Propafenone

C01B - Antiarrhythmics ATC C01BC03 Small molecule approved 1989 Oral Natural product Black-box warning

JFDA label: RYTMONORM 300MG TAB

⚠ Black-Box Warning

Mortality:

Mechanism of Action

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.

Indications

Approved

Extended release capsule

Off-label

Paroxysmal atrial fibrillation (pharmacological cardioversion)

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): MI within past 3 months Absolute
Brugada syndrome, sinus bradycardia Absolute
Hypersensitivity to propafenone or any component of the formulation Absolute
bronchospastic disorders or severe obstructive pulmonary disease Absolute
cardiogenic shock Absolute
concurrent use with ritonavir Absolute
marked hypotension Absolute
myasthenia gravis Absolute
severe hepatic impairment Absolute
sinoatrial, AV, and intraventricular disorders of impulse generation and/or conduction (except in patients with a functioning artificial pacemaker) Absolute
uncompensated cardiac failure Absolute
uncorrected electrolyte abnormalities Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (16)

Common angina pectoris · atrial fibrillation · bradycardia · bundle branch block · Cardiac arrhythmia · cardiac conduction delay · cardiac failure · chest pain · edema · first degree atrioventricular block · hypotension · palpitations · syncope · ventricular premature contractions · ventricular tachycardia · widened QRS complex on ECG

Nervous system disorders (8)

Very Common dizziness · Unusual taste

Common anxiety · ataxia · drowsiness · Fatigue · headache · insomnia

Gastrointestinal disorders (9)

Very Common Nausea · vomiting

Common abdominal pain · anorexia · Constipation · diarrhea · dyspepsia · flatulence · xerostomia

Skin and subcutaneous tissue disorders (2)

Common diaphoresis · Skin rash

Musculoskeletal and connective tissue disorders (3)

Common arthralgia · tremor · Weakness

Eye disorders (1)

Common Blurred vision

Respiratory, thoracic and mediastinal disorders (1)

Common Dyspnea

Dosing

Source: Lexicomp

Note: Patients who exhibit significant widening of QRS complex or second- or third-degree AV block may need dose reduction. Atrial fibrillation (to prevent recurrence): Oral: Extended release capsule: 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 Immediate release tablet: 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 Paroxysmal supraventricular tachycardia (to prevent recurrence), ventricular arrhythmias: Oral: Immediate release tablet: 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 Alternate recommendations: Supraventricular tachycardia: Oral: Immediate release: Initial: 150 mg every 8 hours; maximum maintenance dose: 300 mg every 8 hours (ACC/AHA/HRS [Page 2015]). Extended release: Initial: 225 mg every 12 hours; maximum maintenance dose: 425 mg every 12 hours (ACC/AHA/HRS [Page 2015]). Paroxysmal atrial fibrillation, pharmacologic cardioversion (off-label use): Oral: 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. Immediate release tablet: 450 mg (weight

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling; however, 50% of propafenone metabolites (some active) are excreted in the urine; some data suggest that no dosage adjustment is necessary (Burgess, 1989; Fromm, 1994); however, use with caution. Hemodialysis/CVVH: Minimally dialyzable (Burgess, 1989; Seto, 1999); supplemental dose not necessary

There are no dosage adjustment 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 (Rythmol Canadian product labeling 2016)

Warnings & Precautions

Source: Lexicomp

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).

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 (Lindenfeld, 2010).

Hepatic impairment

Use with caution in patients with hepatic impairment.

Lupus erythematosus

Positive 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.

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. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

CAST trial

In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but 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.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events were observed in some animal reproduction studies. Propafenone and its metabolite cross the placenta and can be detected in the newborn (Libardoni 1991). Guidelines are available for use during pregnancy (ESG [Regitz-Zagrosek 2011]). Propafenone may be used for the ongoing management of pregnant women with highly symptomatic SVT. The lowest effective dose is recommended; avoid use during the first trimester if possible (Page [ACC/AHA/HRS 2015]).Until more information is available, when treatment of AF or long term treatment of SVT is needed in pregnant women, propafenone is generally reserved for use when other agents are not effective (ESG [Regitz-Zagrosek 2011]).

Lactation

Propafenone is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	ECG, blood pressure, pulse (particularly at initiation of therapy)

Chemistry & Properties

Formula	C21H27NO3
Molecular weight	341.45 g/mol
IUPAC name	1-[2-[2-hydroxy-3-(propylamino)propoxy]phenyl]-3-phenylpropan-1-one
CAS	54063-53-5
PubChem CID	4932
InChIKey	`JWHAUXFOSRPERK-UHFFFAOYSA-N`
logP	3.24 (XLogP 3.3)
Polar surface area	58.56 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.49
Lipinski violations	0

SMILES

CCCNCC(O)COc1ccccc1C(=O)CCc1ccccc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	IC₅₀ 3.2920000000000007 µM
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	IC₅₀ 4.603399999999999 µM
CYP2D6	Substrate	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
β2-adrenoceptor (ADRB2)	Antagonist	pKi 7.4
β1-adrenoceptor (ADRB1)	Antagonist	pKi 6.7

Transporters

ASBT (Inhibitor)BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)NTCP (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCTN1 (Inhibitor)P-gp (Inhibitor)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Anagrelide	major
Arsenic trioxide	major
Betrixaban	major
Cabozantinib	major
Ceritinib	major
Chloroquine	major
Cisapride	major
Cobicistat	major
Crizotinib	major
Dolasetron	major
Eliglustat	major
Fingolimod	major
Halofantrine	major
Hydroxychloroquine	major
Ivosidenib	major
Lumefantrine	major
Macimorelin	major
Nilotinib	major
Osimertinib	major
Ozanimod	major
Panobinostat	major
Papaverine	major
Pasireotide	major
Pazopanib	major
Ribociclib	major
Siponimod	major
Tamoxifen	major
Toremifene	major
Vandetanib	major
Vemurafenib	major
Venetoclax	major
Abarelix	moderate
Abiraterone	moderate
Adalimumab	moderate
Alectinib	moderate
Alefacept	moderate
Alimemazine	moderate
Alosetron	moderate
Aminophylline	moderate
Anakinra	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
RYTMONORM	Tablet 150 mg	50 tab	Sukhtian Group	5.840
RYTMONORM	Tablet 300 mg	50 tab	Sukhtian Group	12.030