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Propafenone

Class: Class Ic Antiarrhythmics
VA Class: CV300
Chemical Name: 1-Propanone,1-[2-[2-hydroxy-3-(propylamino)propoxy]phenyl]-3- phenylpropan-1-one hydrochloride
Molecular Formula: C21H27NO3
CAS Number: 34183-22-7
Brands: Rythmol

Medically reviewed by Drugs.com on Nov 4, 2021. Written by ASHP.

Introduction

Propafenone is a local anesthetic type Ic antiarrhythmic agent.

Uses for Propafenone

Supraventricular Tachyarrhythmias

Used (as conventional [immediate-release] tablets) to prolong the time to recurrence of symptomatic, disabling paroxysmal supraventricular tachycardia (PSVT) (e.g., AV nodal reentrant tachycardia or AV reentrant tachycardia [Wolff-Parkinson-White, WPW, syndrome]) and symptomatic, disabling paroxysmal atrial fibrillation/flutter (PAF) in patients without structural heart disease.

Used (as extended-release capsules) to prolong the time to recurrence of symptomatic PAF in patients without structural heart disease. Safety and efficacy of extended-release capsules not established in patients with exclusively PSVT or atrial flutter.

One of several drugs that may be used for ongoing management of patients with PSVT who do not have structural or ischemic heart disease; generally reserved for patients in whom other therapies (e.g., catheter ablation, β-adrenergic blocking agents, diltiazem, verapamil) are ineffective or contraindicated.

Comparably effective to quinidine, disopyramide, flecainide, procainamide, sotalol in preventing recurrences of PAF and maintaining sinus rhythm following successful cardioversion of atrial fibrillation.

Safety and efficacy not established in patients with chronic atrial fibrillation.

Has been used for pharmacologic cardioversion of atrial fibrillation or flutter.

May be used for ongoing management of other supraventricular tachycardias (SVTs) (e.g., focal atrial tachycardia, junctional tachycardia).

Because of risk of proarrhythmia, do not use in patients with structural heart disease or ischemic heart disease.

Ventricular Arrhythmias

As conventional (immediate-release) tablets, suppresses and prevents recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained VT, VF). (See Mortality under Cautions.)

Propafenone Dosage and Administration

General

  • Individualize dosage according to individual requirements, response, tolerance, general condition, and cardiovascular status.

  • Initiate therapy (conventional [immediate-release] tablets) for life-threatening ventricular arrhythmias in a hospital.

  • Clinical and ECG evaluation (e.g., Holter monitoring) is recommended during propafenone therapy.

Administration

Administer orally.

Has been administered IV, but parenteral dosage form not commercially available in US.

Oral Administration

Administer conventional (immediate-release) tablets in a consistent manner relative to food intake.

Administer conventional (immediate-release) tablets in 3 equally divided doses daily at 8-hour intervals.

Administer extended-release capsules in equally divided doses every 12 hours without regard to meals.

Swallow extended-release capsules whole; do not crush.

Avoid grapefruit juice. (See Drugs, Foods, and Herbal Supplements under Interactions.)

Dosage

Adjust dosage carefully according to individual requirements and response, patient tolerance, and the general condition and cardiovascular status of the patient.

Consider dosage reduction in patients who develop excessive prolongation of the PR interval, excessive QRS widening, or second- or third-degree AV block.

Usually do not use oral loading doses (conventional [immediate-release] tablets) since acute toxicity may occur. However, oral loading doses (e.g., 450–750 mg as conventional [immediate-release] tablets) have been used with apparent safety for conversion of recent-onset atrial fibrillation to normal sinus rhythm in individuals without heart failure.

Pediatric Patients

Supraventricular Arrhythmias
Oral (conventional [immediate-release] tablets)

Some clinicians suggest maximum daily dosage 600 mg/m2.

Adults

Paroxysmal Atrial Fibrillation/Flutter and Paroxysmal Supraventricular Tachyarrhythmias
Oral (conventional [immediate-release] tablets)

Initially, 150 mg every 8 hours.

Increase dosage after 3–4 days to 225 mg 3 times daily (every 8 hours) if necessary.

If desired therapeutic response is not attained after an additional 3–4 days, increase dosage to 300 mg 3 times daily (every 8 hours).

Oral (extended-release capsules)

Initially, 225 mg every 12 hours.

Increase dosage after ≥5 days to 325 mg every 12 hours if necessary.

If desired therapeutic response is not attained after an additional 5 days, increase dosage to 425 mg every 12 hours.

If a dose is missed, only administer the next scheduled dose; do not double next dose.

When switching from conventional (immediate-release) tablets to extended-release capsules, the dosage conversion ratio is not a 1:1 substitution (e.g., a patient who currently is receiving 150 mg every 8 hours of conventional (immediate-release) tablets may be switched to 325 mg of extended-release capsules every 12 hours).

Conversion of Atrial Fibrillation to Normal Sinus Rhythm†
Oral (conventional [immediate-release] tablets)

150–600 mg, as a single dose.

IV†

2 mg/kg (over 10 minutes) as a single dose.

Self-administration for Conversion of PAF†
Oral (conventional [immediate-release] tablets)

Adults weighing 70 kg or more: May use a single oral loading dose of 600 mg 5 minutes after noting the onset of palpitations.

Adults weighing < 70 kg: May use a single oral loading dose of 450 mg 5 minutes after noting the onset of palpitations.

Do not take more than a single oral dose during a 24-hour period.

Ventricular Arrhythmias
Oral (conventional [immediate-release] tablets)

Initially, 150 mg every 8 hours.

Increase dosage after 3–4 days to 225 mg 3 times daily if necessary.

If desired therapeutic response is not attained after an additional 3–4 days, increase dosage to 300 mg 3 times daily.

Prescribing Limits

Pediatric Patients

Supraventricular Arrhythmias
Oral (conventional [immediate-release] tablets)

Some clinicians suggest maximum daily dosage of 600 mg/m2.

Adults

Supraventricular Arrhythmias
Oral (conventional [immediate-release] tablets)

Maximum daily dosage is 900 mg.

Life-threatening Ventricular Arrhythmias
Oral (conventional [immediate-release] tablets)

Maximum daily dosage is 900 mg.

Special Populations

Hepatic Impairment

When conventional (immediate-release) tablets are used, reduce dosage by approximately 70–80%; monitor patients for signs of toxicity, including hypotension, somnolence, bradycardia, conduction disturbances, seizures, and/or ventricular arrhythmias.

Geriatric Patients and Those with Myocardial Damage

During initiation of therapy (conventional [immediate-release] tablets), gradual dosage escalation should be performed in geriatric patients and those with marked previous myocardial ischemia.

Cautions for Propafenone

Contraindications

  • Patients with uncontrolled CHF (conventional [immediate-release] tablets), CHF (extended-release capsules).

  • Cardiogenic shock.

  • Sinoatrial, AV, or intraventricular disorders of impulse generation and/or conduction (e.g., sick sinus node syndrome, AV block) unless an artificial pacemaker is present.

  • Bradycardia.

  • Severe hypotension.

  • Bronchospastic disorders.

  • Marked electrolyte imbalance.

  • Known hypersensitivity to propafenone.

Warnings/Precautions

Warnings

Mortality

In CAST study, excessive rate of mortality and nonfatal cardiac arrest reported in patients with asymptomatic or mildly symptomatic non-life-threatening ventricular arrhythmias and recent MI (>6 days but <2 years previously) who were receiving encainide or flecainide compared with placebo. The applicability of these results to other populations (e.g., those without recent MI) or to other antiarrhythmic drugs is uncertain.

Limit use of propafenone or other class I agents in patients with ventricular arrhythmias to those with life-threatening arrhythmias; use in patients with less severe ventricular arrhythmias, even when symptomatic, is not recommended.

Arrhythmogenic and Cardiac Conduction Effects

Potential for new and/or more severe arrhythmias, especially in those with CHF (NYHA class III or IV) or myocardial ischemia.

Risk of clinically important conduction disturbances; degree of lengthening of PR and QRS intervals may increase progressively with increasing dosage and plasma propafenone concentrations.

Reduce dosage or discontinue the drug if 2nd- or 3rd-degree AV block occurs. (See Contraindications under Cautions.)

Evaluate clinical status and ECG prior to and during propafenone therapy to monitor for appearance of arrhythmias and to determine the need for continued therapy.

Monitor patients with permanent artificial pacemakers and, if necessary, reprogram pacemakers.

Cardiovascular Effects

Potential for new or worsened CHF, particularly in patients with preexisting heart failure or ejection fraction <30%.

Use with caution (conventional [immediate-release] tablets) in patients with a history of CHF or myocardial dysfunction.

Discontinue therapy if CHF worsens (unless caused by the cardiac arrhythmia); fully compensate CHF before therapy is reinitiated.

Hematologic Effects

Possible reversible granulocytopenia and agranulocytosis.

Carefully evaluate patients in whom unexplained fever and/or decreased WBC counts occur (especially during the initial 3 months of therapy). WBC counts generally return to normal within 2 weeks following discontinuance.

Bronchospastic Disease

Possible inhibition of bronchodilation produced by endogenous catecholamines; use generally not recommended in patients with asthma/bronchospastic disease or nonallergic bronchospastic disease (e.g., chronic bronchitis, emphysema). (See Contraindications under Cautions.)

General Precautions

Hepatic Impairment

Extensively metabolized in liver; use with caution in those with hepatic impairment.

Renal Impairment

Several metabolites excreted by kidneys; use with caution in those with renal impairment.

Antinuclear Antibodies.

Possible positive antinuclear antibody (ANA) titers.

Monitor carefully patients who develop an abnormal ANA test following initiation of therapy; consider discontinuation of therapy if titers remain elevated or increase further.

Impaired Spermatogenesis

Transient, reversible decreases (within normal range) in sperm count may occur.

Myasthenia Gravis

Possible exacerbation of myasthenia gravis. Avoid use in patients with this condition.

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk. Caution if used in nursing women.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Has been used successfully and without unusual adverse effects in a limited number of infants and children for the management of various refractory supraventricular (e.g., PSVT, junctional ectopic tachycardia, atrial fibrillation or flutter) and ventricular (e.g., VPCs, VT) arrhythmias.

Geriatric Use

Conventional (immediate-release) tablets: Insufficient experience to determine whether geriatric patients ≥65 years of age respond differently than younger adults. Select dosage with caution; start at the lower end of dosing range due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Extended-release capsules: No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Extensively metabolized in liver; use with caution. Careful monitoring for excessive pharmacological effects recommended. Reduce dosage. (See Special Populations under Dosage and Administration.)

Renal Impairment

Use with caution. Careful monitoring for excessive pharmacological effects recommended.

Common Adverse Effects

Conventional (immediate-release) tablets: Unusual taste, nausea and/or vomiting, dizziness, constipation, headache, fatigue, blurred vision, and weakness. First-degree AV block and intraventricular conduction delay in patients with ventricular arrhythmia.

Extended-release capsules: Constipation, diarrhea, dry mouth, nausea, vomiting, unusual taste, fatigue, weakness, dizziness, headache, somnolence, anxiety, dyspnea, ecchymosis, upper respiratory infection, abnormalities in liver function tests (e.g., increased serum concentrations of alkaline phosphatase), hematuria.

Interactions for Propafenone

Metabolized by CYP2D6 and to a lesser extent by CYP1A2, CYP3A4.

Inhibits CYP2D6.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP2D6, CYP1A2, or CYP3A4 with possible alteration in metabolism of propafenone and/or other drugs. Monitor patients.

Drugs Metabolized by p-Glycoprotein Transporter

Effect of propafenone on the p-glycoprotein transport system not evaluated.

Drugs Affecting QT Interval

Do not use with drugs that prolong the QT interval.

Antiarrhythmic Agents

Use extreme caution when propafenone is administered with other antiarrhythmic agents. Reserve concomitant use for management of life-threatening arrhythmias unresponsive to propafenone monotherapy. Do not use propafenone (extended-release capsules) with class Ia or III antiarrhythmic agents.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Possible increased incidence of cardiovascular effects

Increased propafenone concentrations

Concomitant use not recommended

β-adrenergic blocking agents (e.g., metoprolol, propranolol)

Increased β-adrenergic blocking agent concentrations and terminal elimination half-life

Use concomitantly with caution; consider β-adrenergic blocking agent dosage reduction

Calcium channel-blocking agents

No evidence of clinically important adverse interactions

Cimetidine

Increased propafenone steady-state plasma concentrations

Cyclosporine

Increased cyclosporine concentrations

Desipramine

Increased propafenone concentrations

Increased desipramine serum concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Consider desipramine dosage reduction

Digoxin

Increased serum or plasma digoxin concentrations

Carefully monitor serum digoxin concentrations and adjust digoxin dosage

Diuretics

No evidence of clinically important adverse interactions

Erythromycin

Increased propafenone concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Fluoxetine

In extensive-metabolizer phenotypes, increased peak plasma concentrations and AUC of propafenone

Grapefruit juice

Possible increased plasma concentrations of unchanged propafenone and potential adverse effects

Avoid concomitant use

Haloperidol

Increased haloperidol concentrations

Use concomitantly with caution; consider haloperidol dosage reduction

Imipramine

Increased imipramine concentrations

Use concomitantly with caution; consider imipramine dosage reduction

Ketoconazole

Increased propafenone concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Lidocaine

Possible pharmacologic interaction (additive or antagonistic cardiac effects and additive toxicity)

Orlistat

Possible limited absorption of propafenone

Possibility of severe adverse effects with abrupt discontinuance of orlistat

Paroxetine

Increased propafenone concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Phenobarbital

Decreased plasma propafenone concentrations

Quinidine

Increased plasma propafenone concentrations

Concomitant use not recommended

Rifampin

Increased metabolism of propafenone resulting in decreased plasma propafenone concentrations and antiarrhythmic activity

Ritonavir

Increased propafenone concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Saquinavir

Increased propafenone concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Sertraline

Increased propafenone concentrations

Use concomitantly with caution; reduce propafenone hydrochloride dosage

Theophylline

Increased serum theophylline concentrations and toxicity

Venlafaxine

Increased venlafaxine concentrations

Use concomitantly with caution; consider venlafaxine dosage reduction

Warfarin

Increased plasma warfarin concentrations and corresponding PTs

Monitor PTs or INRs; adjust warfarin dosage

Propafenone Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration of conventional (immediate-release) tablets.

Absolute bioavailability of conventional (immediate-release) tablets is 5–50%.

Bioavailability of 325-mg extended-release capsules (given twice daily) similar to 150-mg conventional (immediate-release) tablets (given 3 times daily).

Food

Food does not appear to affect bioavailability of conventional (immediate-release) tablets or extended-release capsules during multiple-dose administration.

Special Populations

In patients with marked hepatic impairment, bioavailability of conventional (immediate-release) tablets is about 60–70%.

Distribution

Extent

Rapidly distributed into lung, liver, and heart tissue.

Propafenone crosses the placenta and is distributed into milk.

Plasma or Serum Protein Binding

81–97% (mainly α1 acid glycoprotein).

Special Populations

In patients with severe hepatic dysfunction, approximately 88% of propafenone is bound to plasma proteins.

Elimination

Metabolism

Extensively metabolized by first-pass metabolism (hydroxylation) in the liver, via CYP2D6 to an active metabolite (5-hydroxypropafenone [5-OHP]) and dealkylation via CYP1A2 and CYP3A4 to another active metabolite (N-depropylpropafenone [NDPP]).

Elimination Route

Eliminated principally in feces via biliary excretion as metabolites and in urine or feces as unchanged drug (<1%).

Half-life

Immediate-release tablets: Averages 1–3 hours (range: 2–10 hours).

Special Populations

In patients with poor metabolizer phenotypes (approximately 5–10% of Caucasians), propafenone is metabolized principally via CYP3A4 and CYP1A2; CYP2D6 is subject to genetic polymorphism.

Extensive metabolizers convert propafenone rapidly into 5-OHP and NDPP, while poor metabolizers convert it slowly to NDPP and 5-OHP usually not detectable.

Poor metabolizers have increased plasma propafenone concentrations relative to individuals with the extensive-metabolizer phenotype and are more likely to experience β-blocking and adverse effects of the drug.

In poor metabolizers, plasma elimination half-life and steady-state half-life average about 8-13 (range: 10–32 hours) and 17 hours, respectively; decreased clearance of the drug observed.

In patients with moderate to severe hepatic impairment, half-life is about 9 hours.

Stability

Storage

Oral

Conventional (immediate-release) Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15-30°C).

Extended-release Capsules

Tight containers at 25°C (may be exposed to 15-30°C).

Actions

  • Membrane-stabilizing antiarrhythmic agent; exhibits local anesthetic effects.

  • Combines with fast sodium channels within the myocardium and inhibits rapid sodium influx, which decreases the maximal rate of depolarization of phase 0 of the action potential.

  • Combines with fast sodium channels in both their active and inactive state and inhibits recovery after repolarization in a time- and voltage-dependent manner, which is associated with subsequent dissociation of the drug from the sodium channels.

  • Exhibits electrophysiologic effects characteristic of class Ic antiarrhythmic agents, which slowly attach to and dissociate from transmembrane sodium channels.

  • Produces dose-related decrease in intracardiac conduction within the His-Purkinje system, AV node, and intraventricular pathways.

  • Produces dose-related increases in PR, QRS, AH, and HV intervals; at higher workload and heart rates, dose-related increases in QT interval occur.

  • Increases effective refractory period (ERP) during ventricular pacing.

  • Exhibits a dose-dependent negative inotropic effect.

  • Exhibits β-adrenergic blocking activity.

Advice to Patients

  • Importance of taking propafenone in a consistent manner relative to food.

  • Importance of not ingesting grapefruit juice concomitantly with propafenone.

  • If a dose of extended-release capsules is missed, only administer the next scheduled dose; do not double next dose.

  • Advise patients who self-administer conventional (immediate-release) tablets for conversion of paroxysmal atrial fibrillation to remain in a supine or sitting position until resolution of palpitations or for a period of ≥4 hours following the dose. Importance of informing clinician if palpitations do not resolve within 6–8 hours, if new symptoms (e.g., dyspnea, presyncope, syncope) occur, or a marked increase in heart rate develops.

  • Advise patients to promptly report fever, sore throat, chills, or any other manifestation of infection.

  • Importance of immediately informing clinician if excessive or prolonged diarrhea, sweating, vomiting, loss of appetite or thirst occurs.

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Propafenone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

225 mg

RythmolSR

Reliant

325 mg

RythmolSR

Reliant

425 mg

RythmolSR

Reliant

Tablets, film-coated

150 mg*

Propafenone Hydrochloride Tablets

Rythmol (scored)

Reliant

225 mg*

Propafenone Hydrochloride Tablets

Rythmol (scored)

Reliant

300 mg*

Propafenone Hydrochloride Tablets

Rythmol (scored)

Reliant

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 14, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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