On Package Inserts and Innovation

Every doctor knows of the package insert: the little paper with tons of fine print that is enclosed with medication bottles.

In short: package inserts are the formal "labeling" mandated by the the Food and Drug Administration (FDA) for new drugs.

Recently, I have had a chance to review a package insert in detail for one of the most common antiarrhythmic drugs I prescribe: amiodarone.

I was surprised to find that over my years as an electrophysiologist, that I have been prescribing amiodarone "off label" for every patient I treat with atrial fibrillation, an arrhythmia in the heart's upper chambers. That's because Amiodarone is technically only approved for use in treating lower chamber (ventricular) arrhythmias:

Because of its life-threatening side effects and the substantial management difficulties associated with amiodarone use (see
“WARNINGS” below), Pacerone® (Amiodarone HCl) Tablets are indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other
available antiarrhythmics or when alternative agents could not be tolerated.

1. Recurrent ventricular fibrillation.
2. Recurrent hemodynamically unstable ventricular tachycardia.

That's it. No indication for the treatment of atrial fibrillation or other supraventricular tachycardias (SVT's)... just ventricular fibrillation and ventricular tachycardia.

Not that this was a problem when the package insert was first developed. At that time, the original package contained the prevailing knowledge about the drug based on carefully developed clinical trials. The information was carefully reviewed by federal regulators to assure the prescribing information was as up to date and informative as possible. Every known problem with the drug was carefully mentioned to protect patients as much as possible. No doubt, that was a laudible goal.

But doctors later recognized the effectiveness of amiodarone to treat certain supraventricular arrhythmias like atrial fibrillation and quickly moved to adopt the drug into their therapeutic armamentarium. Case reports came first, then clinical trials - soon a new indication for the drug was born.

Cardiologists or electrophysiologists cannot follow the package insert recommendations for Amiodarone (or many other drugs) when they feel Amiodarone is the best drug to treat atrial fibrillation. But here we are years after the package inserts were developed, treating a huge number of patients with atrial fibrillation with a drug technically not approved for that indication by the FDA.

Fortunately, professional organizations have come to our support the cause by issuing clinical "guidelines" acknowledging the real world clinical use of amiodarone treatment:

Although amiodarone is not approved for use in the treatment of atrial fibrillation (AF) by the FDA, it is the most commonly used antiarrhythmic drug for this purpose. This is based on 1 year efficacy rates for maintaining sinus rhythm of greater than 60%, compared to 50% or less for other antiarrhythmic agents.

Yet we cannot help but note that the above FDA package insert for amiodarone (Pacerone) was revised "0508" (which I can only assume meant May, 2008), well after these non-FDA clinical guidelines were written.

Which leads me to several considerations:

1) It appears there is no incentive for government agencies to modify published package inserts or recommendations for therapy after market release despite safety and efficacy data to the contrary.

2) With compensation for cost-effective therapies increasingly tied to doctor "performance" using "state of the art information," will incentives for innovative new therapies diminish as a result?

3) Finally, if clinical innovation is somehow preserved, we can only wonder if government-controlled recommendations for therapies proposed in the immediate future by MEDPAC (that also reguire approval by Congress) will ever be updated once they become etched in policy stone - much like we see now with drug package inserts. Will we ever be able to advance care to our patients when new therapeutic recommendations surface without a literal act of Congress?

If our history with package inserts is any indication, it seems doubtful.

-Wes