As every parent knows, children are not just little adults. Doctors know this too, but for them it means more than whether children think green ketchup is a good idea. Doctors know that when they prescribe medicine for children, they can't just divide the adult dose by two or three. The way a child's body uses a medicine, the length of time it takes for the medicine to leave the child's body, the side effects that the child will experience, and the effects on a growing child's physical and mental development all may be different from the way the same medicine would affect an adult, or even another child who is older or younger. And when the child has epilepsy, the complications multiply because a child's seizures may be different in cause or effect from an adult's seizures, even if they look similar.
The difficulty for the doctor is that it's hard to find information about prescribing medicines for children. More often than not, the official "package insert" says something like "The safety and efficacy in children under age 16 have not been established." This does not mean that it is unsafe to use this medicine in children or that it won't work for children. It just means that nobody has performed studies ("clinical trials") in which the medicine is tested in large numbers of children. Traditionally, drug companies have regarded testing in children as unnecessary, since the FDA did not require it. It also may be considered too expensive if few children are likely to use the product. Even if the company wants to conduct studies in children, sometimes parents are reluctant to consent, especially if they think their child may be given a placebo instead of the real medication.
The U.S. Food and Drug Administration (FDA) has recognized for many years that the scarcity of information about how to use medicines in children is a problem. Some regulations were put in place in the 1990s with the objective of increasing the number of studies performed using children. One offers an incentive of an additional 6 months of patent protection or exclusivity for all forms of a medication if the manufacturer carries out studies with children according to FDA requirements. As of December 2001, Neurontin (gabapentin), Topamax (topiramate), and Trileptal (oxcarbazepine) had completed this voluntary process and added information about children to their labeling. Lamictal (lamotrigine) has been involved in the process.
Another FDA regulation, called the "Pediatric Rule," was struck down by a federal court in October 2002 and the government has decided to pursue new legislation in Congress rather than appeal the decision. This rule required testing in children under certain circumstances.
Since few seizure medicines have been studied well enough to get official FDA approval for use with children, doctors often do what is called "off-label prescribing." This means prescribing an FDA-approved medicine for a type of disorder or an age group that is not listed on the label as one of the approved uses for that medicine. It is perfectly legal. The FDA does not control how medicines are used. Off-label prescribing also is regarded as safe, as long as the doctor meets the "standard of care" for the community.
As an example of how common off-label prescribing is, consider Depakote (valproate). Depakote is widely viewed as the first-choice seizure medicine for primary generalized tonic-clonic seizures, but it is not approved by the FDA for that purpose, so every doctor who prescribes it does so off-label. Off-label prescribing is especially common when treating newborns and infants (less than 2 years old), because very few medicines are approved for that age group. One recent estimate was that 75 of the 80 medicines most commonly prescribed for newborns and infants were being prescribed off-label.
A particular problem that makes off-label use of seizure medicines even more likely is that new seizure medicines are generally tested in clinical trials as add-on (adjunctive) therapy rather than as medicines that are used alone (monotherapy). Doctors often prefer to use monotherapy to treat their patients because monotherapy usually has fewer side effects, lower cost, and no drug interactions to worry about. But if a seizure medicine has not been approved for monotherapy, that kind of use is off-label.
Not all use of seizure medicines in children is off-label, of course. Besides the widely used older medicines, for which uses and dosages are given for many (but not all) age groups and seizure types, some of the newer seizure medicines also have approved uses for children under 16. (See the list of FDA-approved uses for new AEDs in children under 16.)
Of course, no matter what medicine doctors prescribe, they must carefully calculate the most appropriate dosage for the child's age and weight. Because few clinical trials have tested the use of seizure medicines in children, the doctor must decide on the correct dose based not only on adult doses (which have been tested in clinical trials) but also on experience in using the medicine with other children. Dosages for children are usually expressed as a certain number of milligrams per kilogram per day (mg/kg/day). The "kg" refers to the child's weight in kilograms. One kilogram is about 2.2 pounds, so a 22-pound toddler weighs 10 kilograms and will get 100 mg of medicine each day if the recommended dosage is 10 mg/kg/day.
Parents often worry that their child's medication is too strong or too weak because the number of milligrams in each pill is quite different from the number in another kind of pill. Doctors know that the effective dose of different medicines varies widely. For instance, the usual dose of Trileptal (oxcarbazepine) for a 10-kilogram toddler is 150 mg per day (15 mg/kg/day). But if the doctor prescribed Lamictal (lamotrigine) for the same child, the dose would probably be only 50 mg per day (5 mg/kg/day). This doesn't mean that the Lamictal would be less effective; the two medications are just different. If you are concerned about the dosage of your child's medication, discuss it with the doctor.
Doctors can get information about dosages for children from articles published in medical journals that report on the use of the medicine by children. Not all of the studies reported fit the requirements that would be needed for FDA approval of using that medicine for that particular disorder in children, but they all add some information to the doctor's pool of knowledge. The FDA recently began allowing drug manufacturers to distribute some of these articles to doctors, which should help to increase their knowledge about off-label uses and dosage.
Sometimes doctors want to perform tests to measure the amount of the medication in the child's blood. This is called a "blood level" or "drug level." There is no "right" blood level for all children. Occasionally, knowing the level may help the doctor to tell how the child's body is using the drug and may warn the doctor and parents to be on the lookout for seizures, troublesome side effects, or poor adherence to the schedule of taking the medicine. Most of the time, however, there is no need to measure the blood level. If the child is having frequent seizures and no side effects, the doctor does not need a blood level to know that the dosage should be increased. Similarly, if the child is having trouble with side effects, the dosage should be lowered. Measuring the blood level of medication is very rarely necessary in managing a child's epilepsy.
Topic Editor:Steven C. Schachter, M.D.
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