Propafenone

Propafenone
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

WARNING See full prescribing information for complete Boxed Warning. MORTALITY: In the National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind trial in subjects with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than 6 days but less than 2 years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in subjects assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this trial was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any IC antiarrhythmic to have a significant proarrhythmic risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

Overview

Propafenone is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease, recurrent paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease, and life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include chest pain, edema, palpitations, constipation, nausea, taste alteration, vomiting, dizziness, anxiety, dyspnea, and fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

PAF, PSVT, or Ventricular Arrhythmia

• Dosing Information

• 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/day).
• Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day).
• If additional therapeutic effect is needed, the dose of RYTHMOL may be increased to 300 mg every 8 hours (900 mg/day). The usefulness and safety of dosages exceeding 900 mg per day have not been established.
• 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.
• 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.
• 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 proa

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Propafenone in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Propafenone in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Propafenone in pediatric patients.

Contraindications

• Heart failure
• Cardiogenic shock
• Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (e.g., sick sinus syndrome, AV block) in the absence of an artificial pacemaker
• Brugada Syndrome
• Bradycardia
• Marked hypotension
• Bronchospastic disorders or severe obstructive pulmonary disease
• Marked electrolyte imbalance

Warnings

WARNING See full prescribing information for complete Boxed Warning. MORTALITY: In the National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind trial in subjects with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than 6 days but less than 2 years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in subjects assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this trial was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any IC antiarrhythmic to have a significant proarrhythmic risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

• Proarrhythmic Effects

• Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole, and torsade de pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. 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. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2)].

• 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. 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. 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. 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.

• 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. 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%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial [see Boxed Warning: Mortality] suggests that an increased risk of proarrythmia is present throughout treatment.

• In a trial of sustained-release propafenone (RYTHMOL SR®), there were too few deaths to assess the long-term risk to patients. 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. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

• Unmasking Brugada Syndrome

• 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 [see Contraindications (4)].

• Use With Drugs That Prolong the QT Interval and Antiarrhythmic Agents

• 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. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with RYTHMOL. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.

• 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 US 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 with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

• Use in Patients With a History of Heart Failure

• Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt heart failure.

• 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 definitely related to propafenone HCl. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. CHF attributable to propafenone HCl developed rarely (<0.2%) in ventricular arrhythmia subjects who had no previous history of CHF. CHF occurred in 1.9% of subjects studied with PAF or PSVT.

• 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.

• 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), Clinical Pharmacology (12.2)].

• 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. Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone HCl. 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%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.

• In a US trial in 523 subjects 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 on 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 with 3% to 40% in patients with normal liver function. In 8 subjects with moderate to severe liver disease, the mean half-life was approximately 9 hours. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects.

• Use in Patients With Renal Dysfunction

• Approximately 50% of propafenone metabolites are excreted in the urine following administration of RYTHMOL.

• In patients with impaired renal function, monitor for signs of overdosage [see Overdosage (10)].

• Use in Patients With Myasthenia Gravis

• Exacerbation of myasthenia gravis has been reported during propafenone therapy.

• Elevated ANA Titers

• 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 erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

• Impaired Spermatogenesis

• Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone. 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.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Propafenone in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Propafenone in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Propafenone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Propafenone during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Propafenone with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Propafenone with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Propafenone with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Propafenone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Propafenone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Propafenone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Propafenone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Propafenone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Propafenone in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Propafenone in the drug label.

Condition1

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Propafenone in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Propafenone in the drug label.

Pharmacology

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Propafenone in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Propafenone in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Propafenone in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Propafenone in the drug label.

Condition1

• Description

How Supplied

Storage

There is limited information regarding Propafenone Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Propafenone in the drug label.

Precautions with Alcohol

• Alcohol-Propafenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Rythmol®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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