Amiodarone (Cordarone, Pacerone) is the most effective, and certainly, the strangest, antiarrhythmic drug ever developed. (Here is a review of the unusual efficacy and the unusual side effects of amiodarone.) One of the strangest aspects of the drug is its history. It is a history that explains much about why, to this day, many of the more unusual features of the drug are poorly understood by many doctors who prescribe it.

Development

Amiodarone was developed by a Belgian company in 1961 as a drug for treating angina (chest discomfort related to coronary artery disease) and quickly became a popular anti-angina drug in Europe and South America. However, by the choice of the drug company (probably to avoid the unusually tough American regulatory environment), amiodarone was not offered for release in the United States.

After a few years a physician in Argentina, Dr. Mauricio Rosenbaum, noticed that amiodarone seemed to reduce cardiac arrhythmias in his patients with heart disease. He began using the drug extensively for heart rhythm disturbances and then began to publish his results, which were extraordinarily impressive. Clinicians from all over the world (except in the United States) quickly began using the drug to treat cardiac arrhythmias of all sorts. The reputation of amiodarone spread far and wide—amiodarone, the word was, was a unique antiarrhythmic drug that almost always worked, and had virtually no side effects.

Both of these assertions, of course, proved false.

Use in America

Beginning in the late 1970s, American electrophysiologists (heart rhythm specialists) began to obtain amiodarone from Canada and Europe to use in their patients with life-threatening arrhythmias who did not respond to any other drugs. (The FDA sanctioned this activity on a compassionate-use basis.) The early word from Americans seemed to confirm what was being said all over the world—amiodarone was very safe and very effective.

Within a few years, more than 10,000 American patients with potentially lethal arrhythmias were estimated to be receiving amiodarone. Of course, because of the way amiodarone was being distributed, nobody really knew how many patients were receiving the drug. More importantly, because the FDA was not involved in any of this (except to approve of the use of the drug for compassionate reasons), nobody was compiling information on the drug's effectiveness or safety.

Side Effects Discovered

However, many American doctors studied the effects of amiodarone on their own patients somewhat more rigorously than our overseas colleagues had done. As a result, within a year or two, our view of amiodarone began to change. Amiodarone was indeed more effective at suppressing arrhythmias than any other drug we had ever seen (though by no means as effective as had been advertised), but it produced a bizarre series of side effects including difficult thyroid disorders, skin discoloration, and potentially life-threatening lung toxicity that doctors around the world seemed to have "missed." The side effects had been missed, for the most part, because they were so unusual and unexpected and because their onset tended to be insidious and late.

When the side effects of amiodarone began to be described in medical publications, the FDA became reluctant to approve the drug. However, the FDA soon had little choice. In the mid-1980s, the foreign manufacturers of amiodarone threatened to cut off the American supply (not entirely unreasonably, since they had supplied free drugs to thousands and thousands of Americans for more than 5 years). Simply cutting Americans off from the drug would produce a medical (and hence, possibly a political) disaster. So, in 1985, in sharp contrast to any other drug in modern history, amiodarone became FDA-approved without rigorous, FDA-sanctioned randomized clinical trials.

FDA Approval

Respectful of the drug's newly-discovered and very troublesome toxicity, the FDA approved the drug only for life-threatening arrhythmias for which no other treatment was feasible, and required a black-box warning regarding its dangerous side effects. Noting that the drug was indeed very effective for non-life-threatening arrhythmias, the FDA urged the manufacturers to conduct randomized clinical trials to gain formal approval for indications such as atrial fibrillation, noting that conducting such trials would teach us much about true incidence and seriousness of the drug's side effects. Those trials were never done (possibly because such trials are very expensive, and by this time the patent on amiodarone was expiring, opening the door for generic manufacturers to begin selling it), and the original restrictions on the use of amiodarone have persisted to this day.

And as a result, the use of amiodarone for atrial fibrillation (the most common reason it is prescribed today) remains off-label.

The Bottom Line

The strange history of amiodarone may explain why some doctors who prescribe this drug seem unaware of the breadth and the subtle nature of many of its side effects and why some of them do not adequately monitor their patients who take amiodarone or fully inform their patients as to what to watch out for. Everyone taking prescription drugs ought to make themselves aware of possible side effects so they can help their doctors recognize when those side effects may be occurring. This general rule is doubly true for amiodarone.