4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

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.

Dose increases should not be attempted until the patient has been receiving treatment for three to four days.

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

Elderly population: No overall differences in safety or effectiveness were observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out, therefore, these patients should be carefully monitored. Treatment should be initiated gradually and with particular caution in small incremental doses.

The same applies to maintenance therapy. Any dose increases that may be required should not be undertaken until after five to eight days of therapy.

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

Liver/Renal Impairment: In patients whose liver and/or kidney function is impaired, there may be drug accumulation after standard therapeutic doses. Nonetheless, patients with these conditions can still be titrated on propafenone hydrochloride under ECG and plasma level monitoring.

Method of administration

Owing to the bitter taste and surface anesthetic action of propafenone, the film-coated tablets and sugar-coated tablets should be swallowed whole (without chewing) with liquid.

4.3. Contraindications

Known hypersensitivity to the active ingredient, propafenone hydrochloride or to any of the excipients listed in the Full List of Excipients section.

Arythmol is contraindicated in patients with known Brugada Syndrome (see Special Warnings and Precautions for Use).

Arythmol is contraindicated in patients with significant structural heart disease such as patients with an incident of myocardial infarction within the last 3 months, uncontrolled congestive heart failure where left ventricular output is less than 35%, cardiogenic shock (unless arrhythmia-induced), severe symptomatic bradycardia, manifest electrolyte imbalance (e.g., potassium metabolism disorders), severe obstructive pulmonary disease or severe 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.

Due to the potential for increased plasma concentrations, co-administration of ritonavir is contraindicated.

4.4. Special warnings and precautions for use

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 conduction block or 1:1 conduction (see section 4.8).

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

As with some other class Ic anti-arrhythmic agents, patients with significant structural heart disease may be predisposed to serious adverse events. Therefore propafenone is contraindicated in these patients (see section 4.3).

A Brugada syndrome may be unmasked or Brugada like electrocardiogram (ECG) changes may be provoked after exposure to propafenone in previously asymptomatic carriers of the syndrome. After initiating therapy with propafenone, as ECG should be performed to rule out changes suggestive of Brugada syndrome.

Propafenone like other antiarrhythmics may cause proarrhythmic effects, i.e., it may cause new or worsen preexisting arrhythmias (see section 4.8). 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.

This medicine contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Potential increase in adverse reactions may occur when propafenone is taken in conjunction with local anaesthetics (e.g., pacemaker implantation, surgery or dental work) and other medicinal products which have an inhibitory effect on the heart rate and/or myocardial contractility (e.g., beta blockers, tricyclic antidepressants).

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 lidocaine have been reported to increase the risks of central nervous system side effects of lidocaine.

Increased plasma levels and/or blood levels of propranolol, metoprolol, desipramine, ciclosporin, theophylline and digoxin have been reported during propafenone therapy. Doses of these medicinal products should be reduced, as appropriate, if signs of overdose are observed.

Elevated levels of plasma propafenone may occur when propafenone is used concomitantly with SSRIs, such as fluoxetine and paroxetine. Concomitant administration of propafenone and fluoxetine in extensive metabolisers increases the S-propafenone Cmax and AUC by 39 and 50% and the R-propafenone Cmax and AUC by 71 and 50%. Lower doses of propafenone may therefore be sufficient to achieve the desired therapeutic response.

Close monitoring of the clotting status in patients receiving concomitant oral anticoagulants (e.g., phenprocoumon, warfarin) is recommended as propafenone may enhance the plasma levels of these medicinal products resulting in an increased prothrombin time. Doses of these medicinal products should be adjusted if necessary.

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

Medicinal products that inhibit CYP2D6, CYP1A2 and CYP 3A4 e.g., ketoconazole, cimetidine, quinidine, erythromycin and grapefruit juice might lead to increased levels of propafenone. When propafenone is administered with inhibitors of these enzymes, the patients should be closely monitored and the dose adjusted accordingly.

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.

Concomitant use of propafenone and phenobarbital and/or rifampicin (CYP3A4 inducers) may reduce the antiarrythmic efficacy of propafenone as a result of a reduction in propafenone plasma levels. Hence, response to propafenone hydrochloride therapy should be monitored during concomitant chronic phenobarbital and/or rifampicin treatment.

Special populations

Paediatric population

Interaction studies have only been performed in adults. It is not known whether the extent of interactions is similar in the paediatric age group to that in adults.

4.6. Pregnancy and lactation

Pregnancy:

There are no adequate and well-controlled studies in pregnant women. Propafenone should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Propafenone is known to pass the placental barrier in humans. The concentration of propafenone in the umbilical cord has been reported to be about 30% of that in the maternal blood.

Lactation:

Excretion of propafenone in human breast milk has not been studied. Limited data suggests that propafenone may be excreted in human breast milk. Propafenone should be used with caution in nursing mothers.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

a. Summary of the safety profile

The most frequent and very common adverse reactions related to propafenone therapy are dizziness, cardiac conduction disorders and palpitations.

b. Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with propafenone.

The reactions considered at least possibly related to propafenone are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed. The frequencies are based on clinical trial data from propafenone SR. It is expected that the adverse reactions and frequencies for IR formulations would be similar.

System Organ Class

Very common

≥1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥1/1,000 to < 1/100

Not Known

(cannot be estimated from the available data)

Blood and lymphatic system disorders

Thrombocytopenia

Agranulocytosis

Leukopenia

Granulocytopenia

Immune system disorders

Hypersensitivity1

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Anxiety

Sleep disorders

Nightmare

Confusional state

Nervous system disorders

Dizziness2

Headache

Dysgeusia

Syncope

Ataxia

Paraesthesia

Convulsion

Extrapyramidal symptoms

Restlessness

Eye disorders

Vision blurred

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Cardiac conduction disorders3

Palpitations

Sinus bradycardia

Bradycardia

Tachycardia

Atrial flutter

Ventricular tachycardia

Arrythmia4

Ventricular fibrillation

Cardiac failure5

Heart rate reduced

Vascular disorders

Hypotension

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Abdominal pain

Vomiting

Nausea

Diarrhoea

Constipation

Dry mouth

Abdominal distension

Flatulence

Retching

Gastrointestinal disturbance

Hepatobiliary disorders

Hepatic function abnormal6

Hepatocellular injury

Cholestasis

Hepatitis

Jaundice

Skin and subcutaneous tissue disorders

Urticaria

Pruritus

Rash

Erythema

Acute generalized exanthematous pustulosis

Musculoskeletal and connective tissue disorders

Lupus-like syndrome

Reproductive system and breast disorders

Erectile dysfunction

Sperm count decreased7

General disorders and administration site conditions

Chest pain

Asthenia

Fatigue

Pyrexia

1 May be manifested by cholestasis, blood dyscrasias and rash

2 Excluding vertigo

3 Including sinoatrial block, atrioventricular block and intraventricular block

4 Propafenone may be associated with proarrhythmic effects which manifest as an increase in heart rate (tachycardia) or ventricular fibrillation. Some of these arrhythmias can be life- threatening and may require resuscitation to prevent a potentially fatal outcome

5 An aggravation of preexisting cardiac insufficiency may occur

6 This term covers abnormal liver function tests, such as aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased and blood alkaline phosphatase increased

7 Decreased sperm count is reversible upon discontinuation of propafenone

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of overdosing:

Myocardial symptoms: The effects of propafenone 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 fibrillation and cardiac arrest. Reduction of contractility (negative inotropic effect) can cause hypotension which, in severe cases, can lead to cardiovascular shock.

Non-cardiac signs and symptoms: Metabolic acidosis, headache, dizziness, blurred vision, paraesthesia, tremor, nausea, constipation, dry mouth and convulsions have been reported on overdose. Death has also been reported.

In severe cases of poisoning, clonic-tonic convulsions, paraesthesia, somnolence, coma and respiratory arrest may occur.

Treatment:

In addition to general emergency measures, the patient's vital parameters should be monitored in an intensive care setting, and rectified, as appropriate.

Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.

Attempts to achieve elimination via haemoperfusion are of limited efficacy.

Owing to high protein binding (> 95%) and the large volume of distribution, haemodialysis is ineffective.