What are the indications, dosing (IV and oral loading and maintenance), monitoring requirements, contraindications, and alternative therapies for amiodarone?

Amiodarone: Comprehensive Clinical Guide

Indications

Amiodarone is indicated for life-threatening ventricular arrhythmias refractory to other therapies, including ventricular fibrillation and hemodynamically unstable ventricular tachycardia. 1

FDA-Approved Indications

• Initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) 1
• Hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy 1

Evidence-Based Off-Label Uses

• Cardiac arrest: VF or pulseless VT unresponsive to defibrillation and epinephrine—administer 300 mg IV/IO bolus, followed by 150 mg if arrhythmia persists 2
• Stable wide-complex tachycardia: Hemodynamically stable monomorphic VT, though onset takes 20–30 minutes with most conversions after 6–8 hours 3, 2
• Atrial fibrillation with heart failure: Rate control when beta-blockers, calcium channel blockers, and digoxin fail or are contraindicated (Class IIa recommendation) 3, 2
• Atrial fibrillation rhythm control: Most effective agent for long-term sinus rhythm maintenance, particularly in patients with left ventricular dysfunction 3, 4, 5
• Pre-excited atrial fibrillation (WPW): Use standard rapid IV regimen while avoiding AV-nodal blockers 3
• Perioperative cardiac surgery: Prophylactic use to prevent postoperative arrhythmias 5
• ICD adjunct therapy: Reduces frequency of shocks in patients with implantable cardioverter-defibrillators 4, 5

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Intravenous Dosing

Standard Loading Protocol for Life-Threatening Arrhythmias

The FDA-approved regimen delivers approximately 1,000 mg over the first 24 hours: 1

• Rapid loading dose: 150 mg diluted in 100 mL D5W over 10 minutes 3, 2, 1
• Early maintenance infusion: 1 mg/min for 6 hours (≈360 mg total) 3, 2, 1
• Late maintenance infusion: 0.5 mg/min for remaining 18 hours (≈540 mg total) 3, 2, 1
• Maximum daily dose: Do not exceed 2.2 g in any 24-hour period 3, 2

Breakthrough Arrhythmias

• Repeat 150 mg loading doses over 10 minutes for recurrent VF or unstable VT 3, 2
• Up to 6–8 additional boluses may be given within 24 hours if needed 3

Hemodynamically Stable Arrhythmias

• Administer 150 mg (or 5 mg/kg, ≈300 mg) over 1 hour, followed by standard maintenance infusion 3

Critical Administration Requirements

Amiodarone must be delivered by volumetric infusion pump—drop-counter devices can underdose by up to 30%. 3, 1

• Diluent: Use 5% dextrose in water (D5W) exclusively; normal saline causes precipitation 3, 2, 1
• Concentration: Peripheral infusions must not exceed 2 mg/mL; higher concentrations require central venous catheter to avoid severe phlebitis 3, 2, 1
• Central line preferred: Administer through dedicated central venous catheter whenever possible 3
• In-line filter: Must be used during administration 3, 2, 1
• Container: Infusions >2 hours must use glass or polyolefin bottles, not evacuated glass containers 1
• Maximum infusion rate: Do not exceed 30 mg/min initially 3

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Oral Dosing

Loading Phase

Oral loading requires 600–800 mg daily in divided doses until a cumulative 10-gram total is reached, typically over 1–2 weeks. 3, 6

• Standard loading: 600–800 mg/day divided into 2–3 doses (e.g., 300 mg twice daily) 3, 6
• High-dose inpatient loading: 400–600 mg daily for 2–4 weeks 3
• Very high-dose option: Up to 1,200 mg daily in monitored inpatient settings 3
• Cumulative target: Continue until approximately 10 grams total administered 3, 6

Maintenance Phase

After completing the 10-gram load, reduce to 200 mg daily for most patients. 3, 6

• Standard maintenance: 200–400 mg daily 3, 6
• Low-dose option: Some patients require only 100–200 mg daily 3, 6
• Dosing principle: Use the lowest effective dose to minimize toxicity 3

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Transition from IV to Oral Therapy

Timing and Overlap Strategy

Begin oral amiodarone while IV infusion continues at 0.5 mg/min, due to amiodarone's extremely long half-life (15–100 days, average 58 days). 3, 6

• After approximately 8 hours of IV infusion, patients are ready to begin oral loading 6
• Continue IV infusion for 24 hours after first oral dose, then discontinue 6

Conversion Dosing Based on IV Duration

• <1 week IV therapy: Start 800–1,600 mg oral daily 6
• 1–3 weeks IV therapy: Start 600–800 mg oral daily 6
• Continue oral loading until 10-gram cumulative total, then reduce to maintenance 3, 6

Monitoring During Transition

• Daily 12-lead ECG to assess QT interval and detect heart block 6
• Monitor blood pressure for persistent hypotension 6
• Check heart rate every 4–6 hours initially, then at least daily 6
• Continuous telemetry for at least 24 hours after IV discontinuation 6

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Contraindications

Absolute Contraindications

Second- or third-degree AV block without a functioning pacemaker is an absolute contraindication. 3, 2, 1

• Known hypersensitivity to amiodarone or iodine 1
• Cardiogenic shock 1
• Marked sinus bradycardia 1
• Sick-sinus syndrome without pacemaker 2
• Acute inflammatory lung disease 2

Relative Contraindications (Use Only if Life-Threatening and No Alternatives)

• Baseline heart rate <60 bpm: Bradycardia occurs in 4.9% of IV patients; use extreme caution unless pacemaker present 3, 2
• Systolic blood pressure <100 mmHg: Hypotension occurs in 16–26% of patients 3, 2
• Moderate or severe left ventricular dysfunction: Increased risk of hemodynamic compromise 3, 2
• Hepatic dysfunction: Use with extreme caution 2

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Monitoring Requirements

During IV Administration

Continuous ECG monitoring is mandatory for heart rate, AV conduction abnormalities, QT prolongation, PR interval, and QRS duration. 3, 2

• Cardiac rhythm: Monitor continuously for bradycardia, AV block, and arrhythmia recurrence 3, 2
• Blood pressure: Monitor for hypotension (16–26% incidence); if develops, slow infusion and consider vasopressors, inotropes, or volume expansion 2
• ECG parameters: Track PR interval, QRS duration, and QT interval; QT >500 ms mandates dose adjustment 3, 2
• Defibrillator availability: Must be immediately accessible throughout infusion 2
• Bradycardia response: If heart rate decreases by 10 bpm, reduce infusion rate 3

During Oral Therapy

• Heart rate: Monitor weekly initially, then reassess after each dose change 3
• ECG: Reassess after each dose change, measuring PR interval, QRS duration, and QT interval 3
• Liver function: Check every 6 months during maintenance therapy 3
• Thyroid function: Check every 6 months during maintenance therapy 3
• Pulmonary screening: Monitor for pulmonary toxicity (occurs in 1–17% of patients) 5

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Major Drug Interactions

Critical Dose Adjustments Required

When starting amiodarone, reduce digoxin dose by 50% immediately—amiodarone doubles digoxin levels. 3, 2

• Warfarin: Reduce dose by 30–50% and monitor INR at least weekly; interaction peaks at 7 weeks 3, 2
• Beta-blockers and calcium channel blockers: Reduce doses approximately 6 weeks after starting amiodarone due to additive AV-node suppression and bradycardia risk 3, 6, 2

Other Significant Interactions

• QT-prolonging agents: Avoid concurrent use without specialist consultation 2
• Grapefruit juice: Patients must avoid completely—inhibits CYP3A metabolism and increases plasma levels 3, 1
• CYP450 interactions: Amiodarone inhibits CYP1A2, CYP2C9, CYP2D6, and CYP3A, increasing exposure to other drugs 1

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Adverse Effects and Toxicity

Cardiovascular (Most Common Reasons for IV Discontinuation)

• Hypotension: Occurs in 16–26% of IV patients 3, 2
• Bradycardia: Occurs in 4.9% of IV patients, 1–3% of oral patients 3, 6
• AV block: Monitor for second- or third-degree block requiring pacemaker 3
• QT prolongation: Common but rarely causes torsades de pointes 3, 4

Non-Cardiac Toxicity (Dose-Dependent)

• Corneal microdeposits: Occur in >90% of patients 5
• Pulmonary toxicity: Occurs in 1–17%; potentially fatal pulmonary fibrosis 3, 5
• Thyroid dysfunction: Hypothyroidism (6%), hyperthyroidism (0.9–2%) 5
• Hepatotoxicity: Elevated enzymes (15–30%), hepatitis/cirrhosis (<3%, 0.6% annually) 5
• Photosensitivity: Occurs in 25–75% 5
• Blue-gray skin discoloration: Occurs in 4–9% 5
• Peripheral neuropathy: 0.3% annually 5
• Optic neuropathy/neuritis: ≤1–2% 5

Gender-Specific Risk

• Female patients have higher incidence of amiodarone-induced bradycardia requiring permanent pacemaker 3

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Alternative Therapies

When Amiodarone Is Contraindicated or Ineffective

For stable monomorphic VT, procainamide is the primary alternative—infuse at 20–50 mg/min until arrhythmia suppression, hypotension, ≥50% QRS prolongation, or cumulative dose of 17 mg/kg. 3, 2

• Lidocaine: Initial IV dose 1–1.5 mg/kg for ventricular arrhythmias when amiodarone unavailable 3, 2
• Sotalol: May treat both VT and SVT but requires careful QT monitoring and has significant pro-arrhythmic risk 3
• Class Ic agents (flecainide, propafenone): Reasonable for SVT but contraindicated in structural heart disease 3
• Electrical cardioversion: Prioritize immediately if patient becomes hemodynamically unstable during pharmacologic therapy 3, 2

First-Line Agents for Rate Control in Atrial Fibrillation

• Beta-blockers or nondihydropyridine calcium channel blockers: Class I recommendation; more predictable pharmacokinetics and lower toxicity than amiodarone 3
• Digoxin: Preferred in heart failure or LV dysfunction; does not worsen bradycardia as significantly 3

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Clinical Pearls and Common Pitfalls

Onset of Action

The antiarrhythmic effect of IV amiodarone typically becomes apparent 20–30 minutes after administration, with most conversions to sinus rhythm after 6–8 hours and ≥1 gram total dose—making it unsuitable as first-line therapy unless the patient is hemodynamically stable. 3, 2

Pharmacokinetics

• Elimination half-life averages 58 days (range 15–100 days), causing significant overlap between IV and oral dosing 3, 7
• Maximal effects and most significant adverse effects not attained before 90–150 days of treatment 7
• Antiarrhythmic protection may persist up to 150 days after discontinuation 7

High-Risk Scenarios

• Concomitant AV-nodal blockers: Beta-blockers, calcium channel blockers, or digoxin create additive effects and increase bradycardia risk 3
• Hypokalemia: Maintain serum potassium >4 mmol/L to reduce pro-arrhythmic risk 3
• Pregnancy: Use only if potential benefit justifies fetal risk; fetal hypothyroidism reported in ≈17% of cases 2

Efficacy Data

• 62% of patients remain in sinus rhythm at 1 year with amiodarone versus 23% with class I agents 6
• Median time to AF recurrence: 487 days with amiodarone versus 74 days with sotalol 6
• Most AF recurrences occur within first month after cardioversion; continue therapy through this high-risk period 6

Anticoagulation After Cardioversion

• Maintain therapeutic anticoagulation for minimum 4 weeks after cardioversion in all patients 6
• Continue indefinitely in those with CHA₂DS₂-VASc ≥1 (men) or ≥2 (women) 6

3, 6, 2, 1, 7, 8, 4, 5, 9