When should amiodarone be held?

When to Hold Amiodarone

Hold amiodarone immediately if liver enzymes exceed three times the upper limit of normal (unless the patient faces high risk of life-threatening arrhythmia recurrence), if pulmonary toxicity develops with worsening dyspnea or cough, or if second- or third-degree heart block occurs without pacemaker support. 1, 2

Cardiovascular Indications to Hold

Conduction Abnormalities:

• Discontinue amiodarone in patients with second- or third-degree heart block who lack a pacemaker, as this represents an absolute contraindication 1
• Stop or reduce the infusion rate immediately if bradycardia develops during treatment (occurs in 1-3% of oral therapy patients and 4.9% of IV therapy patients) 1
• Hold or reduce IV infusion if hypotension occurs (seen in 16% of patients receiving IV amiodarone) 1

QT Prolongation:

• Consider holding in patients with significant QT prolongation, though torsades de pointes remains rare with amiodarone despite universal QT interval prolongation 1

Pulmonary Toxicity (Most Serious Non-Cardiac Adverse Effect)

Immediate discontinuation is required for pulmonary toxicity, which occurs in 2-17% of patients and represents the most serious potential adverse effect. 1, 2

Clinical Presentation:

• Any report of worsening dyspnea or cough demands immediate assessment and consideration of holding amiodarone 1, 2
• Typical presentation includes subacute cough and progressive dyspnea with patchy interstitial infiltrates on chest radiographs and reduced diffusing capacity on pulmonary function tests 2
• Adult respiratory distress syndrome occurs at a rate of 1% annually 2

Management:

• Primary treatment involves withdrawal of amiodarone, supportive care, and in some cases corticosteroids 2
• Toxicity is reversible in most instances after discontinuation 2
• Congestive heart failure must be ruled out early as it can mimic amiodarone pneumonitis 2

Hepatic Toxicity

Hold amiodarone if liver transaminase levels are three times higher than normal, unless the patient is at high risk for recurrence of life-threatening arrhythmia. 1, 2

• Liver toxicity occurs at a rate of 0.6% annually in patients receiving long-term therapy 2
• Patients with liver toxicity are rarely symptomatic 2
• Elevated aminotransferase and alkaline phosphatase levels are seen in 4-25% of patients 3

Thyroid Dysfunction

Thyroid abnormalities occur in 2-10% of patients, with hypothyroidism being two to four times more common than hyperthyroidism. 2, 3

Management Approach:

• In hypothyroid patients with strong clinical indication for amiodarone, the drug may be continued with appropriate thyroid hormone supplementation 2
• For amiodarone-induced hyperthyroidism, treatments include withdrawal of amiodarone (if safe), addition of antithyroid medications or prednisone, or surgical thyroidectomy 2
• Consider holding if thyroid dysfunction becomes severe and cannot be managed with appropriate therapy 1

Ocular Toxicity

Refer patients with changes in visual acuity or peripheral vision for ophthalmologic evaluation and consider holding if optic neuropathy is confirmed. 1

• Optic neuropathy and optic neuritis, sometimes progressing to total blindness, have been described in a small number of patients 2
• Corneal microdeposits occur in nearly all patients but seldom affect vision and rarely necessitate discontinuation 2

Neurologic Toxicity

Neurologic side effects are often dosage-related and improve with dose reduction rather than complete discontinuation. 2

• Neurologic toxicity can include ataxia, paresthesias, and tremor 2
• Peripheral neuropathy occurs at a rate of 0.3% annually 2
• Neurologic side effects were reported in 20-40% of patients in some studies 3

Drug Interaction Considerations

Warfarin Interaction:

• When initiating amiodarone in patients on warfarin, reduce warfarin dose by one-third to one-half and monitor INR at least weekly for the first 6 weeks 1, 4
• Amiodarone increases prothrombin time by 100% after 3-4 days and can result in serious or fatal bleeding 4

Digoxin Interaction:

• Reduce digoxin dose by approximately 50% when starting amiodarone, as digoxin levels typically double 1, 4
• Administration of oral amiodarone regularly results in a 70% increase in serum digoxin concentration after one day, potentially reaching toxic levels 4

Other Antiarrhythmics:

• Reduce quinidine and procainamide doses by one-third when administered with amiodarone 4
• Adjust flecainide dosage when co-administered, as plasma levels increase in the presence of oral amiodarone 4

Monitoring Requirements to Identify When to Hold

Routine Monitoring:

• Monitor liver function tests and thyroid studies every 6 months during maintenance therapy 1, 2
• Perform chest radiograph and pulmonary function tests if pulmonary toxicity is suspected 1
• Closely monitor heart rate, especially during the first week of treatment 1
• For patients on warfarin, check prothrombin time and INR at least once weekly during the first 6 weeks 1

Critical Caveat:

• Routine screening for adult respiratory distress syndrome is of limited value because pulmonary toxicity can develop rapidly with no antecedent abnormalities on chest radiographs or pulmonary function tests 2

Special Considerations for IV Administration

Hold or reduce the rate of IV amiodarone if heart block, bradycardia, or hypotension occurs during infusion. 1

• IV amiodarone should not be used in patients with bradycardia or heart block who do not have a pacemaker 1
• Continuous ECG monitoring for heart rate, AV conduction abnormalities, and QT prolongation is mandatory during IV administration 5

Dosage-Related Adverse Effects

Many adverse effects are dosage-related and may improve with dose reduction rather than complete discontinuation. 2

• Gastrointestinal side effects (nausea, anorexia, constipation) are dosage-related and usually improve when dosage is reduced 2
• Higher doses of ≥400 mg/day have been linked to increased complications 6
• After initial loading, 200 mg/day in many patients maintains arrhythmia control and minimizes the frequency of side effects 3