Non-cardiac related adverse events occurring in greater than or equal to 2% of the patients in any of the RAFT propafenone SR treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: blurred vision, constipation, diarrhea, dry mouth, flatulence, nausea, vomiting, fatigue, weakness, upper respiratory tract infection, blood alkaline phosphatase increased, hematuria, muscle weakness, dizziness (excluding vertigo), headache, taste disturbance, tremor, somnolence, anxiety, depression, ecchymosis.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 10/2016.
Dysuria, nocturia, oliguria, pyuria, renal failure, urinary casts, urinary frequency, urinary incontinence, urinary retention, urine abnormal.
These events were more likely in subjects with pre-existing heart failure and coronary artery disease. New onset of heart failure attributable to propafenone developed in less than 0.2% of patients with ventricular arrhythmia and in 1.9% of patients with paroxysmal AF or PSVT. In clinical trial experience with RYTHMOL immediate-release, new or worsened heart failure has been reported in 3.7% of patients with ventricular arrhythmia.
Hearing impaired, tinnitus, vertigo.
Updated October 5, 2016.
( 6.1 ). The most commonly reported adverse events with propafenone (greater than 5% and greater than placebo) excluding those not reasonably associated with the use of the drug included the following: dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza.
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.
Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
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. Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes.
Usage Considerations:. RYTHMOL SR is indicated to prolong the time to recurrence of symptomatic atrial fibrillation (AF) in patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease.
Therefore, simultaneous use of RYTHMOL SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions (5.4), Dosage and Administration (2)]. 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. 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.
Small doses of quinidine compley inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers. Avoid concomitant use of propafenone and quinidine. 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 poor metabolizers. A 100-mg dose of quinidine increased steady-state concentrations of propafenone 3 fold. Steady-state plasma concentrations increased by more than 2 fold for propafenone, and decreased 50% for 5-OH-propafenone.
Concurrent use of propafenone with other antiarrhythmic agents has not been well studied. 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 the RYTHMOL SR Atrial Fibrillation Trial (RAFT) trial, there were too few deaths to assess the long-term risk to patients.
Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with RYTHMOL SR. 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). Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. The use of RYTHMOL SR in conjunction with other drugs that prolong the QT interval has not been extensively studied.
Average PR interval prolongation and increases in QRS duration are also dose-related. 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.
( 3 ). Capsules: 225 mg, 325 mg, 425 mg.
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. Therefore, avoid simultaneous use of RYTHMOL SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4), Drug Interactions (7.1)].
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.
Adverse events occurring in 2% or more of the patients in any of the ERAFT propafenone SR treatment groups and not listed above include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia, and hypotension.
Anorexia, dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia.
RYTHMOL SR is contraindicated in the following circumstances:
The incidence of proarrhythmia in patients with less serious or benign arrhythmias, which include patients with an increase in frequency of PVCs, was 1.6%. Overall in clinical trials with RYTHMOL immediate-release (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 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). 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. Of the patients 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.
Amnesia, ataxia, balance impaired, brain damage, cerebrovascular accident, dementia, gait abnormal, hypertonia, hypothesia, insomnia, paralysis, paresthesia, peripheral neuropathy, speech disorder, syncope, tongue hypoesthesia.
Unstable angina, atrial hypertrophy, cardiac arrest, coronary artery disease, extrasystoles, myocardial infarction, nodal arrhythmia, palpitations, pericarditis, sinoatrial block, sinus arrest, sinus arrhythmia, supraventricular extrasystoles, ventricular extrasystoles, ventricular hypertrophy.
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.
In a US uncontrolled, open-label, multicenter trial using the immediate-release formulation in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. About 2.3% (11/474) of all patients had recurrence of SVT during the trial which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event. However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsades de pointes, asystole, and death. Six of the 9 patients that developed ventricular arrhythmias did so within 14 days of onset of therapy.
Abnormal heart sounds, abnormal pulse, carotid bruit, decreased blood chloride, decreased blood pressure, decreased blood sodium, decreased hemoglobin, decreased neutrophil count, decreased plaet count, decreased prothrombin level, decreased red blood cell count, decreased weight, glycosuria present, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, increased blood cholesterol, increased blood creatinine, increased blood glucose, increased blood lactate dehydrogenase, increased blood pressure, increased blood prolactin, increased blood triglycerides, increased blood urea, increased blood uric acid, increased eosinophil count, increased gamma-glutamyltransferase, increased monocyte count, increased prostatic specific antigen, increased prothrombin level, increased weight, increased white blood cell count, ketonuria present, proteinuria present.
It is therefore essential that each patient given RYTHMOL SR be evaluated electrocardiographically prior to and during therapy to determine whether the response to RYTHMOL SR supports continued treatment. Propafenone has caused new or worsened arrhythmias. 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. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret.
Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt heart failure. Proarrhythmic effects more likely occur when propafenone is administered to patients with heart failure (NYHA III and IV) or severe myocardial ischemia. In the US trial (RAFT) in patients with symptomatic AF, heart failure was reported in 4 (1.0%) patients receiving RYTHMOL SR (all doses) compared with 1 (0.8%) patient receiving placebo.
Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval. Propafenone prolongs the PR and QRS intervals in patients with atrial and ventricular arrhythmias.
Brugada Syndrome may be unmasked after exposure to RYTHMOL SR. Perform an ECG after initiation of RYTHMOL SR and discontinue the drug if changes are suggestive of Brugada Syndrome.
Cardiac-related adverse events occurring in greater than or equal to 2% of the patients in any of the RAFT propafenone SR treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: angina pectoris, atrial flutter, AV block first-degree, bradycardia, congestive cardiac failure, cardiac murmur, edema, dyspnea, rales, wheezing, and cardioactive drug level above therapeutic.
Do not crush or further divide the contents of the capsule. RYTHMOL SR can be taken with or without food.
The 425-mg strength is imprinted in red with GS UY2 followed by 425, and also has 3 red bands around ¾ of the circumference of the body. The 225-mg strength is imprinted in red with GS EUG followed by 225. The 325-mg strength is imprinted in red with GS F1Y followed by 325, and also has a single red band around ¾ of the circumference of the body. RYTHMOL SR (propafenone HCl) capsules are supplied as white, opaque, hard gelatin capsules containing either 225 mg, 325 mg, or 425 mg of propafenone HCl.
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 (RAFT) in 523 patients 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.
Alopecia, dermatitis, dry skin, erythema, nail abnormality, petechiae, pruritus, sweating increased, urticaria.
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. 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. Carefully evaluate patients who develop an abnormal ANA test and if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.
Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and C max propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH-propafenone by 69% and 57%, respectively. The concentrations of norpropafenone increased by 30%. In poor 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. 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%.
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Dosage may be increased at a minimum of 5-day intervals to 325 mg given every 12 hours. If additional therapeutic effect is needed, the dose of RYTHMOL SR may be increased to 425 mg given every 12 hours. The dose of RYTHMOL SR must be individually titrated on the basis of response and tolerance. Initiate therapy with RYTHMOL SR 225 mg given every 12 hours.
Arterial embolism limb, deep limb venous thrombosis, flushing, hematoma, hypertension, hypertensive crisis, hypotension, labile blood pressure, pallor, peripheral coldness, peripheral vascular disease, thrombosis.
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. Agranulocytosis has been reported in patients receiving propafenone.
( 1 ) Usage Considerations:. RYTHMOL SR is an antiarrhythmic indicated to prolong the time to recurrence of symptomatic atrial fibrillation (AF) in patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease.
Aectasis, breath sounds decreased, chronic obstructive airways disease, cough, epistaxis, hemoptysis, lung disorder, pleural effusion, pulmonary congestion, rales, respiratory failure, rhinitis, throat tightness.
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.
Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.
Increased bioavailability of propafenone in these patients may result in excessive accumulation. In 8 patients with moderate to severe liver disease administered RYTHMOL immediate-release tablets, the mean half-life was approximay 9 hours. Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximay 70% compared with 3% to 40% in patients with normal liver function when given RYTHMOL immediate-release tablets. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects. No trials have compared bioavailability of propafenone from RYTHMOL SR in patients with normal and impaired hepatic function.
Breast pain, impotence, prostatism.
The frequency of discontinuation due to adverse events was 17%, and the rate was highest during the first 14 days of treatment. The data described below reflect exposure to RYTHMOL SR 225 mg twice daily in 126 patients, to RYTHMOL SR 325 mg twice daily in 135 patients, to RYTHMOL SR 425 mg twice daily in 136 patients, and to placebo in 126 patients for up to 39 weeks (mean: 20 weeks) in a placebo-controlled trial (RAFT) conducted in the US. The most commonly reported adverse events with propafenone (greater than 5% and greater than placebo) excluding those not reasonably associated with the use of the drug or because they were associated with the condition being treated, were dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza.
Anemia, lymphadenopathy, spleen disorder, thrombocytopenia.
Eye hemorrhage, eye inflammation, eyelid ptosis, miosis, retinal disorder, visual acuity reduced.
In patients with impaired renal function, monitor for signs of overdosage.
Chest pain, feeling hot, hemorrhage, malaise, pain, pyrexia. Hepatomegaly.
Decreased libido, emotional disturbance, mental disorder, neurosis, nightmare, sleep disorder.
No clinically important differences in incidence of adverse reactions were noted by age or gender. Too few non-Caucasian patients were enrolled to assess adverse events according to race.
Other adverse events reported with propafenone clinical trials not already listed elsewhere in the prescribing information include the following adverse events by body system and preferred term.
Abdominal distension, abdominal pain, duodenitis, dyspepsia, dysphagia, eructation, gastritis, gastroesophageal reflux disease, gingival bleeding, glossitis, glossodynia, gum pain, halitosis, intestinal obstruction, melena, mouth ulceration, pancreatitis, peptic ulcer, rectal bleeding, sore throat.
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of RYTHMOL SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity.
Arthritis, bursitis, collagen-vascular disease, costochondritis, joint disorder, muscle cramps, muscle spasms, myalgia, neck pain, pain in jaw, sciatica, tendonitis.
Exacerbation of myasthenia gravis has been reported during propafenone therapy.
No trials have been performed to assess the percentage of metabolites eliminated in the urine following the administration of RYTHMOL SR capsules. Approximay 50% of propafenone metabolites are excreted in the urine following administration of RYTHMOL immediate-release tablets.Rythmol