FDA BLACK BOX WARNING
Cordarone (AMIODARONE) 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 life-threatening 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. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months.
The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
FDA BLACK BOX WARNING! INCREASED RISK OF DEATH
In the National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST) (a long-term, multicentered, randomized, double-blind study), in patients with asymptomatic non-life-threatening ventricular (the large chambers of the heart) arrhythmias (rhythm disturbances) who had a heart attack more than six days but less than two years previous, deaths or nonfatal cardiac arrest were seen in 7.7% of those patients treated with encainide or flecainide, members of the Class 1 group of antiarrhythmic drugs, compared to 3.0% in patients receiving an inactive sugar pill or placebo.
Because of the known ability of the Class 1 drugs, such as quinidine, to cause rhythm disturbances, and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening heart rhythm disturbances, the use of the Class 1 drugs should be reserved for patients with life-threatening rhythm disturbances of the ventricles. These warnings now appear in the FDA-approved product labeling, or package insert, for all Class 1 drugs, including: disopyramide (NORPACE and generics), flecainide (TAMBOCOR), mexiletine (MEXITIL and generics), moricizine (ETHMOZINE), procainamide (PROCANBID and generics), propafenone (RYTHMOL), quinidine (DURAQUIN, QUINAGLUTE DURA-TABS, QUINIDEX, and generics), and tocainide (TONOCARD).
When this drug was used to treat rhythm disturbances of the small chambers of the heart (atria), it provided no survival advantage and a higher risk of serious adverse effects than older drugs such as digoxin, the beta-blockers, and the calcium channel blockers diltiazem and verapamil.,
This drug is not approved by the FDA to treat rhythm disturbances of the atria.