Amiodarone

Pronunciation: (A-MEE-oh-duh-rone)Class: Antiarrhythmic agent

Trade Names:Cordarone- Tablets 200 mg

Trade Names:Nexterone- Injection 50 mg/mL

Trade Names:Pacerone- Tablets 100 mg- Tablets 200 mg- Tablets 300 mg- Tablets 400 mg

Amiodarone Hydrochloride for Injection Sandoz Standard (Canada)Apo-Amiodarone (Canada)Gen-Amiodarone (Canada)Novo-Amiodarone (Canada)PMS-Amiodarone (Canada)ratio-Amiodarone (Canada)Sandoz Amiodarone (Canada)

Pharmacology

Prolongs action potential, duration, and refractory period in myocardial cells; acts as noncompetitive inhibitor of alpha- and beta-adrenergic receptors.

Pharmacokinetics

Absorption

Oral

Bioavailability is 35% to 65%; T _max is 3 to 7 h. Concentrations of 1 to 2.5 mg/L are effective with acceptable toxicity. Food increases rate and extent of absorption.

Distribution

Oral

Vd is about 60 L/kg.

Oral/IV

Crosses the placenta; excreted in breast milk. More than 96% protein bound.

IV

Rapidly distributed; serum concentrations decline to 10% of peak values within 30 to 45 min after the end of the infusion. Vd is 40 to 84 L/kg (amiodarone) and 68 to 168 L/kg (N-desethyl amiodarone [DEA]).

Metabolism

Metabolized by CYP3A4 to DEA (active).

Elimination

Eliminated primarily by hepatic excretion into bile; some enterohepatic recirculation may occur; negligible renal excretion. Biphasic elimination with initial 50% reduction in plasma levels after 2.5 to 10 days; terminal t _½ is 26 to 107 days (mean, about 53 days) (oral) and 20 to 47 days (IV). Not dialyzable.

Onset

2 to 3 days but more commonly 1 to 3 wk.

Special Populations

Elderly

Cl is lower and t _½ is increased; monitor closely.

Severe left ventricular dysfunction

The t _½ of DEA is prolonged; monitor closely.

Indications and Usage

Oral

Treatment of life-threatening, recurrent ventricular arrhythmias (ie, ventricular fibrillation and hemodynamically unstable ventricular tachycardia) that do not respond to other antiarrhythmic agents. Use only in patients with the indicated life-threatening arrhythmias because use is accompanied by substantial toxicity.

Parenteral

Initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy; treatment of ventricular tachycardia and fibrillation when oral amiodarone is indicated but patient is unable to take oral medication.

Unlabeled Uses

Conversion of atrial fibrillation and maintenance of sinus rhythm; treatment of supraventricular tachycardia; IV amiodarone has been used to treat atrioventricular (AV) nodal reentry tachycardia.

Contraindications

Oral

Cardiogenic shock, severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree AV block; when bradycardia produces syncope, unless used with pacemaker; hypersensitivity to the drug, including iodine.

Parenteral

Known hypersensitivity to the drug, including iodine; marked sinus bradycardia; second- and third-degree AV block unless functioning pacemaker is available; cardiogenic shock.

Dosage and Administration

Life-Threatening, Recurrent Ventricular ArrhythmiasLoading dose

PO 800 to 1,600 mg/day for 1 to 3 wk. Reduce doses of other antiarrhythmic agents gradually. When adequate arrhythmia control is achieved, reduce dose to 600 to 800 mg/day for 1 mo.

Usual maintenance dose

PO 400 mg/day.

Adults

IV Recommended starting dose is approximately 1,000 mg over the first 24 h administered as follows: rapid administration of 150 mg over first 10 min (15 mg/min), followed by 360 mg over next 6 h (1 mg/min), then 540 mg over remaining 18 h (0.5 mg/min). After first 24 h, continue maintenance infusion rate of 0.5 mg/min (720 mg/24 h).

IV to Oral TransitionAdults

Clinical monitoring is recommended when changing from IV to oral therapy. PO 800 to 1,600 mg amiodarone if duration of IV infusion less than 1 wk; 600 to 800 mg amiodarone if duration of IV infusion 1 to 3 wk; 400 mg amiodarone if duration of IV infusion more than 3 wk.

General Advice

• Tablets
• Administer consistently either with food or on an empty stomach. Administer with food if GI upset occurs. Administer loading doses greater than 1,000 mg in divided doses with food.
• Administer maintenance doses as a single daily dose or, in patients with severe GI intolerance, divide into 2 daily doses.

• Injection
• For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
• Administer by volumetric infusion pump using polyvinyl chloride tubing and an inline filter.
• Prepare infusions that will exceed 2 h in glass or polyolefin bottles containing D5W. Do not use evacuated glass containers because incompatibility of amiodarone with a buffer in container may cause precipitation.
• To prepare first rapid loading infusion, add 3 mL (150 mg) of IV amiodarone to 100 mL D5W (concentration = 1.5 mg/mL).
• To prepare 6 h slow loading infusion and 18 h initial maintenance infusion, add 18 mL (900 mg) of IV amiodarone to 500 mL D5W (concentration = 1.8 mg/mL)
• For maintenance infusions after first 24 h, use infusion solutions containing 1 to 6 mg/mL. Administer concentrations greater than 2 mg/mL via central venous catheter.
• Solution should be clear and may have a pale-yellow coloration. Do not administer if solution is discolored, cloudy, or contains particulate matter.

Storage/Stability

Store tablets at controlled room temperature (68° to 77°F for Cordarone ; 59° to 86°F for Pacerone ). Store injection at controlled room temperature (59° to 77°F). Protect from light and excessive heat.

Drug Interactions

Anticoagulants (eg, warfarin)

Warfarin PT increased by 100% after 3 to 4 days; reduce dose of anticoagulant by one third to one half.

Antihypertensives

Use with caution with beta blockers or calcium channel blockers because of the possible potentiation of bradycardia, sinus arrest, and AV block.

Azole antifungals/fluoroquinolones/macrolides

Reports of QTc prolongation with or without torsades de pointes may occur when used concomitantly with amiodarone.

Cardiac glycosides (eg, digoxin)

Digoxin levels are increased and may result in toxicity. Reduce digoxin dose by approximately 50% or discontinue.

Cholestyramine

Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t _½ .

CYP3A4 inducers (eg, rifampin)

Amiodarone and the metabolite, desethylamiodarone, plasma levels may be reduced, decreasing the pharmacologic effect.

CYP3A4 inhibitors (eg, cimetidine, ritonavir)

Amiodarone plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Fentanyl

In combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Grapefruit juice

Amiodarone plasma concentrations may be elevated, increasing the risk of side effects. Patients taking oral amiodarone should avoid grapefruit juice.

HMG-CoA reductase inhibitors (eg, simvastatin)

Simvastatin plasma levels may be elevated, increasing the risk of adverse reactions (eg, myopathy, rhabdomyolysis).

Lidocaine

Lidocaine plasma concentrations may be elevated, increasing the risk of seizures.

P-glycoprotein and CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (eg, cyclosporine)

Plasma concentrations of drugs metabolized by these CYP enzymes or substrates of P-glycoprotein may be elevated, increasing the risk of side effects.

Protease inhibitors (eg, ritonavir)

Amiodarone plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

St. John's wort

Amiodarone plasma levels may be reduced, decreasing the pharmacologic effects.

Trazodone

QT interval prolongation and torsade de pointes have been reported with coadministration.

Adverse Reactions

Cardiovascular

Oral

Cardiac arrhythmias, CHF, SA node dysfunction (1% to 3%); hypotension, sinus arrest (postmarketing).

Parenteral

Hypotension (20%); bradycardia (6%); cardiac arrest (4%); CHF, ventricular tachycardia (2%); atrial fibrillation, nodal arrhythmia, prolonged QT interval, sinus bradycardia, ventricular fibrillation (less than 2%); asystole/cardiac arrest/electromechanical dissociation, cardiogenic shock, AV block.

CNS

Oral

Abnormal gait/ataxia, dizziness, fatigue, lack of coordination, malaise, paresthesias, tremor/abnormal involuntary movement (4% to 9%); decreased libido, headache, insomnia, sleep disturbances (1% to 3%); confusional states, delirium, disorientation, hallucinations, pseudotumor cerebri (postmarketing).

Dermatologic

Oral

Photosensitivity/Solar dermatitis (4% to 9%); flushing (1% to 3%); erythema multiforme, exfoliative dermatitis, pruritus, skin cancer, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis (postmarketing).

Parenteral

Stevens-Johnson syndrome (less than 2%).

EENT

Oral

Visual disturbances (4% to 9%); abnormal smell sensation (1% to 3%).

GI

Oral

Nausea, vomiting (10% to 33%); anorexia, constipation (4% to 9%); abdominal pain, abnormal salivation, abnormal taste (1% to 3%); pancreatitis (postmarketing).

Parenteral

Nausea (4%); diarrhea, vomiting (less than 2%).

Genitourinary

Oral

Acute renal failure, epididymitis, impotence, renal function impairment, renal insufficiency (postmarketing).

Parenteral

Abnormal kidney function (less than 2%).

Hematologic-Lymphatic

Oral

Coagulation abnormalities (1% to 3%); agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenia (postmarketing).

Hepatic

Oral

Abnormal liver function tests (4% to 9%); nonspecific hepatic disorders (1% to 3%); cholestatic hepatitis, cirrhosis, hepatitis (postmarketing).

Parenteral

Liver function test abnormalities (4%); increased ALT and AST, thrombocytopenia (less than 2%).

Local

Cellulitis, edema, erythema, necrosis, pain, pigment changes, phlebitis, skin sloughing, thrombophlebitis, venous thrombosis at injection site.

Musculoskeletal

Oral

Muscle weakness, myopathy, rhabdomyolysis (postmarketing).

Respiratory

Oral

Pulmonary inflammation or fibrosis (4% to 9%); bronchospasm, possibly fatal respiratory disorders (including ARDS, arrest, distress, and failure), bronchiolitis obliterans organizing pneumonia, cough, dyspnea, hemoptysis, hypoxia, pleuritis, pulmonary infiltrates and mass, wheezing (postmarketing).

Parenteral

Lung edema, respiratory disorder (less than 2%).

Miscellaneous

Oral

Edema, hyperthyroidism, hypothyroidism (1% to 3%); anaphylactic/anaphylactoid reaction (including shock), angioedema, fever, granuloma, SIADH, thyroid nodules/thyroid cancer (postmarketing).

Parenteral

Fever (3%); shock (less than 2%).

Precautions

Warnings Oral only Amiodarone is used for life-threatening arrhythmias only. Potentially fatal pulmonary toxicities include hypersensitivity pneumonitis or interstitial/alveolar pneumonitis. Rates of clinically manifested disease are as high as 10% to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day. Fatality rate approximates 10%. Liver injury may occur and has been fatal in a few cases. Proarrhythmic effects, significant heart block, or sinus bradycardia has occurred. Patients must be hospitalized during loading dose administration. Even in patients at high risk of arrhythmic death, in whom toxicity of amiodarone is an acceptable risk, every effort should be made to utilize alternative agents first because of the major management problems posed by amiodarone that could be life-threatening in a population at risk of sudden death. Because absorption and elimination are variable, maintenance-dose selection is difficult and dosage reduction or discontinuation of treatment is not unusual. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden.

Monitor Monitor effectiveness in long-term prevention of ventricular tachycardia and ventricular fibrillation using ambulatory monitoring, programmed electrical stimulation, or a combination of these, as appropriate. Hepatic Obtain liver enzymes before starting therapy and periodically thereafter during long-term therapy. Ophthalmic Perform regular ophthalmic exams, including funduscopy and slit-lamp exam, during amiodarone administration. Pulmonary Obtain baseline chest x-ray and pulmonary function tests, including diffusion capacity. Repeat chest x-ray, history, and physical exam every 3 to 6 mo thereafter. QTc prolongation Monitor for QTc prolongation during IV infusion of amiodarone. Thyroid Monitor thyroid function before starting therapy and periodically thereafter, especially in elderly patients and any patient with history of thyroid nodules, goiter, or other thyroid dysfunction.

Pregnancy

Category D .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Cautiously make dose selection, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function and comorbidity.

Photosensitivity

Occurs in about 10% of patients.

ARDS

Has been reported in patients receiving IV amiodarone who have experienced lung injuries from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia. Postoperative occurrences of ARDS have been reported in patients receiving oral amiodarone who have undergone cardiac or noncardiac surgery.

Benzyl alcohol

Benzyl alcohol, contained in IV amiodarone products as a preservative, has been associated with fatal gasping syndrome in neonates (children younger than 1 mo of age).

Bradycardia and AV block

Occurs with IV amiodarone but is not dose related. Treat by slowing infusion rate or discontinuing IV amiodarone; insertion of temporary pacemaker may be required. Treat patients with known predisposition to bradycardia or AV block in setting where temporary pacemaker is available.

Corneal refractive laser surgery

Most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone.

Electrolyte disturbance

Correct any potassium or magnesium deficiency before starting amiodarone therapy.

Grapefruit juice

Avoid grapefruit juice during amiodarone treatment because of risk of increased amiodarone plasma levels and toxicity.

Hypotension

Hypotension is the most common adverse reaction seen with IV amiodarone. Hypotension occurs most often during first several hours of treatment and appears to be related to rate of infusion. Monitor infusion rate closely and do not exceed recommended rates of infusion. Treat hypotensive episodes initially by slowing infusion rate; be prepared to provide additional standard therapy (eg, positive inotropic agents, vasopressor drugs, volume expansion).

Liver injury

Hepatic enzyme elevations occur frequently in patients on oral amiodarone, but most patients are asymptomatic. If liver enzyme increase exceeds 3 × ULN, or doubles in patient with elevated baseline, consider discontinuing amiodarone or reducing the dose. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death have been associated with administration of IV amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended; monitor initial concentration of IV amiodarone and rate of infusion closely to avoid exceeding recommended doses and infusion rates. Reduce rate of administration or discontinue IV amiodarone if evidence of progressive hepatic injury noted.

Neonatal hypo- or hyperthyroidism

Congenital goiter/hypothyroidism and hyperthyroidism have been reported in children exposed in-utero to amiodarone.

Ophthalmic effects

Optic neuropathy or neuritis, resulting in visual impairment (in some cases progressing to permanent blindness), has been reported. If symptoms of visual impairment appear, prompt ophthalmic examination is recommended. Appearance of optic neuropathy or neuritis calls for reevaluation of amiodarone therapy. Corneal microdeposits appear in majority of adults and may cause visual halos or blurred vision. Corneal microdeposits are reversible upon dose reduction or termination of treatment.

Peripheral neuropathy

Rare cases of peripheral neuropathy have been reported during chronic amiodarone administration. Discontinuation of amiodarone results in slow and incomplete resolution of symptoms.

Pulmonary toxicity

Acute-onset (days to weeks) pulmonary injury (bronchospasm, cough, dyspnea, fever, hemoptysis, hypoxia, pulmonary infiltrates and/or mass on x-ray, wheezing) has been reported. Some cases have progressed to respiratory failure and/or death. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Any new respiratory symptoms should suggest pulmonary toxicity and history, physical exam, chest X-ray, and pulmonary function tests (with diffusion capacity) should be repeated and evaluated. Reduce dose, or preferably withdraw amiodarone, if pulmonary toxicity is suspected

Skin discoloration

A blue-gray discoloration of exposed skin may occur during long-term treatment. Risk may be increased in patients with fair complexion or those with excessive sun exposure.

Surgery

Patients on amiodarone and undergoing general surgery may be more sensitive to myocardial depressant and conduction effects of halogenated inhalational anesthetics. Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone have been reported.

Thyroid abnormalities

Can cause hypo- or hyperthyroidism. Arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism.

Worsened arrhythmia

Carefully assess potential risks and benefits of coadministering amiodarone with any drug known to prolong the QTc interval, or when treating patients with thyroid dysfunction, because of the possibility of arrhythmia breakthrough or exacerbation of arrhythmia.

Overdosage

Symptoms

Bradycardia, hypotension, life-threatening cardiac arrhythmias.

Patient Information

• Advise patient or caregiver that injectable amiodarone will be prepared and administered by health care provider in a medical setting.
• Advise patient or caregiver to read the Medication Guide carefully before starting therapy, and to read and check for new information each time the medication is refilled.
• Advise patient to take each dose consistently either with or without food. Advise patient to take with food if stomach upset occurs.
• Instruct patient to avoid drinking grapefruit juice while taking amiodarone.
• Instruct patient not to change the dose or stop taking unless advised by health care provider.
• Advise patient that if medication is stopped because of side effects, side effects may persist for a long time because the amiodarone stays in the body for months after treatment is stopped.
• Instruct patient to contact health care provider or seek medical assistance right away if any of the following occur: blurred vision, seeing halos, or eyes sensitive to sunlight; chest pain, coughing, or spitting up blood; difficulty breathing, unexplained shortness of breath, or wheezing; feeling light-headed or faint; feeling more tired than usual; feeling of pins and needles or numbness in hands, legs, or feet; heart pounding, skipping beats, beating very fast or very slowly; muscle weakness, uncontrolled movements, poor coordination, or trouble walking; passing brown or dark-colored urine; persistent nausea, stomach pain, or vomiting; yellowing of skin or eyes.
• Advise patient to notify health care provider if any of the following occur: bluish discoloration of skin; changes in menstruation; heat or cold intolerance; restlessness; swelling or lump in neck; thinning hair; unexplained sweating; unexplained weight loss or gain; weakness; any other bothersome side effect or unexplained feelings.
• Advise patient to avoid unnecessary exposure to direct and indirect sunlight or tanning lamps and to use sunscreen and wear protective clothing to avoid photosensitivity reactions during therapy. Advise patient to discontinue therapy and notify health care provider if any of the following occur following exposure to sunlight or artificial UV light (eg, sunlamp): blistering; itching; rash; redness; sensation of skin burning; swelling.
• Caution women of childbearing potential to avoid becoming pregnant during treatment with amiodarone.

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