Rythmol Sr

— THERAPEUTIC DISORDERS TREATED —
  • CHF and arrhythmias
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Rythmol Sr Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Propafenone HCl 225mg, 325mg, 425mg; ext-rel caps.

    Pharmacological Class

    Class IC antiarrhythmic.

    See Also

    How Supplied

    Tabs—Contact supplier; SR caps—60

    How Supplied

    Extended-release caps—60

    • 225mg: White capsule imprinted in red with GS EUG followed by 225.

    • 325mg: White capsule imprinted in red with GS F1Y followed by 325; single red band around ¾ of the circumference of the body.

    • 425mg: White capsule imprinted in red with GS UY2 followed by 425; 3 red bands around ¾ of the circumference of the body.

    Storage

    Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

    Manufacturer

    GlaxoSmithKline

    Generic Availability

    YES

    Rythmol Sr Indications

    Indications

    To prolong recurrence of symptomatic atrial fibrillation in patients without structural heart disease.

    Indications

    Usage Considerations

    • Use of propafenone in patients with permanent atrial fibrillation or in patients exclusively with atrial flutter or PSVT has not been evaluated.
    • Do not use propafenone to control ventricular rate during atrial fibrillation.
    • In patients with atrial fibrillation and atrial flutter, use propafenone with drugs that increase the atrioventricular nodal refractory period.
    • The effect of propafenone on mortality has not been determined.

    Rythmol Sr Dosage and Administration

    Adult

    Individualize. Not interchangeable on a mg-to-mg basis with immediate-release form (see full labeling). Swallow whole. Initially 225mg every 12hrs. May increase at 5-day intervals to 325mg every 12hrs; max 425mg every 12hrs. When switching from 150mg three times daily of the immediate-release form, start Rythmol SR at 325mg twice daily. QRS widening, 2nd or 3rd degree AV block, or hepatic impairment: reduce dose.

    Children

    Not established.

    Renal Impairment

    Approximately 50% of propafenone metabolites are excreted in the urine. Monitor for signs of overdosage in patients with impaired renal function.

    Hepatic Impairment

    Severe liver dysfunction increases the bioavailability of propafenone to approximately 70%. The clearance of propafenone is reduced and the elimination half-life increased. Carefully monitor patients with impaired hepatic function for excessive effects.

    Other Modifications

    Exacerbation of myasthenia gravis has been reported during propafenone therapy.

    Propafenone may transiently impair spermatogenesis in males.

    Rythmol Sr Contraindications

    Contraindications

    Heart failure. Cardiogenic shock. SA, AV and intraventricular disorders of impulse generation or conduction (eg, sick sinus syndrome, AV block), unless paced. Known Brugada Syndrome. Bradycardia. Marked hypotension. Bronchospastic disorders. Severe obstructive pulmonary disease. Marked electrolyte imbalance.

    Rythmol Sr Boxed Warnings

    Boxed Warning

    Mortality.

    Boxed Warning

    Mortality Risk

    National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST)

    • Long-term, multicenter, randomized, double-blind trial included patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than 6 days but less than 2 years previously.
    • Increased rate of death or reversed cardiac arrest was observed in patients treated with encainide or flecainide compared with placebo.
    • Average duration of treatment with encainide or flecainide was 10 months.
    • Based on findings, it is prudent to consider any Class IC antiarrhythmic to have significant proarrhythmic risk in patients with structural heart disease.
    • Antiarrhythmic agents should generally be avoided in patients with non-life-threatening arrhythmias, even if the patient is experiencing unpleasant, but not life-threatening, signs/symptoms.

    Rythmol Sr Warnings/Precautions

    Warnings/Precautions

    Significant proarrhythmic risk in structural heart disease. Avoid in patients with non-life-threatening ventricular arrhythmias. Monitor ECG, pacemakers before and during therapy. May provoke overt heart failure. Discontinue if ECG changes are suggestive of Brugada Syndrome. Monitor for agranulocytosis. Hepatic or renal dysfunction: monitor. Elderly. Labor & delivery, fetal/neonatal: monitor. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Proarrhythmic Effects

    • Propafenone has caused new or worsened arrhythmias.
    • It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval.
    • Patients should be evaluated electrocardiographically prior to and during therapy to determine whether response supports continued treatment.
    • Propafenone prolongs the QRS interval in the electrocardiogram; changes in the QT interval may be difficult to interpret.

    Unmasking Brugada Syndrome

    • Perform ECG after initiating treatment with propafenone.
    • Discontinue if changes are suggestive of Brugada syndrome.

    History of Heart Failure

    • Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects.
    • Proarrhythmic effects more likely when administered to patients with heart failure (NYHA III and IV) or severe myocardial ischemia.

    Conduction Disturbances

    • Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block.
    • Do not give to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker.

    Effects on Pacemaker Threshold

    • Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators.
    • Monitor and reprogram these devices accordingly during and after treatment.

    Agranulocytosis

    • Generally occurs within the first 2 months of propafenone therapy.
    • White cell counts usually normalize 14 days after discontinuation of therapy.

    Elevated ANA Titers

    • Positive ANA titers have been reported in patients receiving propafenone.
    • Usually not associated with clinical symptoms.
    • Evaluate patients who develop an abnormal ANA test.
    • Consider discontinuing therapy if persistent or worsening elevation of ANA titers is detected.

    Pregnancy Considerations

    No drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes have been identified based on available data.

    Propafenone and its metabolite have been shown to cross the placenta. Fetal/neonatal monitoring for signs of arrhythmia recommended during and after treatment with propafenone.

    Monitor patients treated with propafenone continuously for arrhythmias during labor and delivery.

    Nursing Mother Considerations

    Propafenone and its active metabolite are present in human milk; levels are likely low.

    There are no data on the effects of propafenone on the breastfed infant or the effects on milk production.

    Consider the benefits to the mother vs the potential risks to the breastfed infant.

    Pediatric Considerations

    The safety and effectiveness of propafenone in pediatric patients have not been established.

    Geriatric Considerations

    No overall differences observed between patients 65 years of age and older and younger patients.

    Dose should be increased more gradually during the initial phase of treatment taking into account the effect of age on pharmacokinetics and pharmacodynamics of propafenone.

    Renal Impairment Considerations

    Approximately 50% of propafenone metabolites are excreted in the urine. Monitor for signs of overdosage in patients with impaired renal function.

    Hepatic Impairment Considerations

    Severe liver dysfunction increases the bioavailability of propafenone to approximately 70%. The clearance of propafenone is reduced and the elimination half-life increased. Carefully monitor patients with impaired hepatic function for excessive effects.

    Other Considerations for Specific Populations

    Exacerbation of myasthenia gravis has been reported during propafenone therapy.

    Propafenone may transiently impair spermatogenesis in males.

    Rythmol Sr Pharmacokinetics

    Absorption

    Maximal plasma levels of propafenone are reached between 3 to 8 hours.

    Distribution

    Propafenone is greater than 95% protein bound.

    Metabolism

    Hepatic (CYP2D6, CYP3A4, CYP1A2).

    In over 90% of patients, propafenone is rapidly and extensively metabolized with an elimination half-life from 2 to 10 hours. 

    In <10% of patients, metabolism of propafenone is slower because the 5-hydroxymetabolite is not formed or is minimally formed; the estimated propafenone elimination half-life ranges from 10 to 32 hours.

    Elimination

    Extensive metabolizers: Elimination half-life from 2 to 10 hours. 

    Slow metabolizers: Elimination half-life from 10 to 32 hours.

    Rythmol Sr Interactions

    Interactions

    Avoid drugs that may prolong the QT interval (eg, antiarrhythmics, some phenothiazines, tricyclic antidepressants, oral macrolides). Avoid concomitant Class IA and III antiarrhythmics (including quinidine, amiodarone). Potentiates β-blockers, warfarin, digoxin (consider reducing their doses when starting propafenone). Potentiated by CYP2D6 inhibitors (eg, desipramine, paroxetine, ritonavir, sertraline) and CYP3A4 inhibitors (eg, ketoconazole, saquinavir, erythromycin, grapefruit juice); avoid simultaneous use with both. Antagonized by rifampin. May be antagonized by orlistat. Local anesthetics may increase CNS effects.

    Rythmol Sr Adverse Reactions

    Adverse Reactions

    Unusual taste, nausea, vomiting, dizziness, constipation, headache, fatigue, 1st degree AV block, intraventricular conduction delay, palpitations, chest pain, dyspnea, anxiety, upper respiratory tract infection, edema, influenza, angina pectoris, atrial flutter, heart failure, bradycardia, blurred vision; new or worsened arrhythmias, conduction disturbances, elevated ANA titers, exacerbation of myasthenia gravis.

    Rythmol Sr Clinical Trials

    Clinical Trials

    Rythmol SR has been evaluated in patients with a history of electrocardiographically documented recurrent episodes of symptomatic AF in 2 randomized, double-blind, placebo-controlled trials (RAFT and ERAFT).

    RAFT

    • Rythmol SR 225mg twice daily, Rythmol SR 325mg twice daily, Rythmol 425mg twice daily and placebo were compared.
    • Patients with symptomatic, episodic AF; 59% male, mean age 63 years, 91% white, 6% black.
    • Rythmol SR was administered for up to 39 weeks.
    • Compared with placebo, Rythmol SR was shown to significantly prolong the time to first recurrence of symptomatic atrial arrhythmia, predominantly AF from day 1 of randomization (primary endpoint).
    • Hazard ratio compared with placebo: 
      • Rythmol SR 225mg twice daily (n=126): 0.67 (95% CI, 0.49-0.93)
      • Rythmol SR 325mg twice daily (n=135): 0.43 (95% CI, 0.31-0.61)
      • Rythmol SR 425mg twice daily (n=136): 0.35 (95% CI, 0.24-0.51)
    • The antiarrhythmic effect was not influenced by the individual use of calcium channel blockers, beta blockers, or digoxin.

    ERAFT

    • Rythmol SR 325mg twice daily, Rythmol SR 425mg twice daily and placebo were compared.
    • 293 patients with documented electrocardiographic evidence of symptomatic paroxysmal AF; 61% male, 100% white, mean age of 61 years.
    • Double-blind treatment phase consisted of a 4-day loading period followed by a 91-day efficacy period.
    • Rythmol SR was shown to prolong the time to the first recurrence of symptomatic atrial arrhythmia from day 5 of randomization (primary endpoint).
    • Both doses were superior to placebo.
    • Antiarrhythmic effect was not influenced by use of calcium channel blockers, beta blockers, or digoxin.

    Rythmol Sr Note

    Not Applicable

    Rythmol Sr Patient Counseling

    Patient Counseling

    Agranulocytosis risk: Report promptly any signs of infection such as fever, sore throat, or chills.

    Report any change in OTC, prescription or supplement use.

    Report symptoms associated with altered electrolyte balance (eg, excessive or prolonged diarrhea, sweating, vomiting, loss of appetite, thirst).

    Do not double the next dose if a dose is missed; next dose should be taken at the usual time.

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