Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Viatris Ltd, PO Box 11-183, Ellerslie, AUCKLAND www.viatris.co.nz Telephone 0800 168 169
Rytmonorm is contraindicated in the presence of:
A Brugada syndrome may be unmasked or Brugada like electrocardiogram (ECG) changes may be provoked after exposure to Rytmonorm in previously asymptomatic carriers of the syndrome. After initiating therapy with Rytmonorm, an ECG should be performed to rule out changes suggestive of Brugada syndrome.
In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomised, double-blind study in patients with asymptomatic non-life-threatening arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months.
The applicability of these results to other populations (e.g., those without recent myocardial infarctions) or to other antiarrhythmic drugs is uncertain, but at present it is prudent to consider any antiarrhythmic agent to have a significant risk in patients with structural heart disease.
Rytmonorm like other antiarrhythmic agents, may cause new or worsen pre-existing arrhythmias (see section 4.8). Such proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, ventricular fibrillation or torsade de pointes; i.e., tachycardia that is more sustained or more rapid which may lead to fatal consequences. It is therefore essential that each patient given Rytmonorm be evaluated electrocardiographically and clinically prior to, and during therapy to determine whether the response to Rytmonorm supports continued treatment.
Overall in clinical trials with propafenone, 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or VF). Of the patients who had a worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in patients with less serious or benign arrhythmias, which included patients with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST study (see above) suggest that an increased risk is present throughout treatment.
Patients with bronchospastic diseases or obstruction of the airways, should in general not receive propafenone or other agents with beta-adrenergic-blocking activity.
As with other class 1c anti-arrhythmic agents, patients with significant structural heart disease may be predisposed to serious adverse effects. Therefore, propafenone hydrochloride is contraindicated in these patients (see section 4.3).
During treatment with oral propafenone in patients with depressed baseline function (mean EF=33.5%), no significant decreases in ejection fraction were seen. In clinical trial experience, new or worsened CHF has been reported in 3.7% of patients; of those 0.9% were considered probably or definitely related to Rytmonorm. Of the patients with congestive heart failure probably related to propafenone, 80% had preexisting heart failure and 85% had coronary artery disease. CHF attributable to Rytmonorm developed rarely (< 0.2%) in patients who had no previous history of CHF. As Rytmonorm exerts both beta blockade and a (dose-related) negative inotropic effect on cardiac muscle, patients with congestive heart failure should be fully compensated before receiving Rytmonorm. If congestive heart failure worsens, Rytmonorm should be discontinued (unless congestive heart failure is due to the cardiac arrhythmia) and, if indicated, restarted at a lower dosage only after adequate cardiac compensation has been established.
Rytmonorm slows atrioventricular conduction and also causes first degree AV block. Average PR interval prolongation and increases in QRS duration are closely correlated with dosage increases and concomitant increases in propafenone plasma concentrations. This incidence of first degree, second degree, and third degree AV block observed in 2,127 patients was 2.5%, 0.5% and 0.2% respectively. Development of second or third degree AV block requires a reduction in dosage or discontinuation of Rytmonorm. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in patients receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.
There is the potential for conversion of paroxysmal atrial fibrillation to atrial flutter with accompanying 2:1 conduction block or 1:1 conduction (see section 4.8).
Rytmonorm may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during the therapy.
One case of agranulocytosis with fever and sepsis probably related to the use of propafenone was seen in US clinical trials. The agranulocytosis appeared after 8 weeks of therapy. Propafenone therapy was stopped and the white cell count had normalised by 14 days. The patient recovered. In the course of over 800,00 patients' years during marketing outside the U.S. since 1978, seven additional cases have been reported. In one of these, concomitant captopril, a drug known to cause agranulocytosis was used. Unexplained fever and/or decrease in a white cell count particularly during the first three months of therapy warrant consideration of possible agranulocytosis/granulocytopenia. Patients should be instructed to promptly report the development of any signs of infection such as fever, sore throat or chills.
Propafenone is highly metabolised by the liver and should therefore, be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3 to 40% for patients with normal liver function. In eight patients with moderate to severe liver disease, the mean half-life was approximately 9 hours. As a result, the dose of propafenone given to patients with impaired hepatic function should be approximately 20 to 30% of the dose given to patients with normal hepatic function. Careful monitoring for excessive pharmacological effects (see section 4.9) should be carried out.
A considerable percentage of propafenone metabolites (18.5% to 38%) of the dose/48 hours) are excreted in the urine. Until further data are available, Rytmonorm (propafenone HCl) should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for signs of overdosage (see section 4.9).
Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration. Evaluation of the effects of short-term propafenone administration on spermatogenesis in 11 normal subjects suggest that propafenone produces a reversible short-term drop (within normal range) in sperm count. Subsequent evaluation in 11 patients receiving propafenone chronically have suggested no effect of propafenone on sperm count.
The safety and efficacy of Rytmonorm in children has not been established.
There do not appear to be any age related differences in adverse reaction rates in the most commonly reported adverse reactions. Because of the possible increased risk of impaired hepatic or renal function in this age group, Rytmonorm should be used with caution. The effective dose may be lower in these patients.
Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosus (positive rechallenge); it resolved completely upon discontinuation of therapy. Patients who develop an abnormal ANA test should be carefully evaluated and, if persistent or worsening elevation of ANA titers is detected, consideration should be given to discontinuing therapy.
Interaction studies have only been performed in adults.
Small doses of quinidine completely inhibit the hydroxylation metabolic pathway, making all patients, in effect, slow metabolisers (see section 5.2). When propafenone hydrochloride is administered with quinidine, the patient should be closely monitored and the dose adjusted accordingly.
A possible potentiation of drug side effects may occur when propafenone hydrochloride is taken in conjunction with local anesthetics (e.g., pacemaker implantation, surgery or dental work) and other drugs which have an inhibitory effect on the heart rate and/or myocardial contractility.
No significant effects on the pharmacokinetics of Rytmonorm or lidocaine have been seen following their concomitant use in patients. However, concomitant use of Rytmonorm and intravenous lidocaine have been reported to increase the risks of central nervous system side effects of lidocaine.
Rytmonorm produces dose-related increases in serum digoxin levels ranging from about 35% at 450 mg/day to 85% at 900 mg/day of propafenone without affecting digoxin renal clearance. These elevations of digoxin levels were maintained for up to 16 months during concomitant administration. Plasma digoxin levels of patients on concomitant therapy should be measured, and digoxin dosage should ordinarily be reduced when propafenone is started, especially if a relatively large digoxin dose is used or if plasma concentrations are relatively high.
A possible potentiation of drug side effects may occur when propafenone hydrochloride is taken in conjunction with drugs which have an inhibitory effect on the heart rate and/or myocardial contractility (e.g. beta blockers).
In a study involving healthy subjects, concomitant administration of propafenone and propranolol has resulted in substantial increases in propranolol plasma concentration and elimination half-life with no change in propafenone plasma levels from control values. Similar observations have been reported with metoprolol. Propafenone appears to inhibit the hydroxylation pathway for the two beta-antagonists (just as quinidine inhibits propafenone metabolism). Increased plasma concentrations of metoprolol could overcome its relative cardioselectivity. While the therapeutic range for beta-blockers is wide, a reduction in dosage may be necessary during concomitant administration with propafenone.
Close monitoring of the clotting status in patients receiving concomitant oral anticoagulants (e.g. phenprocoumon, warfarin) is recommended as Rytmonorm may enhance the efficacy of these drugs resulting in increased prothrombin time. Doses of these medicinal products should be reduced, as appropriate, if signs of overdose are observed.
In a study of eight healthy subjects receiving propafenone and warfarin concomitantly, mean steady-state warfarin plasma concentration increased 39% with a corresponding increase in prothrombin times of approximately 25%.
Concomitant administration of Rytmonorm and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentration of propafenone with no detectable changes in electrocardiographic parameters beyond that measured on propafenone alone. When propafenone hydrochloride is administered with cimetidine, the patient should be closely monitored, and the dose adjusted accordingly.
Due to the potential for increased plasma concentrations, co-administration of ritonavir and Rytmonorm is contraindicated (see section 4.3).
Limited experience with propafenone combined with calcium antagonists and diuretics has been reported without evidence of clinically significant adverse reactions.
Concomitant use of propafenone hydrochloride and rifampin may reduce the antiarrhythmic efficacy of propafenone hydrochloride as the result of a reduction in the propafenone plasma levels.
Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4, e.g. ketoconazole, erythromycin and grapefruit juice might lead to increased levels of propafenone hydrochloride. When propafenone hydrochloride is administered with inhibitors of these enzymes, the patient should be closely monitored, and the dose adjusted accordingly.
Phenobarbital is a known inducer of CYP3A4. Response to propafenone hydrochloride therapy should be monitored during concomitant chronic phenobarbital use.
Co-administration of Rytmonorm with drugs metabolized by CYP2D6 (such as venlafaxine) might lead to increased levels of these drugs. Increases in desipramine, ciclosporine and theophylline plasma levels or blood levels have been reported during Rytmonorm therapy. Doses of these medicinal products should be reduced, as appropriate, if signs of overdose are observed.
Combination therapy of amiodarone and Rytmonorm 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.
Elevated levels of plasma propafenone may occur when Rytmonorm is used concomitantly with SSRIs, such as fluoxetine and paroxetine. Concomitant administration of Rytmonorm and fluoxetine in extensive metabolisers increased the S propafenone Cmax and AUC by 39 and 50% and the R propafenone Cmax and AUC by 71 and 50%. Lower doses of Rytmonorm may be sufficient to achieve the desired therapeutic response.
A possible potentiation of drug side effects may occur when propafenone hydrochloride is taken in conjunction with drugs which have an inhibitory effect on the heart rate and/or myocardial contractility (e.g. tricyclic antidepressants).
There are no adequate and well-controlled studies in pregnant women. Propafenone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Propafenone hydrochloride 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.
It is not known whether the use of propafenone during labour or delivery has immediate or delayed adverse effects on the foetus, or whether it prolongs the duration of labour or increases the need for forceps delivery or other obstetrical intervention.
Excretion of propafenone hydrochloride in human breast milk has not been studied. Limited data suggests that propafenone hydrochloride may be excreted in human breast milk. Propafenone hydrochloride should be used with caution in nursing mothers.
No data available. For pre-clinical fertility data refer to section 5.3.
It is important to note that blurred vision, dizziness, fatigue or postural hypotension may affect the patient’s speed of reaction to the point where the patient’s ability to operate machinery or motor vehicles is impaired.
The most common events were dizziness, cardiac conduction disorders and palpitations. About 20% of patients discontinued due to adverse reactions. Results from controlled trials and post-marketing experience with propafenone are shown below.
The reactions are displayed by MedDRA 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 with this or other formulations of Rytmonorm; frequency cannot be estimated from the available data). Within each frequency grouping, adverse effects are presented in order of decreasing seriousness when the seriousness could be assessed.
Uncommon: Thrombocytopenia
Not known: Agranulocytosis, leukopenia, granulocytopenia, anemia, bruising, increased bleeding time, leukocytopenia, purpura
Not known: Hypersensitivity1, positive ANA test
Common: Anorexia
Uncommon: Decreased appetite
Common: Anxiety, sleep disorders
Uncommon: Nightmare
Not known: Confusional state
Very common Dizziness2
Common: Headache, dysgeusia, weakness
Uncommon: Syncope, Ataxia, Paresthesia
Not known: Convulsion, extrapyramidal symptoms, restlessness, abnormal dreams, abnormal speech, abnormal vision, apnoea, coma, depression, memory loss, numbness, psychosis/mania, seizures, tinnitus, unusual smell sensation
Common: Vision blurred
Not known: Eye irritation
Uncommon: Vertigo
Very common: Cardiac conduction disorders3, palpitations
Common: Sinus bradycardia, bradycardia, tachycardia, atrial flutter, AV dissociation/block, angina, congestive heart failure, QRS interval prolonged
Uncommon: Ventricular tachycardia, arrhythmia4
Not known: Ventricular fibrillation, cardiac failure5, heart rate reduced, flushing, hot flushes, sick sinus syndrome, supraventricular tachycardia
Uncommon: Hypotension
Not known: Orthostatic hypotension including postural hypotension
Common:Dyspnea
Common:Abdominal pain, vomiting, nausea, diarrhea, constipation, dry mouth, dyspepsia
Uncommon Abdominal distension, flatulence
Not known: Retching, gastrointestinal disturbance, gastroenteritis
Common:Hepatic function abnormal6
Not known: Hepatocellular injury, cholestasis, hepatitis, jaundice
Uncommon: Urticaria, pruritus, rash, erythema
Not known: Alopecia, acute generalised exanthematous pustulosis
Not known: Lupus-like syndrome, muscle cramps, muscle weakness
Uncommon: Erectile dysfunction
Not known: Sperm count decreased7
Common: Chest pain, asthenia, fatigue, pyrexia
Not known: Kidney failure, nephrotic syndrome
Not known: Hyponatremia/inappropriate ADH secretion, increased glucose
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 suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
