Special Warning : אזהרת שימוש

Warnings

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

Notes:
1. Propafenone may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during therapy.
2. Propafenone should be administered with caution to patients with supraventricular tachycardia and structural heart disease with decrease of the left ventricular function.
3. Propafenone should be administered with caution to patients with atrial flutter who are not treated with drugs that decrease atrial-ventricular conduction.


RYTHMEX                    26 3.   2014, RH                        Page 3 of 11 4. There is the potential for conversion of paroxysmal atrial fibrillation to atrial flutter with accompanying 2:1 conduction block or 1:1 conduction (see Adverse Reactions).
5. As with other class 1c anti-arrhythmic agents, patients with significant structural heart disease may be predisposed to serious adverse events, therefore propafenone is contraindicated in these patients (see Contraindications).
6. Propafenone hydrochloride should be used with caution in patients with obstruction of the airways, e.g., asthma.

Brugada Syndrome
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, an ECG should be performed to rule out changes suggestive of Brugada syndrome.

Acceleration of Ventricular Rate
Propafenone, like other antiarrhythmic agents, may cause new or worsened arrhythmias. Such proarrhythmic effects range from an increase in frequency of VPCs to the development of more severe ventricular tachycardia; e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm with potentially fatal consequences.

Overall incidence reported in clinical trials with propafenone, where patients had new or worsened ventricular tachycardia is about 5.3 %. Their frequency appears to be related to the underlying cardiac disease.
It is therefore essential that each patient given propafenone be evaluated electrocardiographically and clinically prior to, and during therapy, to determine whether the response to propafenone supports continued treatment.
Patients with bronchospastic disease should, in general, not receive propafenone or other agents with β-adrenergic blocking activity.

Depressed Myocardial Function
Chronic propafenone therapy has been safely and successfully administered to patients with ejection fractions lower than 35%. However, since propafenone exerts a mild, dose-related negative inotropic effect on cardiac muscle, patients with congestive heart failure should be fully compensated before receiving Rythmex. If following propafenone therapy, congestive heart failure worsens, the drug should be discontinued, and, if indicated, restarted at a lower dosage only after adequate cardiac compensation has been established.

Conduction Disturbances
Propafenone slows atrioventricular conduction and may cause first degree AV block. PR interval prolongation and increases in QRS duration are closely correlated with dosage increases and concomitant increases in propafenone plasma concentrations.
Progression to second or third degree AV block requires a reduction in dosage or discontinuation of Rythmex. Bundle branch block and intraventricular conduction delay have been reported in patients receiving propafenone.

Hematologic Disturbances
Unexplained fever and/or decrease in white cell count, probably due to idiosyncratic reaction, particularly during the first three months of therapy, warrant consideration of possible hematologic reactions. Patients should be instructed to promptly report the development of any signs of infection such as fever, sore throat, or chills.


RYTHMEX                      26 3.   2014, RH                         Page 4 of 11 Use in Pregnancy
There are no adequate and well controlled studies in pregnant women.
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.
Propafenone should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Use during Lactation
Excretion of propafenone in human breast milk has not been studied. Limited data suggest that propafenone may be excreted in human breast milk.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, prescription of Rythmex should be given critical consideration in accordance with present views on the use of drugs. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pre-clinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction.

Adverse Reactions

Reactions from Clinical Trials or Postmarketing Surveillance
Summary of the safety profile
The most frequent and very common adverse reactions related to propafenone therapy are dizziness, cardiac conduction disorders and palpitations

The clinical adverse reactions that occurred in at least one of the 885 patients receiving propafenone hydrochloride SR (sustained release formulation is not available in Israel) in five phase II studies and two phase III studies are shown in the Table below. It is expected that the adverse reactions and frequencies for regular release formulations would be similar. This table also includes adverse reactions 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.

MedDRA System           Very       Common           Uncommon                Not Known Organ Class          common       = 1/100 to       =1/1,000 to         (cannot be estimated =1/10         <1/10            < 1/100            from the available data)
Blood and lymphatic                               Thrombocytopenia       Agranulocytosis system disorders                                                         Leukopenia Granulocytopenia
1
Immune system                                                            Hypersensitivity disorders
Metabolism and                                    Decreased appetite nutrition disorders
Psychiatric disorders              Anxiety        Nightmare              Conftsional state Sleep disorders
RYTHMEX                    26 3.   2014, RH                            Page 5 of 11 MedDRA System            Very         Common             Uncommon                   Not Known Organ Class           common         = 1/100 to         =1/1,000 to           (cannot be estimated =1/10           <1/10              < 1/100              from the available data)
2
Nervous system          Dizziness       Headache         Syncope                  Convulsion disorders                               Dysgeusia        Ataxia                   Extrapyramidal Paresthesia              Symptoms
Restlessness
Eye disorders                           Vision blurred
Ear and labyrinth                                        Vertigo disorders
Cardiac disorders       Cardiac         Sinus            Ventricular              Ventricular fibrillation 5 conduction      bradycardia      tachycardia              Caridac failure 3                                   4 disoders        Bradycardia      Arrhythmia               Heart rate reduced Palpitations    Tachycardia
Atrial flutter
Vascular disorders                                       Hypotension              Orthostatic hypotension Respiratory, thoracic                   Dyspnea and mediastinal disorders
Gastrointestinal                        Abdominal        Abdominal                Retching disorders                               pain             distension               Gastrointestinal Vomiting         Flatulence               disturbance
Nausea
Diarrhoea
Constipation
Hepatobiliary                           Hepatic                                   Hepatocellular injury disorders                               function                                  Cholestasis 6 abnormal                                  Hepatitis
Jaundice
Skin and subcutaneous                                    Urticaria tissue                                                   Pruritus disorders                                                Rash
Erythema
Musculoskeletal and                                                               Lupus-like syndrome connective tissue disorders
7
Reproductive system                                      Erectile dysftnction     Sperm count decreased and breast disorders
General disorders and                   Chest pain administration site                     Asthenia conditions                              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.


RYTHMEX                         26 3.   2014, RH                                Page 6 of 11 Reporting of suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product.
Any suspected adverse reaction should be reported.

Precautions
Use in Patients with Impaired Hepatic Function
Propafenone is highly metabolized by the liver and should therefore be administered cautiously to patients with impaired hepatic function. The dose of propafenone given to patients with impaired hepatic function should be the lowest recommended dosage for patients with normal hepatic function. Careful monitoring for excessive pharmacological effects should be carried out.

Use in Patients with Impaired Renal Function
Since a considerable percentage of propafenone metabolites are excreted in the urine, Rythmex should be administered cautiously to patients with impaired renal function.


Neuromuscular Dysfunction
Exacerbation of myasthenia gravis has been reported during propafenone therapy.
Effects on ability to drive and use machines
Propafenone may affect the patient's alertness and impair the individual's mental ability (blurred vision, dizziness, fatigue and postural hypotension). This should be taken into consideration when engaging in activities requiring mental alertness such as driving a car or operating machinery, especially when consumption of alcohol is also involved.

Effects on Driving