Rythmol

Generic Name: Propafenone Hydrochloride
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

Introduction

Local anesthetic-type class IC antiarrhythmic agent.^{3 10 38 134 289 310}

Uses for Rythmol

Paroxysmal Atrial Fibrillation/Flutter and Paroxysmal 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 syndrome, WPW syndrome]) and symptomatic, disabling paroxysmal atrial fibrillation/flutter (PAF) in patients without structural heart disease.^{1 3 67 68 90 91 92 93 94 99 101 102 105 107 108 109 110 132 133 173 187 206 211}

Comparably effective to quinidine, disopyramide, flecainide, procainamide, sotalol in preventing recurrences of PAF and maintaining sinus rhythm following successful cardioversion of atrial fibrillation.^{3 68 89 129 133 183 200 201 202 204 205}

Used (as extended-release capsules) to prolong the time to recurrence of symptomatic PAF in patients without structural heart disease.²⁸⁹

Safety and efficacy of extended-release capsules not established in patients with exclusively PSVT or atrial flutter.²⁸⁹

Safety and efficacy not established in patients with chronic atrial fibrillation.^{1 289} Generally, do not use to control ventricular rate in patients with atrial fibrillation, but conventional (immediate-release) tablets may be useful in controlling ventricular response rate in patients with stable but rapid atrial fibrillation/flutter and ventricular preexcitation via an accessory pathway (e.g., WPW syndrome).^{269 272 288}

Treatment of PSVT (using IV† propafenone [IV dosage form not commercially available in the US]) in patients with preserved ventricular function refractory to vagal maneuvers, IV adenosine (the drug of choice), AV nodal blocking agents (e.g., calcium-channel blocking agents), and electrical cardioversion therapy or in whom such therapy is not feasible or desirable.²⁸⁸

Conversion of Atrial Fibrillation to Normal Sinus Rhythm

Used (as conventional [immediate-release] tablets and IV†) in the conversion of recent-onset (≤48 hours duration)³¹⁰ atrial fibrillation (e.g., after open-heart surgery) to normal sinus rhythm†; some consider propafenone first-line therapy.^{15 68 88 89 90 101 103 104 109 110 111 195 196 197 198 199 207 208 211 272}

Self-administration for Conversion of PAF

Used for out-of-hospital self-administration (“pill-in-the-pocket” approach) as a single oral loading dose† (conventional (immediate-release) tablets) to terminate recent-onset PAF†; may result in reduced hospitalizations and emergency room visits of patients with mild or no heart disease.^{158 160 211 272 290 294 309}

Ventricular Arrhythmias

As conventional (immediate-release) tablets, suppresses and prevents recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained VT, VF).^{1 3} (See Mortality under Cautions.)

Rythmol Dosage and Administration

General

• 
  

  Individualize dosage according to individual requirements, response, tolerance, general condition, and cardiovascular status.^{1 2 3 9 15 28 47 68}

  
  


• 
  

  Initiate therapy (conventional [immediate-release] tablets) for life-threatening ventricular arrhythmias in a hospital.^{1 273}

  
  


• 
  

  Clinical and ECG evaluation (e.g., Holter monitoring) is recommended during propafenone therapy.^{1 3 289}

  
  

Administration

Administer orally.

Has been administered IV†.^{3 17 31 76 88 89 90 95 96 97 98 100 102 104 106 110 119 122 133 183}

Oral Administration

Administer conventional (immediate-release) tablets in a consistent manner relative to food intake.^{6 9 128 256 272 273}

Administer conventional (immediate-release) tablets in 3 equally divided doses daily at 8-hour intervals.¹

Administer extended-release capsules in equally divided doses every 12 hours without regard to meals.²⁸⁹

Swallow extended-release capsules whole; do not crush.²⁸⁹

Avoid grapefruit juice.^{272 273} (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.^{1 2 3 9 15 28 47 68 289}

Consider dosage reduction in patients who develop excessive prolongation of the PR interval, excessive QRS widening, or second- or third-degree AV block.^{1 2 3 15 90}

Usually do not use oral loading doses (conventional [immediate-release] tablets) since acute toxicity may occur.^{3 6 272 273} 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.^{68 89 90 101 109 160 195 196 208 272}

Pediatric Patients

Supraventricular Arrhythmias

Oral (conventional [immediate-release] tablets)

Maximum daily dosage 600 mg/m².²⁷²

Adults

Paroxysmal Atrial Fibrillation/Flutter and Paroxysmal Supraventricular Tachyarrhythmias

Oral (conventional [immediate-release] tablets)

Initially, 150 mg every 8 hours.^{1 2 68}

Increase dosage after 3–4 days to 225 mg 3 times daily (every 8 hours) if necessary.^{1 68 90}

If desired therapeutic response is not attained after an additional 3–4 days, increase dosage to 300 mg 3 times daily (every 8 hours).^{1 68 90}

Oral (extended-release capsules)

Initially, 225 mg every 12 hours.²⁸⁹

Increase dosage after ≥5 days to 325 mg every 12 hours if necessary.²⁸⁹

If desired therapeutic response is not attained after an additional 5 days, increase dosage to 425 mg every 12 hours.²⁸⁹

If a dose is missed, only administer the next scheduled dose; do not double next dose.²⁸⁹

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).^{289 308}

Conversion of Atrial Fibrillation to Normal Sinus Rhythm†

Oral (conventional [immediate-release] tablets)

150–600 mg, as a single dose.^{158 211}

IV†

2 mg/kg (over 10 minutes) as a single dose.^{158 211}

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.^{290 309}

Adults weighing < 70 kg: May use a single oral loading dose of 450 mg 5 minutes after noting the onset of palpitations.^{290 309}

Do not take more than a single oral dose during a 24-hour period.²⁹⁰

Ventricular Arrhythmias

Oral (conventional [immediate-release] tablets)

Initially, 150 mg every 8 hours.^{1 2 68}

Increase dosage after 3–4 days to 225 mg 3 times daily if necessary.^{1 68 90}

If desired therapeutic response is not attained after an additional 3–4 days, increase dosage to 300 mg 3 times daily.^{1 68 90}

Prescribing Limits

Pediatric Patients

Supraventricular Arrhythmias

Oral (conventional [immediate-release] tablets)

Maximum daily dosage is 600 mg/m².²⁷²

Adults

Supraventricular Arrhythmias

Oral (conventional [immediate-release] tablets)

Maximum daily dosage is 900 mg.^{1 9 90 272 273}

Life-threatening Ventricular Arrhythmias

Oral (conventional [immediate-release] tablets)

Maximum daily dosage is 900 mg.^{1 9 90 272 273}

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.^{1 115 193}

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.^{1 3}

Cautions for Rythmol

Contraindications

• 
  

  Patients with uncontrolled CHF (conventional [immediate-release] tablets),¹ CHF (extended-release capsules).²⁸⁹

  
  


• 
  

  Cardiogenic shock.^{1 3 289}

  
  


• 
  

  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.^{1 3 6 234 289}

  
  


• 
  

  Bradycardia.^{1 3 289}

  
  


• 
  

  Severe hypotension.^{1 3 289}

  
  


• 
  

  Bronchospastic disorders.^{1 289}

  
  


• 
  

  Marked electrolyte imbalance.^{1 3 289}

  
  


• 
  

  Known hypersensitivity to propafenone.^{1 289}

  
  

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.^{1 116 117 149 155 234 235 289} The applicability of these results to other populations (e.g., those without recent MI) or to other antiarrhythmic drugs is uncertain.^{1 6 48 62 118 168 234 235}

Limit use of propafenone or other class I agents in patients with ventricular arrhythmias to those with life-threatening arrhythmias;^{1 116 117} use in patients with less severe ventricular arrhythmias, even when symptomatic, is not recommended.¹

Arrhythmogenic and Cardiac Conduction Effects

Potential for new and/or more severe arrhythmias,^{1 2 3 4 6 9 15 16 17 18 47 58 67 68 75 113 116 168 230 232 233 234 235} especially in those with CHF (NYHA class III or IV]) or myocardial ischemia.²⁸⁹

Risk of clinically important conduction disturbances;^{1 6 75 136 151 310} degree of lengthening of PR and QRS intervals may increase progressively with increasing dosage and plasma propafenone concentrations.^{1 2 47 233 289 1 2 6 9 47 68 168 233 289}

Reduce dosage or discontinue the drug if 2nd- or 3rd-degree AV block occurs.¹ (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.^{1 2 168}

Monitor patients with permanent artificial pacemakers and, if necessary, reprogram pacemakers.^{1 2 3 225 229 289}

Cardiovascular Effects

Potential for new or worsened CHF, particularly in patients with preexisting heart failure or ejection fraction <30%.^{1 2 3 4 9 13 17 47 68 75 117 289}

Use with caution (conventional [immediate-release] tablets) in patients with a history of CHF or myocardial dysfunction.^{1 117 168 235 236}

Discontinue therapy if CHF worsens (unless caused by the cardiac arrhythmia); fully compensate CHF before therapy is reinitiated.¹

Hematologic Effects

Possible reversible granulocytopenia^{3 47} and agranulocytosis.^{1 47}

Carefully evaluate patients in whom unexplained fever and/or decreased WBC counts occur (especially during the initial 3 months of therapy).^{1 289} WBC counts generally return to normal within 2 weeks following discontinuance.^{1 289}

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).^{1 3 15 40 67 68 173 215 289} (See Contraindications under Cautions.)

General Precautions

Hepatic Impairment

Extensively metabolized in liver; use with caution in those with hepatic impairment.^{1 3 8 11 15 33 68 178 289}

Renal Impairment

Several metabolites excreted by kidneys; use with caution in those with renal impairment.^{1 13 289}

Antinuclear Antibodies.

Possible positive antinuclear antibody (ANA) titers.^{1 289}

Monitor carefully patients who develop an abnormal ANA test following initiation of therapy; consider discontinuation of therapy if titers remain elevated or increase further.^{1 289}

Impaired Spermatogenesis

Transient, reversible decreases (within normal range) in sperm count may occur.^{1 289}

Myasthenia Gravis

Possible exacerbation of myasthenia gravis.^{1 52 289} Avoid use in patients with this condition.³

Specific Populations

Pregnancy

Category C.^{1 289}

Lactation

Distributed into milk.^{3 289} Caution if used in nursing women.²⁸⁹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 273 289}

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.^{3 68 146 212 213 214 216 217 218 220 272} However, adenosine is the drug of choice for treatment of supraventricular tachycardia in children.^{288 310}

Geriatric Use

Conventional (immediate-release) tablets: Insufficient experience to determine whether geriatric patients ≥65 years of age respond differently than younger adults.¹ 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.¹

Extended-release capsules: No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.²⁸⁹

Hepatic Impairment

Extensively metabolized in liver; use with caution.^{1 3 8 11 15 33 68 178 289} Careful monitoring for excessive pharmacological effects recommended.¹ Reduce dosage.^{1 3 8 11 15 33 68 178 289} (See Special Populations under Dosage and Administration.)

Renal Impairment

Use with caution.¹ Careful monitoring for excessive pharmacological effects recommended.¹

Common Adverse Effects

Conventional (immediate-release) tablets: Unusual taste, nausea and/or vomiting, dizziness, constipation, headache, fatigue, blurred vision, and weakness.¹ First-degree AV block and intraventricular conduction delay in patients with ventricular arrhythmia.¹

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.²⁸⁹

Interactions for Rythmol

Metabolized by CYP2D6 and to a lesser extent by CYP1A2, CYP3A4.^{1 131 190 285 286 289}

Inhibits CYP2D6.^{1 289}

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.^{1 131 190 285 286 289} Monitor patients.¹

Drugs Metabolized by p-Glycoprotein Transporter

Effect of propafenone on the p-glycoprotein transport system not evaluated.^{1 289}

Drugs Affecting QT Interval

Do not use with drugs that prolong the QT interval.²⁸⁹

Antiarrhythmic Agents

Use extreme caution when propafenone is administered with 1 or more antiarrhythmic agents.^{3 68 288}

Reserve concomitant use for management of life-threatening arrhythmias unresponsive to monotherapy with propafenone (immediate-release tablets) or another antiarrhythmic agent.^{3 68 288}

Do not use propafenone (extended-release capsules) with class Ia or III antiarrhythmic agents.²⁸⁹

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Amiodarone	Possible increased incidence of cardiovascular effects1 13 287 288 289 Increased propafenone concentrations1 289	Concomitant use not recommended 1 289
β-adrenergic blocking agents (e.g., metoprolol, propranolol)	Increased β-adrenergic blocking agent concentrations and terminal elimination half-life1 246 247 289	Use concomitantly with caution; consider β-adrenergic blocking agent dosage reduction1 6 9 13 247 289
Calcium channel-blocking agents	No evidence of clinically important adverse interactions1 289
Cimetidine	Increased propafenone steady-state plasma concentrations1 289
Cyclosporine	Increased cyclosporine concentrations1 250 289
Desipramine	Increased propafenone concentrations1 289 Increased desipramine serum concentrations1	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289 Consider desipramine dosage reduction1
Digoxin	Increased serum or plasma digoxin concentrations1 3 9 85 124 125 245 279 280 281 282 283 289	Carefully monitor serum digoxin concentrations and adjust digoxin dosage 1 3 9 85 124 125 245 283 289
Diuretics	No evidence of clinically important adverse interactions1 289
Erythromycin	Increased propafenone concentrations1 289 1 131 190 285 286 289	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289
Fluoxetine	In extensive-metabolizer phenotypes, increased peak plasma concentrations and AUC of propafenone1 289
Grapefruit juice	Possible increased plasma concentrations of unchanged propafenone and potential adverse effects1 257 258 259 260 261 262 289	Avoid concomitant use272 273
Haloperidol	Increased haloperidol concentrations1 289	Use concomitantly with caution; consider haloperidol dosage reduction1 289
Imipramine	Increased imipramine concentrations1 289	Use concomitantly with caution; consider imipramine dosage reduction1 289
Ketoconazole	Increased propafenone concentrations1 131 190 285 286 289	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289
Lidocaine	Possible pharmacologic interaction (additive or antagonistic cardiac effects and additive toxicity) 1 2 9 13 122 289
Orlistat	Possible limited absorption of propafenone1 289 Possibility of severe adverse effects with abrupt discontinuance of orlistat1 289
Paroxetine	Increased propafenone concentrations1 131 190 285 286 289	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289
Phenobarbital	Decreased plasma propafenone concentrations3
Quinidine	Increased plasma propafenone concentrations1 3 123 289 Possible increased incidence of cardiovascular effects288	Concomitant use not recommended 1 289
Rifampin	Increased metabolism of propafenone resulting in decreased plasma propafenone concentrations and antiarrhythmic activity1
Ritonavir	Increased propafenone concentrations1 131 190 285 286 289	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289
Saquinavir	Increased propafenone concentrations1 131 190 285 286 289	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289
Sertraline	Increased propafenone concentrations1 131 190 285 286 289	Use concomitantly with caution; reduce propafenone hydrochloride dosage1 131 190 285 286 289
Theophylline	Increased serum theophylline concentrations and toxicity1 289
Venlafaxine	Increased venlafaxine concentrations1 289	Use concomitantly with caution; consider venlafaxine dosage reduction1 289
Warfarin	Increased plasma warfarin concentrations and corresponding PTs1 3 6 9 13 15 248 289	Monitor PTs or INRs;275 adjust warfarin dosage 1 3 9 13 248 289

Rythmol Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration of conventional (immediate-release) tablets.^{1 3 15 17 33 40 67 68 133 136}

Absolute bioavailability of conventional (immediate-release) tablets is 5–50%.^{33 174 180}

Bioavailability of 325-mg extended-release capsules (given twice daily) similar to 150-mg conventional (immediate-release) tablets (given 3 times daily).²⁸⁹

Food

Food does not appear to affect bioavailability of conventional (immediate-release) tablets or extended-release capsules during multiple-dose administration.^{2 289}

Special Populations

In patients with marked hepatic impairment, bioavailability of conventional (immediate-release) tablets is about 60–70%.^{1 2 178 289}

Distribution

Extent

Rapidly distributed into lung, liver, and heart tissue.^{3 4 15}

Propafenone crosses the placenta and is distributed into milk.^{3 64 72}

Plasma or Serum Protein Binding

81–97% (mainly α₁ acid glycoprotein).^{3 138 187 188 289}

Special Populations

In patients with severe hepatic dysfunction, approximately 88% of propafenone is bound to plasma proteins.²⁸⁹

Elimination

Metabolism

Extensively metabolized by first-pass metabolism (hydroxylation) in the liver,^{1 33 132 133 136} via CYP2D6 to an active metabolite (5-hydroxypropafenone [5-OHP])^{1 131 190 289} and dealkylation via CYP1A2 and CYP3A4 to another active metabolite (N-depropylpropafenone [NDPP]).^{1 131 289}

Elimination Route

Eliminated principally in feces via biliary excretion as metabolites and in urine or feces as unchanged drug (<1%).^{2 3 4 33 67 68 136}

Half-life

Immediate-release tablets: Averages 1–3 hours (range: 2–10 hours).^{1 2 4 6 7 10 11 12 14 15 16 28 33 37 39 67 68 71 129 133 138 181 187}

Special Populations

In patients with poor metabolizer phenotypes (approximately 5–10% of Caucasians), propafenone is metabolized principally via CYP3A4 and CYP1A2;^{1 131} CYP2D6 is subject to genetic polymorphism.^{1 131 190}

Extensive metabolizers convert propafenone rapidly into 5-OHPand NDPP,^{1 15}