Amiodarone
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Amiodarone
- Amiodarone: From Ventricular Fibrillation to Catecholaminergic Polymorphic Ventricular Tachycardia
Amiodarone: From Ventricular Fibrillation to Catecholaminergic Polymorphic Ventricular Tachycardia
One-Sentence Summary
Amiodarone is an antiarrhythmic drug, originally used to treat ventricular fibrillation. The TxGNN model's top-ranked prediction is catecholaminergic polymorphic ventricular tachycardia (CPVT), but only 9 publications (mostly case reports and cohort descriptions, none showing amiodarone efficacy) and no clinical trials support it. Among the other predictions, ventricular tachycardia is far better supported, with 18 clinical trials and 20 publications, although this is largely an established use rather than true repurposing.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ventricular fibrillation (the approved indication text is not recorded in the New Zealand licence data) |
| Predicted New Indication | Catecholaminergic polymorphic ventricular tachycardia (top-ranked); ventricular tachycardia and incessant infant ventricular tachycardia are the better-supported predictions |
| TxGNN Prediction Score | 99.78% (CPVT) |
| Evidence Level | L4 for CPVT (L1 for ventricular tachycardia; L2 for incessant infant ventricular tachycardia) |
| New Zealand Market Status | Cancelled only (no currently valid authorisation) |
| Number of Authorizations | 3 (all cancelled) |
| Recommended Decision | Hold for CPVT; Proceed with Guardrails for ventricular tachycardia and incessant infant ventricular tachycardia |
Why is This Prediction Reasonable?
Detailed mechanism of action data are not available for this report. Based on known pharmacology, amiodarone is a class III antiarrhythmic with multichannel effects (potassium, sodium and calcium channel block plus beta-adrenergic antagonism). It prolongs action potential duration and refractoriness. Pharmacology data compiled for this report also list interactions with Nav1.5, Kv1.7 and the M5 receptor.
CPVT (rank 1): CPVT is caused by RYR2 or CASQ2 dysfunction, which leaks calcium during diastole and triggers delayed afterdepolarisations. Amiodarone's calcium-channel and beta-blocking actions offer a plausible but weak link. Guideline-preferred therapy is beta-blockers, with flecainide as an add-on, and amiodarone is generally considered ineffective for CPVT. The retrieved literature contains no direct evidence of amiodarone efficacy in CPVT, so this prediction is best treated as a research question.
Ventricular tachycardia (rank 3): This is mechanistically adjacent to the original indication, since ventricular tachycardia can degenerate into ventricular fibrillation. Amiodarone directly suppresses re-entrant ventricular arrhythmias.
Incessant infant ventricular tachycardia (rank 2): Paediatric data support amiodarone in refractory incessant tachycardias, but most evidence comes from mixed tachyarrhythmia populations rather than ventricular tachycardia alone.
Lower-ranked predictions (ranks 4–10): Obsolete bundle branch block, rheumatoid arthritis, brachydactyly-syndactyly syndrome, heparin cofactor 2 deficiency, trichotillomania, colobomatous microphthalmia-rhizomelic dysplasia syndrome and gout have no plausible therapeutic link and appear to be knowledge-graph artefacts. For bundle branch block, amiodarone slows conduction and could worsen block. For rheumatoid arthritis, the retrieved literature describes amiodarone toxicity, not benefit. All are held at L5.
Clinical Trial Evidence
There are currently no clinical trials registered for CPVT. The table below lists the most relevant trials for the better-supported prediction, ventricular tachycardia.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01401647 | Phase 3 | Completed | 3024 | ALPS: amiodarone vs lidocaine vs placebo in out-of-hospital cardiac arrest from VF/pulseless VT |
| NCT00000531 | Phase 3 | Completed | Not reported | AVID: antiarrhythmic drugs (mainly amiodarone) vs implantable defibrillators in life-threatening ventricular arrhythmias |
| NCT00383799 | Phase 4 | Terminated | 302 | PROCAMIO: IV amiodarone vs IV procainamide in well-tolerated wide-QRS tachycardia; early termination limits conclusions |
| NCT00257959 | Phase 4 | Completed | 400 | OPTIC: amiodarone plus beta-blocker vs sotalol vs beta-blocker alone for ICD shock prevention |
| NCT03299517 | Phase 4 | Unknown | 80 | Amiodarone vs lidocaine in stable VT in the emergency room |
| NCT03855826 | Phase 4 | Unknown | 756 | Nifekalant vs amiodarone for VT and VF |
| NCT02830360 | Phase 4 | Completed | 416 | VANISH2: catheter ablation vs antiarrhythmic drug therapy after myocardial infarction |
| NCT01722942 | N/A | Unknown | 1100 | CHAGASICS: amiodarone vs ICD for primary prevention in Chagas cardiomyopathy |
| NCT01097330 | Phase 3 | Terminated | 12 | Catheter ablation vs amiodarone for shock prophylaxis in ICD patients |
| NCT03734562 | N/A | Completed | 180 | Substrate ablation vs antiarrhythmic drugs in scar-related monomorphic VT |
Literature Evidence
Literature for the top prediction (CPVT) consists of cohort studies, a general review and case reports, with no amiodarone efficacy data. The table below lists the most relevant publications across the better-supported predictions.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 27354046 | 2017 | RCT | European Heart Journal | PROCAMIO: IV procainamide vs IV amiodarone for tolerated wide-QRS (probably ventricular) tachycardia |
| 16316969 | 2005 | RCT | Circulation | Double-blind trial of IV amiodarone for incessant tachyarrhythmias in children |
| 14508682 | 2003 | Cohort/Case series | European Journal of Pediatrics | Safety and efficacy of IV amiodarone in 23 infants with life-threatening incessant tachycardias |
| 30084131 | 2018 | Cohort | Emergency Medicine Australasia | Paramedic-administered amiodarone for stable VT in the prehospital setting |
| 20730062 | 2010 | Review | Vascular Health and Risk Management | Amiodarone for treatment and prevention of VF and VT |
| 36878200 | 2023 | Review | Cardiology | Pharmacotherapy in ventricular arrhythmias |
| 9137212 | 1997 | Review | J Am Coll Cardiol | Pharmacology and efficacy of IV amiodarone in malignant ventricular arrhythmias |
| 41217320 | 2026 | Trial substudy | J Am Coll Cardiol | VANISH2 substudy: catheter ablation vs sotalol or amiodarone for VT |
| 2114081 | 1990 | Case series | Arch Mal Coeur Vaiss | Incessant idiopathic VT in infants; arrhythmia reduced after oral amiodarone in 5 cases |
| 26513538 | 2015 | Review | Expert Opin Pharmacother | Advances in pharmacologic treatment of ventricular arrhythmias (retrieved for CPVT) |
New Zealand Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2565129 | Max Health | Inj 50 mg per ml, 3 ml ampoule | Not recorded (cancelled) |
| 770639 | Aratac | Tab 200 mg | Not recorded (cancelled) |
| 770620 | Aratac | Tab 100 mg | Not recorded (cancelled) |
All three authorisations are cancelled, so no valid amiodarone product is currently registered in the compiled data.
Safety Considerations
- Disease-level contraindication signals (from knowledge-graph drug-disease edges, not label text):
- Cardiac conduction and rhythm: long QT syndrome (including familial), torsades de pointes, atrioventricular block, sick sinus syndrome
- Thyroid: hypothyroidism, myxedema, congenital hypothyroidism, hyperthyroidism, Graves disease, thyrotoxicosis
- Liver and biliary: liver disease, drug-induced liver injury, gallbladder disease
- Lung: interstitial lung disease, eosinophilic pneumonia, pulmonary eosinophilia, extrinsic allergic alveolitis, hypersensitivity pneumonitis, farmer's lung disease
- Eye and nerve: optic neuritis, optic nerve disease, visual pathway disease, corneal deposit, peripheral nervous system disease, peripheral neuropathy
- Metabolic: potassium deficiency disease
- Pharmacological interactions: The compiled pharmacology data show interactions with the Nav1.5 sodium channel, the Kv1.7 potassium channel and the M5 muscarinic receptor. These are target-level interactions, not drug-drug interaction severity ratings.
- Literature-reported concerns:
- Thyroid dysfunction (hypothyroidism and hyperthyroidism)
- Pulmonary toxicity, including pulmonary fibrosis and diffuse alveolar hemorrhage
- Proarrhythmia
- Iodine load in neonates
- Drug-induced ventricular dyssynchrony in a newborn
- Rhabdomyolysis when combined with atorvastatin and fluconazole
- Interaction with cyclosporine
Package insert warnings and contraindications are not available in the compiled data. Please refer to the package insert for authoritative safety information.
Conclusion and Next Steps
Decision: Hold for CPVT (top-ranked prediction); Proceed with Guardrails for ventricular tachycardia and incessant infant ventricular tachycardia
Rationale:
- For CPVT, the highest-scoring prediction, there are no clinical trials and no literature showing amiodarone efficacy. Guidelines favour beta-blockers and flecainide, and amiodarone is generally considered ineffective, so the finding is a research question (L4).
- Ventricular tachycardia has strong support (L1) from multiple completed Phase 3/4 trials, but this is mostly an established use. Incessant infant ventricular tachycardia has moderate support (L2) from paediatric studies, including a double-blind RCT in mixed incessant tachyarrhythmias. The remaining predictions (ranks 4–10) have no plausible link and are held.
To proceed, the following is needed:
- Package insert warnings and contraindications (currently missing and blocking for safety screening)
- Detailed mechanism of action data
- Clarification of the New Zealand regulatory position, since all three authorisations are cancelled and no approved indication text is recorded
- For incessant infant ventricular tachycardia: studies restricted to ventricular tachycardia, plus a monitoring plan for thyroid, hepatic, pulmonary and proarrhythmic toxicity and for neonatal iodine load
- For CPVT: direct comparative evidence against beta-blockers and flecainide before any further development
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.