorders:

rare: tinnitus, dizziness

Cardiac disorders:

common: proarrhythmia (more likely in patients with structural heart disease).

Not known: dose-related increases in PR and QRS intervals may occur (see section 4.4); modified pacing threshold (see section 4.4).

Uncommon: hypertension. Patients with atrial flutter may develop 1: 1 AV conduction with increased heart rate.

Frequency not known: second and third degree atrioventricular block, cardiac arrest, bradycardia, cardiac insufficiency / congestive heart failure, chest pain, hypotension, myocardial infarction, palpitations, sinus arrest and tachycardia (AT or VT). Exposing a pre-existing Brugada syndrome.

Respiratory, thoracic and mediastinal disorders:

common: dyspnoea

uncommon: bronchospasm

rare: pneumonia

not known: pulmonary fibrosis, interstitial lung disease

Gastrointestinal disorders:

uncommon: nausea, vomiting, constipation, abdominal pain, decreased appetite, diarrhea, dyspepsia, flatulence, dry mouth, taste disturbance

Hepatobiliary disorders:

rare: increased liver enzymes with or without jaundice

not known: hepatic dysfunction

Skin and subcutaneous tissue disorders:

uncommon: pruritus, exfoliative dermatitis, allergic dermatitis, including rash, alopecia

rare: severe urticaria

very rare: photo sensitivity reactions

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia, myalgia

Renal and urinary disorders

Uncommon: polyuria, urinary retention

General disorders and administration site conditions:

common: asthenia, fatigue, fever, edema, malaise

uncommon: swollen lips, tongue and mouth

Although no cause and effect relationship has been established, it is advisable to discontinue administration of ALMARYTM in patients with unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias to eliminate flecainide as a possible cause.

04.9 Overdose -

Overdose with flecainide is a "potentially life-threatening medical emergency." Increased sensitivity to the drug and plasma concentrations above therapeutic levels may also result from drug interactions (see section 4.5).

Animal investigations suggest that the following events may occur following overdose: prolongation of the PR interval, increase in QRS duration, Q-T interval and T wave amplitude; reduction in the rhythm and contractility of the myocardium; conduction disturbances; hypotension; and death from respiratory failure or asystole.

No specific antidote is known. There are no known methods of rapidly removing flecainide from the body. Neither dialysis nor hemoperfusion are effective.

Treatment should be supportive and may include removal of unabsorbed drug from the GI tract. Additional measures may include inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol as well as mechanical ventilation and circulatory assistance (eg balloon dilation). Temporary insertion of a transvenous pacemaker should be considered in the event of blockade. conduction. Due to flecainide's long plasma half-life of approximately 20h, these supportive measures may need to be continued for long periods of time. Forced diuresis with acidification of the urine theoretically promotes urinary excretion of flecainide.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Electrophysiological properties

The results of multiple investigations qualify flecainide acetate as a potent Vaughan-Williams Class 1C antiarrhythmic drug (local anesthetic).

It significantly depresses, to a dose-related extent, conduction within the myocardial tissue by slowing the depolarization of the cardiac cell (phase 0); it is shown to act mainly on the His-Purkinje conduction system (H-V conduction) and, to a lesser extent, on the atrio-ventricular and interatrial nodal conduction.

A significant effect on the refractory period was observed only in the ventricle. The sinus node recovery time (corrected for heart rate of both the spontaneous and stimulated cycle) may significantly increase in some cases, particularly in patients with sinus node disease (see "Warnings").

Hemodynamic properties

Flecainide acetate does not generally change heart rate, although it may rarely be associated with the onset of bradycardia or tachycardia.

However, a slight negative inotropic effect was observed, with a reduction in the ejection fraction after a single dose of 200 mg. The increase or decrease in the ejection fraction was observed during chronic administration of therapeutic doses.

05.2 "Pharmacokinetic properties -

Following oral administration, bioavailability is almost complete (over 90% of the dose) and independent of food. Flecainide does not undergo any significant pre-systemic biotransformation in the liver and, in most cases, induces dose-proportional blood peaks after approximately 3 hours (range 1-6 hours). The established blood levels are reached after 3-5 days from the start of therapy: there has been no evidence of accumulation after prolonged treatment. The therapeutic plasma concentrations of the drug are between 0.2-1.0 mcg / ml.

In healthy subjects, the elimination half-life after single and repeated oral administration is approximately 14 hours. In arrhythmic patients, the plasma elimination half-life for repeated oral administration is approximately 20 hours (range 12-27 hours). The excretion is essentially urinary, for about 30% of the dose as unchanged flecainide and for the rest as metabolites: only 5% is eliminated in the faeces.

In the case of urine with pH ≥8, as, for example, in cases with renal tubular acidosis or in patients on a strictly vegetarian diet, the elimination of flecainide is very slow.

Elimination of flecainide is dependent on renal function. An increase in kidney dysfunction is accompanied by a reduction in the amount of unchanged drug excreted and an increase in the plasma half-life. In the case of concomitant increased metabolism of flecainide, the relationship between renal clearance and elimination of the drug from plasma is not linear.

In patients with NYHA class III heart failure, the elimination of drug from plasma is moderately slowed (mean half-life of 19 hours compared to 14 hours in patients without heart failure); excretion of unchanged drug in urine is also modified. in a similar way.

Plasma levels increase only slightly with increasing age between 20 and 80 years. The elimination of flecainide from plasma may be slowed, albeit insignificantly, in elderly subjects compared to young subjects. Indeed, patients up to 80 years of age were treated with the usual doses of flecainide without increasing adverse reactions.

Flecainide is approximately 40% bound to plasma proteins, regardless of plasma levels when they are between 0.015 - 3.4 mcg / ml. For this reason, no interactions occur between flecainide and other drugs at the protein binding level.

Only 1% of the administered flecainide is removed during hemodialysis.

05.3 Preclinical safety data -

Acute toxicity : in mice, rats, dogs, different single doses of the drug up to 500 mg / kg, administered orally, intravenously and intraperitoneally, induced ataxia, dyspnoea and convulsions. In all species death occurred from respiratory depression. The surviving animals recovered rapidly with no observable residual effect.

Sub-acute toxicity : by repeated oral administration in the rat in doses of 160 mg / kg / day and in the dog at 40 mg / kg / day for three months, modest changes in body weight and in some organs and easily reversible electrocardiographic alterations were observed respectively.

Chronic toxicity : oral doses up to 60 mg / kg / day in mice and dogs for 18 months and in rats for 24 months did not produce any toxic effects on the heart. The predicted electrocardiographic changes proved reversible. Survival indices remained unchanged and no other important signs of toxicity were detected in the parameters (haematological, histological, etc.) examined.

In the various experimental tests, flecainide was found to have no carcinogenic and mutagenic effects, nor did it affect in any way the fertility or reproductive functionality of the treated animals.

In rats and monkeys, no teratogenic effect was observed at doses up to 50 and 80 mg / kg / day, respectively. In rats, a delay in sternal and vertebral ossification was noted at higher doses.

In one species of rabbit (New Zealand) flecainide at a dose of 30 and 35 mg / kg / day has shown a teratogenic effect (stick legs, anomalies of the sternum and vertebrae, anomalies of the ventricular septum of the heart) and an embryotoxic (increased of reabsorption). However, no similar effect was observed when flecainide was administered up to doses of 30 mg / kg / day in another (Dutch) rabbit species.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Each tablet contains :

Gelatinized maize starch 88.4 mg

Microcrystalline cellulose 60 mg

Hydrogenated vegetable oil 4 mg

Magnesium stearate 1.6 mg

Cross-caramellose sodium 10 mg

06.2 Incompatibility "-

Pharmaceutical incompatibilities are not known for flecainide acetate.

06.3 Period of validity "-

Five years from the date of preparation.

06.4 Special precautions for storage -

None.

06.5 Nature of the immediate packaging and contents of the package -

Lithographed cardboard box of 20 and 60 tablets each, in PVC and aluminum blisters.

06.6 Instructions for use and handling -

No particular instructions for use.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Meda Pharma S.p.A. - Viale Brenta 18 - 20139 Milan

08.0 MARKETING AUTHORIZATION NUMBER -

- Almarytm 20 tablets: AIC n ° 025728015

- Almarytm 60 tablets: AIC n ° 025728066

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Almarytm 20 tablets:

AIC: 1986

Renewal: June 2005

10.0 DATE OF REVISION OF THE TEXT -

June 2012

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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