Propafenone has caused new or worsened arrhythmias. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret. It is therefore essential that each patient given Rythmol be evaluated electrocardiographically prior to and during therapy to determine whether the response to Rythmol supports continued treatment. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole, and torsade de pointes.
These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved compley upon discontinuation of therapy. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. Positive ANA titers have been reported in patients receiving propafenone. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.
Adverse reactions reported for greater than 1.5% of 474 subjects with SVT who received Rythmol in US clinical trials are presented in Table 1 by incidence and percent discontinuation, reported to the nearest percent.
Exacerbation of myasthenia gravis has been reported during propafenone therapy.
There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with Rythmol. The use of Rythmol in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides.
Although maternally tolerated doses (up to 270 mg per kg per day, about 3 times the MRHD on a mg per m 2 basis) produced no evidence of embryotoxicity in rats; post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg per kg per day, about 1/3 the MRHD on a mg per m 2 basis). Teratogenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg per kg per day (about 3 times the maximum recommended human dose on a mg per m 2 basis) and 600 mg per kg per day (about 6 times the MRHD on a mg per m 2 basis), respectively.
Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended. Cimetidine.
Animal Data. There are no adequate and well-controlled studies in pregnant women. Pregnancy Category C. Rythmol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In postmarketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block, and acute circulatory failure. Orlistat may limit the fraction of propafenone available for absorption.
Adverse reactions associated with Rythmol occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of subjects treated with Rythmol have discontinued treatment because of adverse reactions.
Agranulocytosis, anemia, bruising, granulocytopenia, leukopenia, purpura, thrombocytopenia. Other.
Generic Name: propafenone hydrochloride Dosage Form: tablet, film coated.
Alopecia, eye irritation, impotence, increased glucose, positive ANA (0.7%), muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus.
Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone HCl. Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone. The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with ventricular arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%).
Rythmol is contraindicated in the following circumstances:
However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients.
CHF attributable to propafenone HCl developed rarely (less than 0.2%) in subjects with ventricular arrhythmia who had no previous history of CHF. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. In clinical trial experience with Rythmol, new or worsened congestive heart failure (CHF) has been reported in 3.7% of subjects with ventricular arrhythmia; of those 0.9% were considered probably or definiy related to propafenone HCl. CHF occurred in 1.9% of subjects studied with PAF or PSVT.
150-mg and 225-mg scored, round, film-coated tablets.
Some less common reactions may also have been dose-related such as first-degree AV block, congestive heart failure, dyspepsia, and weakness. Other adverse reactions included rash, syncope, chest pain, abdominal pain, ataxia, and hypotension. The most common adverse reactions appeared dose-related (but note that most subjects spent more time at the larger doses), especially dizziness, nausea and/or vomiting, unusual taste, constipation, and blurred vision. Adverse reactions reported for greater than or equal to 1% of 2,127 subjects with ventricular arrhythmia who received propafenone in US clinical trials were evaluated by daily dose.
Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4), Clinical Pharmacology (12.2)]. Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related.
Approximay 50% of propafenone metabolites are excreted in the urine following administration of Rythmol.
Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial suggests that an increased risk of proarrythmia is present throughout treatment. The incidence of proarrhythmia in subjects with less serious or benign arrhythmias, which include subjects with an increase in frequency of PVCs, was 1.6%. Overall in clinical trials with Rythmol (which included subjects treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all subjects 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 subjects who had 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.
Cholestasis, elevated liver enzymes (alkaline phosphatase, serum transaminases), gastroenteritis, hepatitis. Hematologic.
Some appeared due to hepatocellular injury, some were cholestatic, and some showed a mixed picture. A number of patients with liver abnormalities associated with propafenone therapy have been reported in postmarketing experience. One case was rechallenged with a positive outcome. Some of these reports were simply discovered through clinical chemistries, others because of clinical symptoms including fulminant hepatitis and death.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
In a US uncontrolled, open-label, multicenter trial in subjects with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these subjects experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects’ arrhythmia behavior or could represent a proarrhythmic event. However, in 4 of the 9 subjects, the ventricular tachycardia was of atrial origin. Six of the 9 subjects that developed ventricular arrhythmias did so within 14 days of onset of therapy.
Agranulocytosis has been reported in patients receiving propafenone. Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills. Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy, and upon discontinuation of therapy the white count usually normalized by 14 days.
In patients with impaired renal function, monitor for signs of overdosage.
Brugada Syndrome may be unmasked after exposure to Rythmol. Perform an ECG after initiation of Rythmol, and discontinue the drug if changes are suggestive of Brugada Syndrome.
Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt heart failure.
Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone. Fluoxetine.
Cardiovascular System. Causality and relationship to propafenone therapy cannot necessarily be judged from these events. In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience.
The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, grapefruit juice) can be expected to cause increased plasma levels of propafenone. Amiodarone. Therefore, simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions (5.4), Dosage and Administration (2)].
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal. The following adverse reactions have been identified during post-approval use of Rythmol.
The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).
Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed. Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270%, and decreased the clearance of digoxin by 31% to 67%.
Avoid concomitant use of propafenone and quinidine. Small doses of quinidine compley inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers. Steady-state plasma concentrations more than doubled for propafenone, and decreased 50% for 5-OH-propafenone. Concomitant administration of quinidine (50 mg 3 times daily) with 150 mg immediate-release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers. A 100-mg dose of quinidine tripled steady-state concentrations of propafenone. Rifampin:.
As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of Rythmol should be increased more gradually during the initial phase of treatment.
Other reactions reported more frequently than on placebo or comparator and not already reported elsewhere included anxiety, angina, second-degree AV block, bundle branch block, loss of balance, congestive heart failure, and dyspepsia. In controlled trials in subjects with ventricular arrhythmia, the most common reactions reported for Rythmol and more frequent than on placebo were unusual taste, dizziness, first-degree AV block, intraventricular conduction delay, nausea and/or vomiting, and constipation. Headache was relatively common also, but was not increased compared with placebo.
Rythmol is indicated to: Usage Considerations:
Increased bioavailability of propafenone in these patients may result in excessive accumulation. Propafenone is highly metabolized by the liver. In 8 subjects with moderate to severe liver disease, the mean half-life was approximay 9 hours. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects. Severe liver dysfunction increases the bioavailability of propafenone to approximay 70% compared with 3% to 40% in patients with normal liver function.
In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose.
In a US trial in 523 subjects with a history of symptomatic AF treated with Rythmol SR, sinus bradycardia (rate less than 50 beats per min) was reported with the same frequency with Rythmol SR and placebo.
% of Subjects Who Discontinued Unusual taste 14% 1.3% Nausea and/or vomiting 11% 2.9% Dizziness 9% 1.7% Constipation 8% 0.2% Headache 6% 0.8% Fatigue 6% 1.5% Blurred Vision 3% 0.6% Weakness 3% 1.3% Dyspnea 2% 1.0% Wide complex tachycardia 2% 1.9% CHF 2% 0.6% Bradycardia 2% 0.2% Palpitations 2% 0.2% Tremor 2% 0.4% Anorexia 2% 0.2% Diarrhea 2% 0.4% Ataxia 2% 0.0%
Abnormal dreams, abnormal speech, abnormal vision, confusion, depression, memory loss, numbness, paresthesias, psychosis/mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo. Gastrointestinal.
Quinidine. Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone C max and AUC by 39% and 50%, respectively, and the R propafenone C max and AUC by 71% and 50%, respectively.
In a US trial of Rythmol SR in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving Rythmol SR (all doses) compared with 1 (0.8%) subject receiving placebo.
Evaluation of the effects of short-term administration of Rythmol on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count. Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone.
Therefore, avoid simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous.
The dose of Rythmol must be individually titrated on the basis of response and tolerance. Initiate therapy with Rythmol 150 mg given every 8 hours (450 mg per day). The usefulness and safety of dosages exceeding 900 mg per day have not been established. Dosage may be increased at a minimum of 3- to 4- day intervals to 225 mg every 8 hours (675 mg per day). If additional therapeutic effect is needed, the dose of Rythmol may be increased to 300 mg every 8 hours (900 mg per day).
Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia. Nervous System.
Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximay 6% of Caucasians in the US population are naturally deficient in CYP2D6 activity and other demographic groups are deficient to a somewhat lesser extent. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.
Hyponatremia/inappropriate ADH secretion, kidney failure.
Incidence (N = 480).
There were 5 deaths, 3 in the pooled group for Rythmol SR (0.8%), and 2 in the placebo group (1.6%). In the overall database of 8 trials of Rythmol SR and immediate-release Rythmol, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo. In a trial of sustained-release propafenone (Rythmol SR ), there were too few deaths to assess the long-term risk to patients. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.
Therefore, avoid simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4), Drug Interactions (7.1)]. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events.
In slow metabolizers, there was a 50% decrease in propafenone plasma concentrations and an increase in the AUC and C max of norpropafenone by 74% and 20%, respectively. Similar results were noted in elderly patients: Both the AUC and C max of propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH‑propafenone by 69% and 57%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. The concentrations of norpropafenone increased by 30%. Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%.
Blood and Lymphatic System: Increased bleeding time. Immune System Lupus erythematosis. Renal and Urinary. Nervous System Apnea, coma.
Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In clinical trials using propafenone immediate-release tablets, subjects who were receiving beta-blockers concurrently did not experience an increased incidence of side effects. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%.Rythmol