Class I antiarrhythmics (anti- arrhythmics).

Propafenone

Each tablet contains 150 mg or 300mg propafenone HCl.

Tablets.

Arythmol is indicated for the prophylaxis and treatment of ventricular arrhythmias. Arythmol is also indicated for the prophylaxis and treatment of paroxysmal supraventricular tachyarrhythmias which include paroxysmal atrial flutter/fibrillation and paroxysmal re-entrant tachycardias involving the AV node or accessory bypass tracts, when standard therapy has failed or is contra-indicated. .

It is recommended that Arythmol therapy should be initiated under hospital conditions, by a physician experienced in the treatment of arrhythmias. The individual maintenance dose should be determined under cardiological surveillance including ECG monitoring and blood pressure control. If the QRS interval is prolonged by more than 20%, the dose should be reduced or discontinued until the ECG returns to normal limits.

Adults: Initially, 150 mg three times daily increasing at a minimum of three-day intervals to 300 mg twice daily and if necessary, to a maximum of 300 mg three times daily.

The tablets should be swallowed whole and taken with a drink after food. A reduction in the total daily dose is recommended for patients below 70 kg bodyweight.

Dosage in impaired liver function: Arythmol is extensively metabolised via a saturable hepatic oxidase pathway. In view of the increased bioavailability and elimination half-life of propafenone, a reduction in the recommended dose may be necessary.

Dosage in impaired renal function: Although the elimination of propafenone and its major metabolite is not affected by renal impairment, Arythmol should be administered cautiously.

A suitable dosage form of Arythmol for children is not available.

Higher plasma concentrations of propafenone have been noted during treatment. Elderly patients may therefore respond to a lower dose.

Known hypersensitivity to propafenone or to any of the other ingredients.

Arythmol is contra-indicated in patients with uncontrolled congestive heart failure, cardiogenic shock (unless arrhythmia-induced), severe bradycardia, uncontrolled electrolyte disturbances, severe obstructive pulmonary disease or marked hypotension.

Arythmol may worsen myasthenia gravis.

Unless patients are adequately paced, Arythmol should not be used in the presence of sinus node dysfunction, atrial conduction defects, second degree or greater AV block, bundle branch block or distal block.

Minor prolongation of the PR interval and intra-ventricular conduction defects (QRS duration of less than 20%) are to be expected during treatment with Arythmol and do not warrant dose reduction or drug withdrawal

The weak negative inotropic effect of Arythmol may assume importance in patients predisposed to cardiac failure.

In common with other anti-arrhythmic drugs, Arythmol has been shown to alter sensitivity and pacing threshold. In patients with pacemakers, appropriate adjustments may be required.

There is potential for conversion of paroxysmal atrial fibrillation to atrial flutter with accompanying 2:1 or 1:1 conduction block.

Because of the beta-blocking effect, care should be exercised in the treatment of patients with obstructive airways disease or asthma.

As with other class IC anti-arrhythmic agents, patients with structural heart disease may be predisposed to serious adverse effects.

It is essential that each patient given Arythmol be evaluated electrocardiographically and clinically prior to and during therapy to determine whether the response to Arythmol supports continued treatment.

The effects of Arythmol may be potentiated if it is given in combination with other local anaesthetic type agents or agents which depress myocardial activity.

Arythmol has been shown to increase the plasma levels of digoxin and caution should be exercised with regard to digitalis toxicity.

Arythmol has been shown to increase the plasma levels of oral anticoagulants, with an accompanying increase in prothrombin time, which may require a reduction in the dose of oral anticoagulants.

Plasma levels of propafenone may be increased by concomitant administration of cimetidine.

Increased propranolol and metoprolol plasma levels have been observed when these beta-blockers were used concurrently with Arythmol. Thus, dose reduction of these beta-blockers may be required. Details of interactions with other beta-blockers are not known.

Coadministration of propafenone hydrochloride with drugs metabolised by CYP2D6 (such as venlafaxine) might lead to increased levels of these drugs.

Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4, e.g. ketoconazole, cimetidine, quinidine, tropisetron, dolasetron, mizolastine, erythromycin and grapefruit juice may lead to increased levels of propafenone hydrochloride. When propafenone hydrochloride is administered with inhibitors of these enzymes, the patients should be closely monitored and the dose adjusted accordingly.

Due to the potential for increased plasma concentrations, co-administration of 800-1200mg/day doses of ritonavir and propafenone hydrochloride is contraindicated.

Combination therapy of amiodarone and propafenone hydrochloride can affect conduction and repolarisation and lead to abnormalities that have the potential to be proarrhythmic. Dose adjustments of both compounds based on therapeutic response may be required.

No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone hydrochloride and intravenous lidocaine have been reported to increase the risks of central nervous system side effects of lidocaine.

Phenobarbital is a known inducer of CYP3A4. Response to propafenone hydrochloride therapy should be monitored during concomitant chronic phenobarbital use.

There has been a report of the lowering of propafenone levels by rifampicin, via the hepatic mixed oxidase system. This reduction may lead to breakthrough arrhythmias.

Cases of possible interactions with cyclosporin (levels increased with deterioration in renal function), theophylline (levels increased), desipramine (levels increased) have also been reported.

Due to the arrhythmogenic effects of tricyclic and related antidepressants and/or neuroleptics, these drugs may interact adversely when used concomitantly with anti-arrhythmic drugs including propafenone.

Concomitant administration of propafenone hydrochloride and fluoxetine in extensive metabolisers increased the S propafenone C_max and AUC by 39 and 50% and the R propafenone C_max and AUC by 71 and 50%. Elevated levels of plasma propafenone may occur when propafenone hydrochloride is used concomitantly with paroxetine. Lower doses of propafenone may be sufficient to achieve the desired therapeutic response.

The following adverse events have been reported with this or other formulations of propafenone hydrochloride. A cause and effect relationship may not have been established.

Blood and lymphatic system disorders

Leukocytopenia and/ or granulocytopenia or thrombocytopenia; agranulocytosis.

Immune system disorders

Allergic reactions, hypersensitivity reactions (manifested by cholestasis, blood dyscrasias).

Metabolism and nutritional disorders

Anorexia

Psychiatric disorders

Anxiety, confusion

Nervous system disorders

Dizziness, headache, syncope, ataxia, restlessness, nightmares, sleep disorders, extrapyramidal symptoms, vertigo, paresthesia. Rare cases of seizures have been reported.

Eye disorders

Blurred vision

Cardiac disorders

A marked reduction in heart rate (bradycardia) or conduction disorders (i.e. sinoatrial, atrioventricular or intraventricular block) may occur. Proarrhythmic effects which manifest as an increase in heart rate (tachycardia), or ventricular fibrillation may also occur.

Vascular disorders

Hypotension, including postural hypotension and orthostatic hypotension

Gastrointestinal disorders

Nausea, vomiting, constipation, dry mouth, bitter taste, abdominal pain, diarrhoea, bloating and retching

Hepatobiliary disorders

Liver abnormalities, including hepatocellular injury, cholestasis, jaundice and hepatitis,

Skin and subcutaneous tissue disorders

Reddening of the skin, rash, pruritis, exanthema, urticaria

Musculoskeletal and connective tissue disorders

Lupus syndrome

Reproductive system and breast disorders

In some cases a diminution of potency and a drop in sperm count have been observed after high doses of Arythmol. This is reversible when treatment is discontinued.

General disorders and administration site conditions

Fatigue, chest pain

Investigations

Elevated liver enzymes (serum transaminases and alkaline phosphatase)

Abbott Laboratories Limited

(POM)

08 June 2009