Version May 2024
In the National Heart, Lung, and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non–life-threatening ventricular arrhythmias who had a myocardial infarction (MI) more than 6 days but less than 2 years previously, an increased rate of death or reversed cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide (class IC antiarrhythmics) compared with that seen in patients assigned to placebo (3%). The average duration of treatment with encainide or flecainide in this study was 10 months.
The applicability of the CAST results to other populations (eg, those without recent MI) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any IC antiarrhythmic to have a significant risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, generally avoid antiarrhythmic agents in patients with non–life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.
Note: Consider for use only in patients without structural or ischemic heart disease. Patients who exhibit significant widening of QRS complex or second- or third-degree AV block may need dose reduction.
Atrial fibrillation, prevention of recurrence:
IR tablet: Oral: Initial: 150 mg every 8 hours; dosage increase may be made at minimum of 3- to 4-day intervals; may increase to 225 mg every 8 hours; if further increase is necessary, may increase to 300 mg every 8 hours.
ER capsule: Oral: Initial: 225 mg every 12 hours; dosage increase may be made at a minimum of 5-day intervals; may increase to 325 mg every 12 hours; if further increase is necessary, may increase to 425 mg every 12 hours.
Paroxysmal atrial fibrillation, pharmacologic cardioversion (off-label use):
Note: May be used on an outpatient basis (“Pill-in-the-pocket”). An initial inpatient cardioversion trial should have been successful before sending patient home on this approach. Patient must be taking an AV nodal-blocking agent (eg, beta-blocker, nondihydropyridine calcium channel blocker) prior to initiation of antiarrhythmic.
IR tablet: Oral: 450 mg (weight <70 kg) or 600 mg (weight ≥70 kg). May not repeat in ≤24 hours (Ref).
Paroxysmal supraventricular tachycardia (to prevent recurrence):
IR tablet: Oral: Initial: 150 mg every 8 hours; dosage increase may be made at minimum of 3- to 4-day intervals; may increase to 225 mg every 8 hours; if further increase is necessary, may increase to 300 mg every 8 hours (Ref).
ER capsule: Oral: Initial: 225 mg every 12 hours; maximum maintenance dose: 425 mg every 12 hours (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (Ref): No dosage adjustment necessary (Ref).
Peritoneal dialysis: Not significantly dialyzable (Ref): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; however, dosage reduction should be considered as drug undergoes hepatic metabolism. Alternatively, in patients with mild to moderate impairment, the following dosing recommendations have been made: Initial: 150 mg once daily; if necessary, may increase dosage by 150 mg/day in divided doses (eg, twice daily, three times daily) at a minimum of 4-day intervals up to maximum of 300 mg every 12 hours (Ref).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Gastrointestinal: Nausea (≤11%), vomiting (≤11%)
Nervous system: Unusual taste (14%; dysgeusia: ≥2%)
1% to 10%:
Cardiovascular: Angina pectoris (≥2%), bradycardia (2%), bundle branch block (1%; including right bundle branch block and left bundle branch block), cardiac conduction disorder (≥2%; including atrioventricular conduction disturbance [slow]; cardiac conduction delay [1%]), chest pain (≥1%), edema (≥2%), heart block (including complete atrioventricular block [<1%]), first-degree atrioventricular block [3%], second-degree atrioventricular block [<1%]), heart failure (≤2%; including worsening of heart failure), heart murmur (≥2%), hypotension (≥2%), palpitations (2%), sinus bradycardia (≥2%), ventricular arrhythmia (new or worsened: ≤5%; including ventricular fibrillation, ventricular premature contractions, ventricular tachycardia)
Dermatologic: Ecchymosis (≥2%)
Gastrointestinal: Anorexia (2%), constipation (8%), diarrhea (2%), flatulence (≥2%), xerostomia (≥2%)
Genitourinary: Hematuria (≥2%)
Hepatic: Increased serum alkaline phosphatase (>1%)
Nervous system: Anxiety (≥2%), asthenia (3%), ataxia (2%), depression, dizziness (9%), drowsiness (≥2%), fatigue (6%), headache (6%), myasthenia (including exacerbation of myasthenia gravis), tremor (2%)
Ophthalmic: Blurred vision (3%)
Respiratory: Dyspnea (2%), rales (≥2%), upper respiratory tract infection (≥2%), wheezing (≥2%)
<1%:
Cardiovascular: Atrioventricular dissociation, flushing, sick sinus syndrome, sinoatrial arrest, sinus pause, supraventricular tachycardia
Dermatologic: Alopecia, pruritus
Endocrine & metabolic: Hot flash
Gastrointestinal: Cholestasis, gastroenteritis
Genitourinary: Impotence
Hematologic & oncologic: Agranulocytosis, anemia, bruise, granulocytopenia, leukopenia, positive ANA titer, purpuric disease, thrombocytopenia
Hepatic: Hepatitis
Nervous system: Abnormal dreams (including nightmares), altered sense of smell, amnesia, confusion, loss of balance, mania, numbness, pain, paresthesia, psychosis, seizure, speech disturbance, vertigo
Neuromuscular & skeletal: Muscle cramps
Ophthalmic: Eye irritation, visual disturbance
Otic: Tinnitus
Renal: Nephrotic syndrome
Frequency not defined:
Cardiovascular: Acute myocardial infarction, atrioventricular nodal arrhythmia, cold extremity, coronary artery disease (including carotid bruit), deep vein thrombosis, embolism of systemic artery, extrasystoles, hypertension, hypertensive crisis, pericarditis, peripheral vascular disease, prolongation P-R interval on ECG, sinoatrial block (including atrial hypertrophy), sinoatrial nodal rhythm disorder, supraventricular extrasystole, syncope, thrombosis, unstable angina pectoris, ventricular hypertrophy, widened QRS complex on ECG
Dermatologic: Dermatitis, diaphoresis, erythema of skin, pallor, skin rash, xeroderma
Endocrine & metabolic: Decreased libido, dehydration, diabetes mellitus, hyperglycemia, hypokalemia, increased lactate dehydrogenase, increased uric acid, ketonuria, weight gain, weight loss
Gastrointestinal: Abdominal distension, abdominal pain, duodenitis, dyspepsia, dysphagia, eructation, gastritis, gastroesophageal reflux disease, gingival hemorrhage, glossalgia, halitosis, intestinal obstruction, melena, oral mucosal ulcer, pancreatitis, peptic ulcer, rectal hemorrhage
Genitourinary: Dysuria, glycosuria, nocturia, oliguria, prostatism, proteinuria, pyuria, urinary frequency, urinary incontinence, urinary retention
Hematologic & oncologic: Decreased neutrophils, eosinophilia, hematoma, hemorrhage, hyperprothrombinemia, hypoprothrombinemia, leukocytosis, lymphadenopathy, monocytosis, petechia, spleen disease
Nervous system: Abnormal gait, cerebrovascular accident, emotional disturbance, hypertonia, hypoesthesia, insomnia, malaise, neurosis, numbness of tongue, sleep disorder
Neuromuscular & skeletal: Arthropathy, costochondritis, muscle spasm, myalgia, tendinopathy
Ophthalmic: Blepharoptosis, decreased visual acuity, miosis, ophthalmic inflammation, retinopathy, retrobulbar hemorrhage
Otic: Auditory impairment
Renal: Casts in urine, increased blood urea nitrogen, increased serum creatinine, renal failure syndrome
Respiratory: Abnormal breath sounds (decreased), atelectasis, cough, epistaxis, hemoptysis, pharyngeal edema, pleural effusion, pulmonary congestion, respiratory failure
Postmarketing:
Cardiovascular: Asystole, torsades de pointes
Dermatologic: Acute generalized exanthematous pustulosis (Huang 2005), psoriasis (Palleschi 2008), urticaria (Incorvaia 2006)
Endocrine & metabolic: Hyponatremia, SIADH
Hematologic & oncologic: Prolonged bleeding time
Hepatic: Hepatomegaly (Younan 2013), hepatotoxicity (Younan 2013), increased gamma-glutamyl transferase (Younan 2013), increased serum alanine aminotransferase (Younan 2013), increased serum aspartate aminotransferase (Younan 2013), increased serum bilirubin (Younan 2013), jaundice (Younan 2013)
Hypersensitivity: Angioedema (Incorvaia 2006)
Nervous system: Coma, myoclonus (Chua 1994), peripheral neuropathy (Galasso 1995)
Neuromuscular & skeletal: Lupus erythematosus
Respiratory: Apnea
Miscellaneous: Fever (O’Rourke 1997)
Hypersensitivity to propafenone or any component of the formulation; sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (except in patients with a functioning artificial pacemaker); known Brugada syndrome; bradycardia; cardiogenic shock; heart failure; marked hypotension; bronchospastic disorders or severe obstructive pulmonary disease; marked electrolyte imbalance
Canadian labeling: Additional contraindications (not in US labeling): MI within past 3 months; severe hepatic impairment; myasthenia gravis; concurrent use with ritonavir.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Agranulocytosis: Agranulocytosis has been reported; generally occurring within the first 2 months of therapy. Upon therapy discontinuation, WBC usually normalized by 14 days.
• CNS effects: May cause dizziness, fatigue, blurred vision; caution patients about performing dangerous tasks (eg, driving, operating machinery).
• Conduction disturbances: Slows atrioventricular conduction, potentially leading to first degree AV block; degree of PR interval prolongation and increased QRS duration are dose and concentration related. Avoid in patients with conduction disturbances (unless functioning pacemaker present).
• Elevated antinuclear antibody titers: Positive antinuclear antibody (ANA) titers have been reported with use. Titers have decreased with and without therapy discontinuation. Positive titers have not usually been associated with clinical symptoms, although at least one case of drug-induced lupus erythematosus has been reported. Consider therapy discontinuation in symptomatic patients with positive ANA titers.
• Hepatotoxicity: Hepatic abnormalities (including fulminant hepatitis and fatalities) have been reported; toxicity appeared due to hepatocellular injury and/or cholestasis.
• Proarrhythmic effects: Can cause life-threatening drug-induced arrhythmias, including ventricular fibrillation, ventricular tachycardia, asystole, and torsade de pointes (Hii 1991). The manufacturer notes that propafenone may increase the QT interval; however, due to QRS prolongation, changes in the QT interval are difficult to interpret. In an evaluation of propafenone (450 mg/day) in healthy individuals compared to other selected antiarrhythmic agents, propafenone did not affect repolarization time (eg, QT, QTc, JT, JTc) only depolarization time (ie, QRS interval) (Sarubbi 1998). Monitor for proarrhythmic effects, and when necessary, adjust dose to prevent QTc prolongation.
Disease-related concerns:
• Brugada syndrome: Initiation of propafenone may unmask Brugada syndrome; obtain ECG after treatment initiation and discontinue if ECG indicative of Brugada syndrome.
• Electrolyte imbalance: Use is contraindicated in patients with uncorrected electrolyte abnormalities. Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.
• Heart failure (HF): Avoid use in patients with HF; similar agents have been shown to increase mortality in this population; may precipitate or exacerbate condition.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition.
• Pulmonary disease: Propafenone use may be considered in patients with obstructive lung disease who do not have bronchospasm (AHA/ACC/HRS [January 2014]). Use in patients with bronchospastic disease or severe obstructive lung disease is contraindicated.
• Renal impairment: Use with caution in patients with renal impairment.
Other warnings/precautions:
• CAST trial: [US Boxed Warning]: In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, non-life-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.
• Pacemakers: May alter pacing and sensing thresholds of artificial pacemakers.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Extended Release 12 Hour, Oral, as hydrochloride:
Rythmol SR: 225 mg [DSC], 325 mg [DSC], 425 mg [DSC] [contains soybean lecithin]
Generic: 225 mg, 325 mg, 425 mg
Tablet, Oral, as hydrochloride:
Generic: 150 mg, 225 mg, 300 mg
Yes
Capsule, 12-hour (Propafenone HCl ER Oral)
225 mg (per each): $0.98 - $10.00
325 mg (per each): $1.18 - $10.00
425 mg (per each): $1.18 - $10.00
Tablets (Propafenone HCl Oral)
150 mg (per each): $1.64
225 mg (per each): $2.33
300 mg (per each): $2.97
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Rythmol: 150 mg, 300 mg
Generic: 150 mg, 300 mg
Oral: Capsules should be swallowed whole; do not crush or chew; may be taken without regard to meals.
The Canadian labeling recommends the tablet be swallowed whole with liquid and to be administered with food.
Bariatric surgery: Capsule, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, selection of IR tablet should be strongly considered for propafenone after bariatric surgery.
Immediate release: Treatment of life-threatening ventricular arrhythmias; to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) or paroxysmal supraventricular tachycardia (PSVT) in patients with disabling symptoms without structural heart disease.
ER capsule: Prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart disease.
Paroxysmal atrial fibrillation (pharmacological cardioversion)
Substrate of CYP1A2 (minor), CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2D6 (weak), P-glycoprotein/ABCB1
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Adagrasib: May enhance the QTc-prolonging effect of Propafenone. Adagrasib may increase the serum concentration of Propafenone. Risk X: Avoid combination
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification
Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Amiodarone: May enhance the QTc-prolonging effect of Propafenone. Risk X: Avoid combination
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Asunaprevir: May increase the serum concentration of Propafenone. Risk X: Avoid combination
Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Risk X: Avoid combination
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Cardiac Glycosides: Propafenone may increase the serum concentration of Cardiac Glycosides. Management: Measure cardiac glycoside serum concentrations before initiating treatment with propafenone. Reduce cardiac glycoside concentrations by either reducing the dose by 30% to 50% or by modifying the dosing frequency. Risk D: Consider therapy modification
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: Monitor therapy
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of CYP3A4 inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: Consider therapy modification
CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Propafenone. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Propafenone. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Propafenone. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Propafenone. Risk C: Monitor therapy
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy
Dabrafenib: May enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Encorafenib: May enhance the QTc-prolonging effect of Propafenone. Encorafenib may decrease the serum concentration of Propafenone. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and reduced propafenone concentrations and efficacy when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Risk C: Monitor therapy
Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy
Etrasimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor therapy
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Fluorouracil Products: QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Fosamprenavir: May increase the serum concentration of Propafenone. Management: Concurrent use of ritonavir-boosted fosamprenavir with propafenone is contraindicated. The use of non-ritonavir-boosted fosamprenavir with propafenone is not specifically contraindicated but should only be undertaken with caution. Risk X: Avoid combination
Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy
Haloperidol: QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Lacosamide: QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy
Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Risk C: Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Methadone: Propafenone may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Mexiletine: Propafenone may increase the serum concentration of Mexiletine. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Risk C: Monitor therapy
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May increase the serum concentration of Propafenone. Risk X: Avoid combination
Ondansetron: QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Orlistat: May decrease the absorption of Propafenone. Risk C: Monitor therapy
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
PAZOPanib: Propafenone may enhance the QTc-prolonging effect of PAZOPanib. Propafenone may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Pentamidine (Systemic): QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
Propranolol: Propafenone may increase the serum concentration of Propranolol. Propranolol may increase the serum concentration of Propafenone. Risk C: Monitor therapy
QT-prolonging Antidepressants (Moderate Risk): QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IA Antiarrhythmics (Highest Risk): Propafenone may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Risk X: Avoid combination
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class III Antiarrhythmics (Highest Risk): Propafenone may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Highest Risk): Propafenone may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Highest Risk): Propafenone may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Class IC Antiarrhythmics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QuiNIDine: Propafenone may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Propafenone. Risk X: Avoid combination
Quinidine (Non-Therapeutic): May enhance the QTc-prolonging effect of QT-prolonging CYP2D6 Substrates. Quinidine (Non-Therapeutic) may increase the serum concentration of QT-prolonging CYP2D6 Substrates. Risk X: Avoid combination
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: Monitor therapy
Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification
Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification
Repotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Repotrectinib. Risk X: Avoid combination
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy
Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification
RisperiDONE: Propafenone may enhance the QTc-prolonging effect of RisperiDONE. Propafenone may increase the serum concentration of RisperiDONE. Management: Monitor for increased risperidone toxicities, including QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ritonavir: May increase the serum concentration of Propafenone. Risk X: Avoid combination
RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy
Saquinavir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy
Simeprevir: May increase the serum concentration of Propafenone. Risk C: Monitor therapy
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification
Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination
Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Tegaserod (Withdrawn from US Market): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod (Withdrawn from US Market). Risk C: Monitor therapy
Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Risk C: Monitor therapy
Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Tipranavir: May increase the serum concentration of Propafenone. Risk X: Avoid combination
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification
Venlafaxine: Propafenone may increase the serum concentration of Venlafaxine. Venlafaxine may increase the serum concentration of Propafenone. Risk C: Monitor therapy
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Propafenone may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Administration of food with single-dose propafenone increased propafenone serum concentrations and bioavailability; however, with multidose administration, propafenone bioavailability was not significantly different between fed and fasted states. Management: Administer without regard to meals.
Propafenone serum concentrations may be increased with concomitant use of grapefruit juice. Management: Monitor for increased effects/toxicity with concomitant use.
When used in males, reversible impairment of spermatogenesis may occur.
Propafenone and the 5-hydroxypropafenone metabolite cross the placenta and can be detected in the newborn (Libardoni 1991).
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of propafenone may be altered (Libardoni 1991).
Untreated maternal arrhythmias may cause adverse events in the mother and fetus; guidelines are available for the management of arrhythmias during pregnancy (ESC [Regitz-Zagrosek 2018]). Propafenone may be used for the ongoing management of pregnant women with highly symptomatic supraventricular tachycardia (SVT). The lowest effective dose is recommended; avoid use during the first trimester if possible (ACC/AHA/HRS [Page 2015]). Use is also recommended for the prevention of SVT in patients with Wolff-Parkinson-White (WPW) syndrome. Until more information is available, when prevention of SVT in patients without WPW syndrome, atrial tachycardia, or atrial fibrillation is needed in pregnant women, propafenone is generally reserved for use when other agents are not effective (ESC [Regitz-Zagrosek 2018]).
Propafenone and the 5-hydroxypropafenone metabolite are present in breast milk.
Based on information from two case reports, the relative infant dose (RID) of propafenone is <1% of the weight-adjusted maternal dose (Libardoni 1991; Wakaumi 2005).
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
The RID of propafenone was calculated by the authors of two case reports. In the first, propafenone was administered orally to the mother during the last trimester of pregnancy (300 mg three times daily) and postpartum; breast milk was sampled prior to the morning dose 3 days after delivery. Milk concentrations were 32 ng/mL (propafenone) and 47 ng/mL (5-hydroxypropafenone). Based on actual maternal weight, the RID was calculated to be ~0.03% (Libardoni 1991). The second case reports milk concentrations following a single dose of propafenone 150 mg orally. Milk was sampled at intervals between 1 and 12 hours after the dose (postpartum age not noted). The highest milk concentrations were observed at 2 hours (propafenone 37.4 ng/mL; 5-hydroxypropafenone 102 ng/mL), and concentrations were undetectable 12 hours after the maternal dose. Authors of this report calculated the RID to be 0.1% (Wakaumi 2005). Infants were not breastfed in either case.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
ECG, blood pressure, pulse (particularly at initiation of therapy)
Propafenone is a class 1c antiarrhythmic agent which possesses local anesthetic properties, blocks the fast inward sodium current, and slows the rate of increase of the action potential. Prolongs conduction and refractoriness in all areas of the myocardium, with a slightly more pronounced effect on intraventricular conduction; it prolongs effective refractory period, reduces spontaneous automaticity and exhibits some beta-blockade activity.
Absorption: Well absorbed
Distribution: Vd: Adults: 252 L
Protein binding: 95% to alpha1-acid glycoprotein
Metabolism: Hepatic via CYP2D6, CYP3A4 and CYP1A2 to two active metabolites (5-hydroxypropafenone and N-depropylpropafenone) then ultimately to glucuronide or sulfate conjugates. Two genetically determined metabolism groups exist (extensive and poor metabolizers); 10% of Caucasians are poor metabolizers. Exhibits nonlinear pharmacokinetics; when dose is increased from 300-900 mg/day, serum concentrations increase tenfold; this nonlinearity is thought to be due to saturable first-pass effect.
Bioavailability: Immediate release (IR): 150 mg: 3.4%; 300 mg: 10.6%; relative bioavailability of extended release (ER) capsule is less than IR tablet; the bioavailability of an ER capsule regimen of 325 mg twice-daily regimen approximates an IR tablet regimen of 150 mg 3 times/day.
Half-life elimination: Extensive metabolizers: 2-10 hours; Poor metabolizers: 10-32 hours
Time to peak, serum: IR: 3.5 hours; ER: 3-8 hours
Excretion: Urine (<1% unchanged; remainder as glucuronide or sulfate conjugates); feces
Hepatic function impairment: Cl is reduced and elimination half-life is increased.
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