AmiodaronePA study guide

Why they happen and how to manage them

Pulmonary toxicity

Direct toxicity or a hypersensitivity pneumonitis; the drug builds up in lung tissue. Management: Baseline chest X-ray and PFTs, repeat X-ray every 3 to 6 months; switch therapy if suspected; steroids may help.

Hypothyroidism or hyperthyroidism

The molecule is iodine rich and blocks conversion of T4 to T3. Management: Check thyroid tests at baseline and periodically; treat or reduce the dose.

Bradycardia, AV block, and QT prolongation

Beta-blocking, calcium-channel, and potassium-channel effects slow the nodes and lengthen repolarization. Management: Monitor ECG and heart rate; correct potassium and magnesium; avoid other QT-prolonging drugs.

Many drug interactions

It inhibits CYP3A, CYP2C9, CYP2D6, and P-glycoprotein, raising warfarin, digoxin, and statin levels. Management: Lower warfarin and digoxin doses when starting; monitor INR and digoxin levels.

Effects that persist after stopping

Very large tissue stores and a half-life measured in weeks. Management: Keep monitoring for months after the last dose.

IV hypotension and phlebitis

Vasodilation related to infusion rate; irritation from concentrated solution. Management: Do not exceed the labeled rate; infuse through a dedicated central venous catheter whenever possible.

Sources: [1][2][3][4][5][6][7][8]

Common and serious

Sources: [1][2][3][4][5]

Narrow therapeutic index

The label does not describe a narrow therapeutic index or direct dosing by measured blood levels of the drug.

Sources: [1][2]

ALT (liver enzyme)

Why

Hepatic injury

When

Baseline and periodically; closely during IV therapy

Act on

Above three times normal, or double a raised baseline: reduce or stop

Normal

4 to 36 U/L.

Sources: [1][2][3][4]

Blood pressure

Why

Hypotension during IV infusion

When

Closely, especially in the first hours of infusion

Act on

Slow the infusion; add vasopressors, inotropes, or fluids

Normal

Below 120/80 mm Hg.

Sources: [1][2]

ECG (rhythm and QT interval)

Why

QTc prolongation, bradycardia, AV block, proarrhythmia

When

Continuous when starting; during IV infusion

Act on

Bradycardia or AV block on IV: slow or stop the infusion

Sources: [1][2][3]

Heart rate

Why

Bradycardia

When

Regularly; closely with beta blockers, calcium channel blockers, digoxin, or sofosbuvir

Act on

Symptomatic bradycardia may need a pacemaker

Normal

60 to 100 beats per minute in adults at rest.

Sources: [1][2][3]

INR (prothrombin time)

Why

Warfarin interaction

When

Closely when amiodarone is started with warfarin

Act on

Cut the warfarin dose by one-third to one-half

Normal

INR 0.8 to 1.1 when not on a blood thinner. On warfarin, the usual target is 2.0 to 3.0.

Sources: [1][2]

Magnesium

Why

Low magnesium worsens QT prolongation and torsade risk

When

Before starting

Act on

Correct before starting

Normal

1.7 to 2.2 mg/dL.

Sources: [1][2]

Potassium

Why

Low potassium worsens QT prolongation and torsade risk

When

Before starting and with diuretics or diarrhea

Act on

Correct before starting

Normal

3.7 to 5.2 mEq/L.

Sources: [1][2][3]

TSH (thyroid-stimulating hormone)

Why

Hypothyroidism or hyperthyroidism

When

Before starting and periodically, especially in older adults or with thyroid disease

Act on

Treat; for hypothyroidism, reduce or stop amiodarone and add thyroid hormone

Normal

0.4 to 4.8 µU/mL.

Sources: [1][2][3]

Adult dose

Oral, life-threatening VF or unstable VT

Load 800 to 1600 mg/day until response, usually 1 to 3 weeks. Then 600 to 800 mg/day for 1 month, then maintenance, usually 400 mg/day. Use the lowest effective dose.

IV, VF or unstable VT

Load 150 mg in 10 minutes (15 mg/min), then 360 mg over 6 hours (1 mg/min), then 0.5 mg/min (540 mg) for the remaining 18 hours. After 24 hours, continue 0.5 mg/min (720 mg per 24 hours). Repeat 150 mg over 10 minutes for breakthrough VF or VT.

IV to oral switch

After less than 1 week of IV: 800 to 1600 mg oral daily. After 1 to 3 weeks: 600 to 800 mg. After more than 3 weeks: 400 mg.

Sources: [1][2][3][4]

Renal adjustment

None. Renal impairment does not change amiodarone or metabolite levels, and urinary excretion is negligible. Not dialyzable.

Sources: [1]

Hepatic adjustment

No defined dose change. It is cleared by the liver and can itself injure the liver, so check transaminases at baseline and periodically, and reduce or stop if they exceed three times normal or double from a raised baseline.

Sources: [1][2]

Boxed warning

Oral Pacerone: pulmonary, hepatic, and cardiac toxicity. Use only for the labeled life-threatening arrhythmias, after other agents. Lung toxicity occurs in up to 17% in some series and is fatal about 10% of the time; get a baseline chest X-ray and pulmonary function tests and repeat the X-ray every 3 to 6 months. Liver injury can be fatal; check transaminases and reduce or stop if they rise above three times normal. It can worsen arrhythmias, so start it where continuous ECG and resuscitation are available. The Nexterone IV label has no boxed warning.

Sources: [1]

Contraindications

• Cardiogenic shock
• Sick sinus syndrome, second- or third-degree AV block, or bradycardia causing syncope, unless a pacemaker is working
• Marked sinus bradycardia (IV)
• Hypersensitivity to amiodarone or any component, including iodine

Sources: [1][2]

Key interactions

Warfarin

Prothrombin time rises by 100% within 3 to 4 days, with risk of serious bleeding. Cut the warfarin dose by one-third to one-half and follow PT closely.

Digoxin

Raises digoxin levels. Reduce digoxin by half or stop it, and watch for toxicity.

Other QT-prolonging drugs (class I and III antiarrhythmics, some fluoroquinolones, macrolides, azoles)

Higher risk of torsade de pointes. Avoid.

Beta blockers, verapamil, diltiazem, digoxin, clonidine, ivabradine

Bradycardia, sinus arrest, and AV block. Monitor heart rate.

Sofosbuvir-containing hepatitis C drugs

Symptomatic, sometimes fatal bradycardia requiring pacemakers. Monitor heart rate.

Simvastatin or lovastatin

Higher statin levels. Limit simvastatin to 20 mg and lovastatin to 40 mg.

Grapefruit juice and CYP3A inhibitors; St. John's wort and cholestyramine

Inhibitors raise amiodarone levels; St. John's wort and cholestyramine lower them.

Any drug, for months after stopping

Because of the very long half-life, interactions persist for weeks to months after the last dose.

Sources: [1][2]

Antidote or reversal

No antidote. Monitor rhythm and blood pressure. Treat bradycardia with a beta-agonist or pacing, and hypotension with inotropes, vasopressors, and volume; for IV overdose, also slow the infusion. Monitor liver enzymes. Neither amiodarone nor its metabolite is removed by dialysis.

Sources: [1][2]

Pregnancy

Can harm the fetus: neonatal hypothyroidism or hyperthyroidism, bradycardia, neurodevelopmental problems, growth restriction, and preterm birth. It crosses the placenta. Advise pregnant patients of the risk and monitor the newborn's thyroid and heart rhythm.

Sources: [1][2]

Lactation

Amiodarone and its metabolite reach 3.5% to 45% of the maternal weight-adjusted dose in milk; infant hypothyroidism and bradycardia have been reported. Breastfeeding is not recommended.

Sources: [1]

Pediatric

Safety and effectiveness in children are not established. In a pediatric IV trial, dose-related hypotension (36%), bradycardia (20%), and AV block (15%) were frequent.

Sources: [1][2]

Geriatric

Clearance is lower and half-life longer after age 65. Start at the low end of the dose range, and monitor thyroid function closely.

Sources: [1][2]