The other day I was changing a light bulb in my stairwell and found that I was unable to reach the light fixture without venturing onto the forbidden top step of the ladder. After a quick glance at the bright yellow disclaimer, I cautiously climbed up, changed the bulb, and went on my way. Was that a smart choice on my part? My wife would say no, but
then again, she is happy with the results. Such is the life of a pediatric electrophysiologist. The list of FDA-approved medications, ablation catheters and equipment, and rhythm management devices is prohibitively limited, and yet care continues to be provided.

The term “off-label” is primarily thought of as a medication-related issue, and refers to medication use not included in the label or package insert. This does not mean that its use in pediatrics is illegal or contraindicated, but that insufficient data exists to show safety and efficacy, often leading to the phrase “safety and efficacy in pediatric patients have not been established.” Given the expanding number of medications that are being released on a nearly daily basis, it is difficult to determine the precise number of FDA-approved medication for pediatrics, but it is safe to say that a great majority of medications lack pediatric use information and labeled as such. According to a 2008 study, 62% of outpatient pediatric prescriptions were off-label, and this percentage increased to 96% when looking at only cardiovascular/renal medications. Not surprising, the percentage was highest in children under the age of 6 years.¹

When considering just antiarrhythmic medications, a review of the package inserts produced the following results (See Figure 1.)

Highlighting the recognized disconnect in recommendations, amiodarone is not FDA approved for pediatric use but is incorporated into the American Heart Association’s Pediatric Advanced Life Support (PALS) Algorithm.

The number of pediatric-approved rhythm management devices and electrophysiology catheters is even more limited. Based upon feedback from representatives of three device companies (Boston Scientific, Medtronic, and St. Jude Medical), there is only one pacemaker that is approved for pediatric use, the Microny pacemaker (St. Jude Medical, St. Paul, MN); no leads (epicardial or endocardial) have pediatric approval. Currently, there are no electrophysiology catheters that have pediatric FDA approval for treatment of pediatric arrhythmias.

The obvious question is, “Why haven’t drug/device studies been done on children?” Simply stated, well-designed studies on children are challenging on many fronts. Unfortunately, there is often little economic incentive for a drug/device company to test a product on children given the relatively small increase in profit they would realize from this “orphan” population — especially if the product is already being used off-label. There is also the ethical dilemma of performing studies on a population that cannot provide informed consent. A common response when a parent is approached for a study is “Great idea, but not on my child,” or in the situation where the parent agrees, the child says no (or makes it impossible to administer the med/apply the monitor/determine symptoms…). The FDA has attempted to motivate drug companies to perform drug testing on children in two ways. One is to entice them with economic incentives (i.e., the Food and Drug Administration Modernization Act of 1997 – FDAMA; reauthorized in January 2002 and extended to 2007 as the Best Pharmaceuticals for Children Act – BPCA), which authorize the drug manufacturer to extend market exclusivity by 6 months if pediatric drug testing is performed. The other is strong (if not forceful) urging (the Pediatric Research Equity Act [PREA]), to permit the FDA to necessitate pediatric studies. Despite these efforts by the FDA, drug testing in children remains uncommon unless there is a perceived large market (e.g., cough medicine, analgesics).

In the face of these challenges, care continues to be provided for children with arrhythmia — but how, and at what cost. To start off, one must recognize that children are not small adults. Medications are metabolized differently in children, sometimes requiring relatively larger (based on weight) or more frequent dosing, or conversely smaller or less frequent dosing. In some cases, certain medications should be avoided altogether. Calcium channel blockers, which are an effective anti-arrhythmic in older children and adults, can cause profound heart failure and/or death in newborns (which lack a well-developed sarcoplasmic reticulum). With regard to cardiac rhythm devices, “out of the box” arrhythmia detection parameters for ICDs are often set at heart rates that children routinely reach during normal play, resulting in inappropriate shocks. And, in the catheterization laboratory, radiofrequency ablation has a higher risk of collateral tissue injury (i.e., inadvertent AV node injury) due to their “miniaturized” heart.

Despite these challenges, the world of a pediatric electrophysiologist is extremely rewarding. We will continue to provide the best care possible while we anxiously await more appropriate FDA-approved medications, ablation catheters/equipment, and rhythm management devices for this patient population, and in all likelihood I will continue to cautiously climb onto the top step of my ladder.

Reference:
1. Bazzano AT, Mangione-Smith R, Schonlau M, et al. Off-Label Prescribing to Children in the United States Outpatient Setting. Acad Pediatr 2009;9:81-88.

Dr. Ian Law is located at the University of Iowa Hospital and Clinic in Iowa City, Iowa.