Arythmol

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.

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

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

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.

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 (see section 4.4, Special Warnings and Precautions for Use), 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.

Animal studies have not shown any teratogenic effects but as there is no experience of the use of the drug in human pregnancy, Arythmol should not be used during pregnancy and lactation.

Blurred vision, dizziness, fatigue and postural hypotension may affect the patient's speed of reaction and impair the individual's ability to operate machinery or motor vehicles.

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)

Experience with overdosage is limited. No specific antidote is known.

Procedures to enhance drug elimination from the body by haemodialysis or haemoperfusion are unlikely to succeed because of the large volume of drug distribution. The effects of propafenone hydrochloride overdose in the myocardium manifest as impulse generation and conduction disorders such as PQ prolongation, QRS widening, suppression of sinus node automaticity, AV block, ventricular tachycardia, ventricular flutter and ventricular fibrillation. Hypotension may also occur. Convulsions, somnolence and death may occur.

The usual emergency measures for acute cardiovascular collapse should be applied. In severe conduction disturbance associated with compromised cardiac function, atropine, isoprenaline or pacemaker therapy may be required. If electrical stimulation is not possible, an attempt should be made to shorten the QRS duration and increase the heart rate with high doses of isoprenaline. Bundle branch block by itself is not an indication for isoprenaline. Hypotension may require inotropic support. Convulsions should be treated with i.v. diazepam.

Propafenone is a class IC anti-arrhythmic agent.

It has a stabilising action on myocardial membranes, reduces the fast inward current carried by sodium ions with a reduction in depolarisation rate and prolongs the impulse conduction time in the atrium, AV node and primarily, in the His-Purkinje system.

Impulse conduction through accessory pathways, as in WPW syndrome, is either inhibited, by prolongation of the refractory period or blockade of the conduction pathway, both in anterograde but mostly retrograde direction.

At the same time, spontaneous excitability is reduced by an increase of the myocardial stimulus threshold while electrical excitability of the myocardium is decreased by an increase of the ventricular fibrillation threshold.

Anti-arrhythmic effects: Slowing of upstroke velocity of the action potential, decrease of excitability, homogenisation of conduction rates, suppression of ectopic automaticity, lowered myocardial disposition to fibrillation.

Propafenone has moderate beta-sympatholytic activity without clinical relevance. However, the possibility exists that high daily doses (900 - 1200 mg) may trigger a sympatholytic (anti-adrenergic) effect.

In the ECG, propafenone causes a slight prolongation of P, PR and QRS intervals while the QTC interval remains unaffected as a rule.

In digitalised patients with an ejection fraction of 35-50%, contractility of the left ventricle is slightly decreased. In patients with acute transmural infarction and heart failure, the intravenous administration of propafenone may markedly reduce the left ventricular ejection fraction but to an essentially lesser extent in patients in the acute stages of infarction without heart failure. In both cases, pulmonary arterial pressure is minimally raised. Peripheral arterial pressure does not show any significant changes. This demonstrates that propafenone does not exert an unfavourable effect on left ventricular function which would be of clinical relevance. A clinically-relevant reduction of left ventricular function is to be expected only in patients with pre-existing poor ventricular function.

Untreated heart failure might then deteriorate possibly resulting in decompensation.

Following oral administration, propafenone is nearly completely absorbed from the gastrointestinal tract in a dose-dependent manner and distributed rapidly in the body.

After a single dose of one tablet, bioavailability is about 50%. With repeated doses, plasma concentration and bioavailability rise disproportionately due to saturation of the first pass metabolism in the liver. Steady state is reached after 3 or 4 days, when bioavailability increases to about 100%. Therapeutic plasma levels are in the range of 150 ng/ml to 1500 ng/ml. In the therapeutic concentration range, more than 95% of propafenone is bound to plasma proteins. Comparing cumulative urinary excretion over 24 hours allowed for the calculation that 1.3% of intravenous (70 mg) and 0.65% of oral (600 mg) propafenone is excreted unchanged in the urine, i.e. propafenone is almost exclusively metabolised in the liver. Even in the presence of impaired renal function, reduced elimination of propafenone is not likely, which is confirmed by case reports and single kinetic studies in patients on chronic haemodialysis. Clinical chemistry values did not differ from those of patients with uncompromised kidneys.

Terminal elimination half-life in patients is 5-7 hours (12 hours in single cases) following repeated doses. A close positive correlation between plasma level and AV conduction time was seen in the majority of both healthy volunteers and patients.

After a plasma level of 500 ng/ml, the PR interval is statistically significantly prolonged as compared to baseline values which allows for dose titration and monitoring of the patients with the help of ECG readings. The frequency of ventricular extrasystoles decreases as plasma concentrations increase. Adequate anti-arrhythmic activity has, in single cases, been observed at plasma levels as low as <500 ng/ml.

None.

Microcrystalline cellulose, maize starch, hypromellose, croscarmellose sodium, purified water, macrogol 6000, titanium dioxide, macrogol 400 and magnesium stearate.

None.

5 years.

Do not store above 30°C.

Arythmol Tablets 150 mg: PVC/aluminium blister strips containing 90 tablets.

Arythmol Tablets 300 mg: PVC/aluminium blister strips containing 60 tablets.

None.

Abbott Laboratories Ltd.,

Abbott House,

Vanwall Business Park,

Vanwall Road,

Maidenhead,

Berkshire,

SL6 4XE,

United Kingdom.

Arythmol 150 mg Tablets PL 00037/0331

Arythmol 300 mg Tablets PL 00037/0332

5 December 2001

02 January 2010