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U.S. Department of Health and Human Services

Safety

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Rythmol SR (propafenone hydrochloride) extended-release capsules

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – October 2010

Summary View

 

WARNINGS AND PRECAUTIONS

Proarrhythmic Effects
  • 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). Of the patients…
Drug Interactions: Simultaneous Use with Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4
  • Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. 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.
  • 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. Therefore, avoid simultaneous use of Rythmol SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
Use in Patients with a History of Heart Failure
  • In clinical trial experience with Rythmol immediate release, new or worsened heart failure has been reported in 3.7% of patients with ventricular arrhythmia. These events were more likely in subjects with preexisting heart failure and coronary artery disease. New onset of heart failure attributable to propafenone developed in <0.2% of patients with ventricular arrhythmia and in 1.9% of patients with paroxysmal AF or PSVT.
Conduction Disturbances
  • 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. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4) and Clinical Pharmacology (12.2)].
  • In a U.S. trial (RAFT) in 523 patients with a history of symptomatic AF treated with Rythmol SR, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with RYTHMOL SR and placebo. Effects of Pacemaker Threshold
  • Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
Agranulocytosis
  • Agranulocytosis has been reported in patients receiving propafenone. 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. 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.
Use in Patients with Hepatic Dysfunction
  • Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3-40% in patients with normal liver function when given Rythmol immediate release tablets. In 8 patients with moderate to severe liver disease administered Rythmol immediate release tablets, the mean half-life was approximately 9 hours. No studies have compared bioavailability of propafenone from Rythmol SR in patients with normal and impaired hepatic function. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects.

ADVERSE REACTIONS and Drug Interactions sections have been substantially revised