Propafenone
| Evidence Level: L3 | Predicted Indications: 8 |
Table of Contents
- Propafenone
- Propafenone: From Atrial Fibrillation and Ventricular Tachycardia to Catecholaminergic Polymorphic Ventricular Tachycardia
Propafenone: From Atrial Fibrillation and Ventricular Tachycardia to Catecholaminergic Polymorphic Ventricular Tachycardia
One-Sentence Summary
Propafenone is a class IC antiarrhythmic originally used to treat atrial fibrillation and ventricular tachycardia. The TxGNN model predicts it may be useful for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), the most credible of its eight predicted indications. Support is limited: 0 registered clinical trials and 10 publications (preclinical studies, cohorts and case reports, with no RCTs).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Atrial fibrillation; ventricular tachycardia |
| Predicted New Indication | Catecholaminergic polymorphic ventricular tachycardia |
| TxGNN Prediction Score | 99.79% |
| Evidence Level | L3 |
| US Market Status | Cancelled only (no currently valid licenses) |
| Number of NDAs | 9 (all cancelled) |
| Recommended Decision | Hold (research question; see Conclusion) |
The original indications come from the TxGNN knowledge graph, not from label text. Every US license record in the data compiled for this report lacks approved-indication text.
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for propafenone is not available in the data compiled for this report. Based on known information, propafenone is a class IC antiarrhythmic (sodium-channel blocker) whose efficacy in ventricular and atrial arrhythmias is established.
CPVT is an inherited arrhythmia caused mainly by ryanodine receptor 2 (RyR2) mutations, which produce spontaneous Ca²⁺ release. Preclinical studies show that propafenone, and its R-enantiomer in particular, blocks RyR2 Ca²⁺ release channels and suppresses arrhythmogenic Ca²⁺ waves, much as flecainide does. Flecainide is the established add-on therapy for CPVT, so propafenone is a mechanistically plausible alternative. A case report describes 35 years of effective treatment with propafenone.
The other seven predictions are much weaker. For manic bipolar disorder, the literature points to propafenone possibly causing mania or psychosis, so the high score is probably a graph artifact. For arrhythmogenic right ventricular cardiomyopathy, case reports show harm (QRS widening, incessant VT). Four predictions (periodic paralysis with transient compartment-like syndrome, Prinzmetal angina, nephrogenic syndrome of inappropriate antidiuresis, trichotillomania) have no literature or trials and no clear mechanistic link. Incessant infant ventricular tachycardia has small, old observational support only.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 30820400 | 2019 | Case report | HeartRhythm Case Rep | 35-year effective treatment of CPVT with propafenone |
| 21270101 | 2011 | Preclinical (mechanistic) | Circ Arrhythm Electrophysiol | RyR2 channel inhibition determines the efficacy of class I antiarrhythmics in CPVT |
| 26121139 | 2015 | Preclinical (mechanistic) | PLoS One | RyR2 channel activity determines the potency of flecainide and R-propafenone against Ca²⁺ waves |
| 21798265 | 2011 | Preclinical (mechanistic) | J Mol Cell Cardiol | Class I antiarrhythmics screened for suppression of Ca²⁺ waves in myocytes lacking calsequestrin |
| 35892906 | 2022 | Systematic review | Life (Basel) | Clinical, genetic and arrhythmic outcomes of CPVT patients from China (background, not propafenone-specific) |
| 39564160 | 2024 | Cohort | Ann Pediatr Cardiol | Long-term (>10 years) clinical course of CPVT patients (background) |
| 23965883 | 2013 | Cohort | Zhongguo Dang Dai Er Ke Za Zhi | Long-term outcomes and predictors of ventricular arrhythmia in pediatric CPVT, including drug effects |
| 36082968 | 2023 | Preclinical/Case study | Clin Exp Pharmacol Physiol | Gain-of-function RyR2 mutation (R1760W) in CPVT |
| 29668588 | 2018 | Case report | Medicine | Delayed diagnosis of CPVT with an RYR2 mutation in a child |
| 42558477 | 2026 | Case report | Front Pediatr | Overlap of long QT syndrome and CPVT in two children with CALM2-related calmodulinopathy |
US Market Information
All nine US licenses are cancelled. None has valid single-ingredient or combination status, and no approved-indication text is recorded.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ANDA202445 | Propafenone Hydrochloride (Aurobindo) | Tablet, film coated | Not recorded |
| ANDA214184 | Propafenone Hydrochloride (Zydus) | Capsule, extended release | Not recorded |
| ANDA213096 | Propafenone Hydrochloride (Aurobindo) | Capsule, extended release | Not recorded |
| ANDA075938 | Propafenone Hydrochloride (Strides) | Tablet, film coated | Not recorded |
| ANDA210339 | Propafenone Hydrochloride (Vitruvias) | Capsule, extended release | Not recorded |
Four further cancelled ANDAs (Northstar, Strides, Rising, Bryant Ranch Prepack) are not listed.
Safety Considerations
- Contraindications and risk conditions (knowledge-graph data, not label text):
- Cardiac: long QT syndrome (including familial), torsades de pointes, myocardial infarction, coronary artery disease and atherosclerosis, hypotensive disorders.
- Hematologic: neutropenia and agranulocytosis (including congenital forms), hemoglobinopathy.
- Organ and other: kidney disease, liver disease, gallbladder disease, potassium deficiency, myasthenia gravis.
- Drug interactions: 100 interactions were found. The sample reviewed included two Major ones, with dolasetron and eliglustat. Many Moderate ones were also listed, including cimetidine, clarithromycin, bupropion, levofloxacin, ondansetron, palonosetron, famotidine, aprepitant, loperamide and alosetron. One Minor interaction was listed, with metronidazole.
- Indication-specific concerns: Structural heart disease and proarrhythmia risk, especially in children, call for specialist oversight. In ARVC, reports of QRS widening and incessant VT argue against use.
Please refer to the package insert for full warnings and contraindications.
Conclusion and Next Steps
Decision: Hold (advance only as a research question for CPVT)
Rationale:
- CPVT has a plausible RyR2-based mechanism and a long-term case report, but no registered trials, no RCTs, and flecainide is already the established option.
- All US licenses are cancelled, and label-based safety data are missing. The other seven predicted indications have no supporting evidence or point to harm.
To proceed, the following is needed:
- FDA package insert warnings and contraindications (a blocking gap for safety screening)
- Mechanism-of-action data from DrugBank
- Comparative or prospective clinical data against flecainide in CPVT
- A safety plan for structural heart disease, pediatric use and QT-prolonging or CYP-interacting drugs
- A route and formulation check, including current US availability
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.