Flecainide Acetate 50mg Tablets.

Each tablet contains 50 mg flecainide acetate.

For a full list of excipients, see section 6.1.

Tablet.

Flecainide tablets are white uncoated tablets marked C on one side and F1 on the other.

Flecainide Acetate is a potent sodium channel blocking agent for the treatment of the conditions listed below.

The effect on the JT interval is insignificant at therapeutic levels.

Flecainide Acetate tablets are indicated for:

a) AV nodal reciprocating tachycardia; arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.

b) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction (see 4.4, Special warnings and special precautions for use). Arrhythmias of recent onset will respond more readily.

c) Symptomatic sustained ventricular tachycardia.

d) Premature ventricular contractions and/or non-sustained ventricular tachycardia which are causing disabling symptoms, where these are resistant to other therapy or when other treatment has not been tolerated.

Flecainide Acetate tablets can be used for the maintenance of normal rhythm following conversion by other means.

Flecainide Acetate tablets are for oral administration.

Posology

Adults: Supraventricular arrhythmias: The recommended starting dosage is 50 mg twice daily and most patients will be controlled at this dose. If required the dose may be increased to a maximum of 300 mg daily.

Ventricular arrhythmias: The recommended starting dosage is 100 mg twice daily. The maximum daily dose is 400 mg and this is normally reserved for patients of large build or where rapid control of the arrhythmia is required. After 3-5 days it is recommended that the dosage be progressively adjusted to the lowest level which maintains control of the arrhythmia. It may be possible to reduce dosage during long-term treatment.

Elderly patients: The rate of flecainide elimination from plasma may be reduced in elderly people. This should be taken into consideration when making dose adjustments.

Children: Flecainide is not recommended in children under12 years as there is insufficient evidence of its use in this age group.

Plasma levels: Based on PVC suppression, it appears that plasma levels of 200-1000 ng/ml may be needed to obtain the maximum therapeutic effect. Plasma levels above 700-1000 ng/ml are associated with increased likelihood of adverse experiences.

Impaired renal function: In patients with significant renal impairment (creatinine clearance of 35ml/min/1.73sq.m. or less) the maximum initial dosage should be 100 mg daily (or 50 mg twice daily). When used in such patients, frequent plasma level monitoring is strongly recommended.

It is recommended that intravenous treatment with Flecainide Acetate should be initiated in hospital.

Treatment with oral Flecainide should be under direct hospital or specialist supervision for patients with:

a) AV nodal reciprocating tachycardia; arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.

b) Paroxysmal atrial fibrillation in patients with disabling symptoms.

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

Known hypersensitivity to the active substance(s) or to any of the excipients. Flecainide is contraindicated in cardiac failure and in patients with a history of myocardial infarction who have either asymptomatic ventricular ectopics or asymptomatic non-sustained ventricular tachycardia.

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

Unless pacing rescue is available, flecainide should not be given to patients with sinus node dysfunction, atrial condition defects, second degree or greater atrio-ventricular block, bundle branch block or distal block.

Electrolyte disturbances should be corrected before using flecainide.

Since flecainide elimination from the plasma can be markedly slower in patients with significant hepatic impairment, flecainide should not be used in such patients unless the potential benefits clearly outweigh the risks. Flecainide should be used with caution in patients with impaired renal function and frequent therapeutic drug monitoring should be undertaken. Plasma level monitoring is strongly recommended in these circumstances.

Flecainide 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 pacing threshold than on the chronic. Flecainide should thus be used with caution in all patients with permanent pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or non-programmable pacemakers unless suitable pacing rescue is available.

Generally, a doubling of either pulse width or voltage is sufficient to regain capture but it may be difficult to obtain ventricular thresholds less than 1 volt at initial implantation in the presence of flecainide.

The minor negative inotropic effect of flecainide may assume importance in patients predisposed to cardiac failure. Difficulty has been experienced in defibrillating some patients. Usually these patients were reported to have pre-existing heart disease with cardiac enlargement, a history of myocardial infarction, arteriosclerotic heart disease and cardiac failure.

Flecainide should be avoided in patients with structural organic heart disease or abnormal left ventricular function.

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

In a large scale, placebo-controlled clinical trial in post-myocardial infraction patients with asymptomatic ventricular arrhythmia, oral flecainide was associated with a 2.2 fold higher incidence of mortality or non-fatal cardiac arrest as compared with its matching placebo. In that same study, an even higher incidence of mortality was observed in flecainide –treated patients with more than one myocardial infraction. Comparable placebo-controlled clinical trials have not been done to determine if flecainide is associated with higher risk of mortality in other patient groups.

Flecainide is a class I anti-arrhythmic and interactions are possible with other anti-arrhythmic drugs where additive effects may occur or where drugs interfere with the metabolism of flecainide. The following known categories of drugs may interact with flecainide:

Cardiac glycosides: Flecainide can cause the plasma digoxin level to rise by about 15%, which is unlikely to be of clinical significance for patients with plasma levels in the therapeutic range. It is recommended that the digoxin plasma level in digitalised patients should be measured not less than 6 hours after any digoxin dose, before or after administration of flecainide.

Class I anti-arrhythmics: Use of flecainide with other sodium channel blockers e.g. quinidine is not recommended. The clearance of flecainide may be decreased by quinidine in patients who are extensive metabolises, since quinidine inhibits the enzyme responsible for the metabolism of flecainide.

Class II anti-arrhythmics: The possibility of additive negative inotropic effects of beta-blockers and other cardiac depressants with flecainide should be recognised.

Class III anti-arrhythmics: When flecainide is given in the presence of amiodarone the usual dosage of flecainide should be reduced by 50% and the patient monitored closely for adverse effects. Plasma level monitoring is strongly recommended in these circumstances.

Class IV anti-arrhythmics: Calcium-channel Blockers: increases myocardial depression and asystole with verapamil.

Other Anti-arrythmics: Concomitant administration of flecainide with other anti-arrhythmic agents may increase myocardial depression.

Antidepressants: fluoxetine increases plasma-flecainide concentration and there is an increased risk of arrhythmias with tricyclics.

Anti-epileptics: Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination.

Anti-psychotics: clozapine – increased risk of arrhythmias

Antihistamines: There is an increased risk of ventricular arrhythmias with mizolastine and terfenadine (avoid concomitant use);

Antimalarials: quinine increases plasma concentration of flecainide, and there is an increased risk of arrhythmias with halofantrine;

Antivirals: plasma concentration increased by ritonavir, lopinavar and indinavir (increased risk of ventricular arrhythmias (avoid concomitant use).

Diuretics: cardiac toxicity increased if hypokalaemia occurs.

Ulcer healing drugs: Cimetidine inhibits metabolism of flecainide. In healthy subjects receiving cimetidine (1g daily) for one week, it was observed that plasma flecainide levels increased by 30% and the half-life increased by 10%.

Anti-smoking aids: Co-administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including flecainide, should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving flecainide, the need to decrease the dose of the original medication should be considered.

Treatment with flecainide is compatible with use of oral anticoagulants.

There is no evidence as to drug safety in human pregnancy.

In New Zealand White rabbits high doses of flecainide caused some foetal abnormalities, but these effects were not seen in Dutch Belted rabbits or rats. The relevance of these findings to humans has not been established. Data have shown that flecainide crosses the placenta to the foetus in patients taking flecainide during pregnancy.

Flecainide is excreted in human milk and appears in concentrations which reflect those in maternal blood.

The risk of adverse effects to the nursing infant is very small.

Flecainide Acetate can cause dizziness, visual disturbances and other neurological effects which may affect the ability to drive or use machines. Patients should be warned not to drive or operate machinery if they feel that they have been affected.

Body as a Whole: Asthenia, fatigue, fever, oedema.

Cardiac disorders: Pro-arrhythmic effects occur but are most likely in patients with structural heart disease and/or significant left ventricular impairment.

In patients with atrial flutter the use of flecainide has been associated with 1:1 AV conduction following initial atrial slowing with resultant ventricular acceleration.

AV block-second-degree and third degree, bradycardia, cardiac failure/congestive cardiac failure, chest pain, hypotension, myocardial infarction, palpitation and sinus pause or arrest and tachycardia (AT or VT).

Skin and subcutaneous tissue disorders: There have been isolated cases of photosensitivity. Allergic skin reactions, including rare reports of serious urticaria. Alopecia.

Gastrointestinal disorders: Occasionally nausea and vomiting. The following have also been reported: abdominal pain, anorexia, constipation, diarrhoea, dyspepsia and flatulence (bloating)

Hepato-biliary disorders: A number of cases of elevated liver enzymes and jaundice have been reported in association with flecainide treatment. So far this has always been reversible on stopping treatment. Hepatic dysfunction has also been reported.

Nervous System Disorders: Most commonly giddiness, dizziness, and light-headedness which are usually transient. Rare instances of dyskinesia, which has improved on withdrawal of flecainide therapy, have been reported. Rare instances of convulsions and, during long-term therapy, a few cases of peripheral neuropathy, paraesthesia and ataxia have been reported. There also have been reports of flushing, headache, hypoaesthesia, increased sweating, somnolence, syncope, tinnitus, tremor and vertigo.

Eye disorders: Visual disturbances, such as double vision and blurring of vision may occur but these are usually transient and disappear upon continuing or reducing the dosage. Extremely rare cases of corneal deposits have also been reported.

Immune system disorders: A small number of cases of increases in anti-nuclear antibodies, with and without systemic inflammatory involvement, have been reported.

Blood and the lymphatic system disorders: Reductions in red and white blood cells and platelets have occasionally been reported. These changes are usually mild.

Psychiatric disorders: Rarely, hallucinations, depression, confusion and amnesia have been reported.

Respiratory disorders: Dyspnoea and extremely rare cases of pneumonitis have been reported.

No specific antidote is known.

There is no known way of rapidly removing flecainide from the body but forced acid diuresis may theoretically be helpful. Neither dialysis nor haemoperfusion are helpful and injections of anticholinergics are not recommended. Treatment may include therapy with an inotropic agent, intravenous calcium, giving circulatory assistance (e.g., balloon pumping) mechanically assisting respiration or temporarily inserting a transvenous pacemaker if there are severe conduction disturbances or the patient's left ventricular function is otherwise compromised.

ATC code: C01B C04

Flecainide acetate is a Class IC antiarrhythmic agent used for the treatment of serious symptomatic ventricular and supraventricular arrhythmias. It should not be used to control asymptomatic ventricular arrhythmias in patients who have previously suffered myocardial infarction. The most common adverse effects affect the central nervous system.

Electrophysiologically, flecainide is a local anaesthetic-type (Class IC) of antiarrhythmic compound. It is an amide type of local anaesthetic, being structurally related to procainamide and encainide in so far as these agents are also benzamide derivatives. The potency of flecainide as an antiarrhythmic agent is associated with the presence and the positions of the trifluoroethody groups on the benzamide ring, which augment the drugs lipophilicity and with the presence of the non-substituted piperidylmethyl group in the amide chain. Flecainide is some 10 times more potent than procainamide and 2-3 times more potent than encainide.

The characterisation of flecainide as a Class IC compound is based on a triad of features: marked depression of the fast sodium channel in the heart; slow onset and offset kinetics of inhibition of the sodium channel (reflecting slow attachment to and dissociation from sodium channels); and the differential effect of the drug on the action potential duration in ventricular muscle versus Purkinje fibres, having no effect in the former and markedly shortening it in the latter. This composite of properties leads to a marked depression in conduction velocity in fibres dependant on the fast-channel fibres for depolarisation but with a modest increase in the effective refractory period when tested in isolated cardiac tissues. At very high concentrations flecainide exerts a weak depressant effect on the slow channel in the myocardium. This is accompanied by a negative inotropic effect. Flecainide has no significant interaction with the autonomic nervous system. The drug does not appear to have a measurable effect on coronary, pulmonary or other regional circulations.

In vitro metabolic studies have confirmed that P450 2D6 is involved in the metabolism of flecainide.

Flecainide is almost completely absorbed after oral administration and does not undergo extensive first-pass metabolism. The bioavailability from flecainide acetate tablets has been reported to be about 90%. Flecainide is extensively metabolised (subject to genetic polymorphism), the 2 major metabolites being m-O-dealkylated flecainide and m-O-dealkylated lactam of flecainide, both of which may have some activity. It is eliminated mainly in the urine, approximately 30% as unchanged drug and the remainder as metabolites. About 5% is excreted in the faeces. Excretion of flecainide is decreased in renal failure, heart failure, and in alkaline urine. Haemodialysis removes only about 1% of unchanged flecainide.

The therapeutic plasma concentration range is generally accepted as 200 to 1000ng per ml. The elimination half-life of flecainide is about 20 hours and it is about 40% bound to plasma proteins. Flecainide passes the placenta and is excreted in breast milk.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Also contains: microcrystalline cellulose, maize starch, pregelatinised maize starch, croscarmellose sodium and magnesium stearate.

Not Applicable.

Three years.

Do not store above 25ºC.

Keep container in the outer carton.

The blister packs are manufactured from 250µm white rigid PVC/PVDC coated with 60g/m² PVDC and 20µm hard temper aluminium foil with 5-7g/m² PVC/PVDC compatible heat seal lacquer.

Pack sizes:

Blister packs: 28, 30, 56, 60, 84, 90, 112, 120, 168, 180.

Not all pack sizes may be marketed.

Not applicable.

Zentiva

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

PL 17780/0023

30 March 2009

22^nd Feb 2011

POM