Class 1 anti-arrhythmic (local anaesthetic) agent

Flecainide

Each ampoule contains 15 ml of a solution of flecainide acetate 10 mg/ml.

Solution for injection.

Tambocor Injection is indicated when rapid control of the following arrhythmias is the main clinical requirement:

a) Ventricular tachyarrhythmias where these are resistant to other treatment.

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

c) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction. Arrhythmias of recent onset will respond more readily. Tambocor Injection is for bolus injection or intravenous infusion.

a) Bolus injection: Tambocor injection can be given in an emergency or for rapid effect by a slow injection of 2mg/kg over not less than ten minutes, or in divided doses. If preferred, the dose may be diluted with 5% dextrose and given as a mini-infusion.

Continuous ECG monitoring is recommended in all patients receiving the bolus dose. The injection should be stopped when there is control of the arrhythmia.

It is recommended that Tambocor injection should be administered more slowly to patients in sustained ventricular tachycardia, with careful monitoring of the electrocardiogram. Similar caution should apply to patients with a history of cardiac failure, who may become decompensated during the administration. For such patients it is recommended that the initial dose is given over 30 minutes. The maximum recommended bolus dose is 150 mg.

b) Intravenous infusion: When prolonged parenteral administration is required, it is recommended that therapy is initiated by slow injection of 2 mg/kg over 30 minutes and continued by intravenous infusion at the following rates:

First hour: 1.5 mg/kg per hour.

Second and later hours: 0.1 - 0.25 mg/kg per hour.

It is recommended that the infusion duration should not exceed 24 hours. However, where this is considered necessary, or for patients receiving the upper end of the dose range, plasma level monitoring is strongly recommended. The maximum cumulative dose given in the first 24 hours should not exceed 600 mg. In patients with severe renal impairment (creatinine clearance of less than 35 ml/min/1.73 sq.m.), each of the above dosage recommendations should be reduced by half.

Transition to oral dosing should be accomplished as soon as possible by stopping the infusion and administering the first required oral dose.

Oral maintenance is then continued as indicated in the relevant oral dosage instructions.

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

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

Tambocor is contra-indicated 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 contra-indicated 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.

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

Electrolyte disturbances should be corrected before using Tambocor.

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. Plasma level monitoring is strongly recommended in these circumstances.

Tambocor is known to increase endocardial pacing thresholds - ie to decrease endocardial pacing sensitivity. This effect is reversible and is more marked on the acute pacing threshold than on the chronic.

Tambocor 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 Tambocor.

The minor negative inotropic effect of flecainide may assume importance in patients predisposed to cardiac failure. Difficulty has been experienced in defibrillating some patients. Most of the cases reported had pre-existing heart disease with cardiac enlargement, a history of myocardial infarction, arterio-sclerotic heart disease and cardiac failure.

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

Tambocor 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 infarction 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 infarction. 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 intereact 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 six hours after any digoxin dose, before or after administration of flecainide.

Class II anti-arrhythmics; the possibility of additive negative inotropic effects of beta-blockers, and other cardiac depressants such as verapamil, with flecainide should be recognised.

Class III anti-arrhythmics; when flecainide is given in the presence of amiodarone, the usual flecainide dosage 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; use of flecainide with other sodium channel blockers is not recommended.

Anti-depressants; fluoxetine increases plasma flecainide concentration; increased risk of arrhythmias with tricyclics; manufacturer of reboxetine advises caution.

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

Anti-histamines; increased risk of ventricular arrhythmias with mizolastine and terfenadine (avoid concomitant use)

Anti-malarials: quinine increases plasma concentration of flecainide.

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

Diuretics: Class effect due to hypokalaemia giving rise to cardiac toxicity.

Ulcer healing drugs: cimetidine inhibits metabolism of flecainide. In healthy subjects receiving cimetidine (1g daily) for one week, plasma flecainide levels increased by about 30% and the half-life increased by about 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 Tambocor is compatible with use of oral anti-coagulants.

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

Cardiovascular: 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 Tambocor has been associated with 1:1 AV conduction following initial atrial slowing with resultant ventricular acceleration. This has been seen most commonly following the use of the injection for acute conversion. This effect is usually short lived and abates quickly following cessation of therapy.

The following adverse effects have also been reported.

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

Skin and Appendages: A range of allergic skin reactions have been reported including rashes and rare but serious reports of urticaria. There have also been isolated cases of photosensitivity.

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

Haematological: Reductions in red blood cells, white blood cells and platelets have been occasionally reported. These changes are usually mild.

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

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

Liver and Bilary System: A number of cases of elevated liver enzymes and jaundice have been reported in association with Tambocor treatment. So far this has always been reversible on stopping treatment. Hepatic dysfunction has also been reported.

Neurological: Most commonly giddiness, dizziness and lightheadedness which are usually transient. Rare instances of dyskinesia have been reported, which have improved on withdrawal of flecainide therapy. 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.

Ophthalmological: 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.

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

Meda Pharmaceuticals

(POM)

19 June 2009