Side Effects of Cordarone (amiodarone)

Cordarone (amiodarone) is an antiarrhythmic medication used to correct abnormal rhythms of the heart. 

Cordarone is considered a “broad spectrum” antiarrhythmic medication, that is, it has multiple and complex effects on the electrical activity of the heart which is responsible for the heart's rhythm. 

In addition to being an antiarrhythmic medication, Cordarone also causes blood vessels to dilate (enlarge). This effect can result in a lowering of blood pressure. Because of this effect, Cordarone also may be of benefit in patients with congestive heart failure.

Common side effects of Cordarone include:

• fatigue,
• eye deposits,
• tremor,
• unsteady gait,
• nausea,
• vomiting,
• constipation,
• weight loss,
• dizziness, and
• visual changes.

Serious side effects of Cordarone include:

• heart block,
• low blood pressure,
• scarring of the lungs (pulmonary fibrosis),
• heart failure,
• cardiac arrest,
• hypothyroidism or hyperthyroidism,
• blue skin discoloration,
• liver failure, and
• cardiogenic shock.

Drug interactions of Cordarone include beta-blockers or calcium channel blockers, resulting in an excessively slow heart rate or a block in the conduction of the electrical impulse through the heart. 

Blood levels of are increased when these drugs are combined with Cordarone:

• digoxin,
• flecainide,
• procainamide,
• quinidine, and
• phenytoin. 

These can inhibit the enzyme that is responsible for the metabolism of Cordarone in the body:

• ritonavir,
• tipranavir,
• indinavir, and
• saquinavir. 

Tricyclic antidepressants and phenothiazines can potentially cause serious arrhythmias when combined with Cordarone. 

Warfarin when taken with Cordarone increases the risk of bleeding. 

Cordarone combined with cholesterol-lowering “statin” drugs can increase the side effects of statins. 

Cordarone inhibits the metabolism of dextromethorphan. 

Grapefruit juice may reduce the breakdown of a Cordarone in the stomach leading to increased amiodarone blood levels. 

Cordarone should not be used during pregnancy because it can harm a fetus. There have been reports of congenital hypothyroidism or hyperthyroidism when Cordarone was administered during pregnancy. 

Cordarone is excreted in breast milk and may cause adverse effects in the infant. Breastfeeding should be discontinued by mothers receiving Cordarone.

WARNING

• Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.
• Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time.
• Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases.
• Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse.
• This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%.
• All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur.
• Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be lifethreatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.
• The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients.
• Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more.
• Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment.

Common side effects

Common side effects include:

• fatigue,
• eye deposits,
• tremor,
• unsteady gait,
• nausea,
• vomiting,
• constipation,
• weight loss,
• dizziness, and
• visual changes.

Amiodarone is also associated with:

• heart block,
• low blood pressure,
• pulmonary fibrosis (scarring of the lungs),
• heart failure,
• cardiac arrest, hypothyroidism or hyperthyroidism,
• blue skin discoloration,
• liver failure, and
• cardiogenic shock.

The following serious adverse reactions are described in more detail in other sections of the prescribing information:

• Pulmonary Toxicity
• Hepatic Injury
• Worsened Arrhythmia
• Visual Impairment and Loss of Vision
• Thyroid Abnormalities
• Bradycardia
• Peripheral Neuropathy
• Photosensitivity and Skin Discoloration

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

At the usual maintenance dose (400 mg/day) and above, Cordarone causes adverse reactions in about three-fourths of all patients, resulting in discontinuation in 7 to 18%.

In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included:

• pulmonary infiltrates or fibrosis,
• paroxysmal ventricular tachycardia,
• congestive heart failure, and
• elevation of liver enzymes.

Other symptoms causing discontinuations less often included:

• visual disturbances,
• photosensitivity,
• blue skin discoloration,
• hyperthyroidism, and
• hypothyroidism.

The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days):

Thyroid

Common: Hypothyroidism, hyperthyroidism.

Cardiovascular

Common: Congestive heart failure, cardiac arrhythmias, SA node dysfunction.

Gastrointestinal

Very common: Nausea, vomiting.

Common: Constipation, anorexia, abdominal pain.

Dermatologic

Common: Solar dermatitis/photosensitivity.

Neurologic

Common: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias, decreased libido, insomnia, headache, sleep disturbances.

Ophthalmic

Common: Visual disturbances.

Hepatic

Common: Abnormal liver-function tests, nonspecific hepatic disorders.

Respiratory

Common: Pulmonary inflammation or fibrosis.

Other

Common: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.

Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Cordarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematologic: hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma.

Immune: anaphylactic/anaphylactoid reaction (including shock), angioedema.

Neurologic: pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), demyelinating polyneuropathy.

Psychiatric: hallucination, confusional state, disorientation, delirium.

Cardiac: hypotension (sometimes fatal), sinus arrest.

Respiratory: eosinophilic pneumonia, acute respiratory distress syndrome in the post-operative setting, bronchospasm, bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, pleural effusion, pleuritis.

Gastrointestinal: pancreatitis, acute pancreatitis.

Hepatic: hepatitis, cholestatic hepatitis, cirrhosis.

Skin and Subcutaneous Tissue Disorders: urticaria, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, pruritus, skin cancer, lupus-like syndrome.

Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis.

Renal: renal impairment, renal insufficiency, acute renal failure.

Reproductive: epididymitis, impotence.

Body as a whole: fever, dry mouth.

Endocrine and metabolic: thyroid nodules/ thyroid cancer, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Vascular: vasculitis.

Because of amiodarone's long half-life, expect drug interactions to persist for weeks to months after discontinuation of amiodarone.

Drug interactions with amiodarone are described in Table 1 below.

Table 1: Amiodarone Drug Interactions