ARTICLE IN BRIEF
✓ The AAN and the Epilepsy Foundation argue against allowing pharmacists to switch patients to generic epilepsy drugs without the consent of physicians.
With four major brand-name antiepileptic drugs (AEDs) scheduled to lose patent protection by 2010, epileptologists are concerned about the possible effects of generic substitution on patients.
The issue of generic switching for epilepsy drugs made front-page news in the Wall Street Journal in a July article about the Epilepsy Foundation's efforts to get state legislatures to make it harder for pharmacists to switch patients to generic epilepsy drugs, which cost less than brand-name drugs. The AEDs scheduled to lose patent protection are: divalproex sodium (Depakote), manufactured by Abbott Laboratories; oxcarbazepine (Trileptal), sold by Novartis; topiramate (Topomax), produced by Ortho-McNeil Neurologics, a division of Johnson & Johnson; and levetiracetam (Keppra), manufactured by UCB Pharmaceuticals, Inc.
Several states and health-care plans require pharmacists to fill prescriptions with the least expensive available drug. The Epilepsy Foundation backs legislation, now pending in Ohio and Massachusetts, which would require a doctor's permission for a pharmacist to switch a patient to a different epilepsy drug, including brand to generic or generic to another generic drug.
Tennessee passed a similar bill this year. A less comprehensive bill was enacted in Illinois last year; a more detailed version, introduced this year, hasn't won approval. AED legislation was also introduced this year in Florida, Connecticut, and 22 other states, but the bills either did not come to a vote or did not win approval.
The Wall Street Journal article pointed out that the Epilepsy Foundation, a nonprofit group, receives funding from GlaxoSmithKline, Abbott Laboratories, and Johnson & Johnson, companies that manufacture epilepsy drugs.
WHAT EPILEPTOLOGISTS THINK
However, for epileptologists, the issue is about the disparity between how AEDs work and the FDA requirements for generic equivalents.
The FDA requires that generics be bioequivalent, meaning they perform in the same manner as the innovator drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the brand-name drug, within a 90 percent confidence interval of 80- to 125-percent.
The confidence interval is fine for brand-to-generic conversion, but what concerns Jacqueline A. French, MD, professor of neurology at the University of Pennsylvania, is the potential for variability from generic to generic, which may not stay within these same bounds.
She explained that if generic A is on the high range of the confidence interval of 80- to 125-percent of the brand name and generic B is on the low range of the confidence interval of 80- to 125-percent, the two drugs may not be within 80- to 125-percent of each other.
In a 2002 studied published in Epilepsy and Behavior (3(6):522–525), researchers pointed out that one form of generic carbamazepine, manufactured by Pharmaceutical Basics/Colmed, had a mean bioavailability of 95 percent, with a range of 80- to 142-percent. Another product, manufactured by Lemmon Company (now Teva Pharmaceuticals), had a mean bioavailability of 88 percent, with a range of 74- to 108-percent.
[Dr. French noted that the confidence intervals for both examples would not be acceptable today, because neither is within the 80- to 125-percent range.]
“Theoretically, patients could take the Lemmon product with a bioavailability of 74 percent and then receive the Pharmaceutical Basics/Colmed product with a bioavailability of 142 percent, nearly doubling their effective dosage,” the study authors wrote.
“It's known that patients can be, and frequently are, switched from one generic to another, if more than one generic is available,” Dr. French said. “So this is not just a question of switching from brand to generic. It's a question of switching from generic A to generic B to generic C to generic D.”
Epileptologists emphasize to their patients the necessity of taking medications on time to maintain consistent drug levels at receptor sites in the brain, but “patients aren't always wonderful about that,” Dr. French said.
Generic switching may mean even less consistency in the medication regiment. “You're only protected when the drug is in the brain receptor site,” Dr. French said. “If there's less drug there, then you may be at risk for having a seizure. It won't happen every time the level is low, but it puts you at risk. It's like playing Russian roulette. Most of the time, the chamber is empty, but if there's a bullet there, there's going to be a problem.”
AEDs have a narrower “therapeutic window” than many other drugs, putting patients at risk both when levels are too low and when they are too high, according to Kimford J. Meador, MD, the Melvin Greer Professor of Neurology at the University of Florida and the director of the Epilepsy Program.
“A drug level depends on a combination of the dose, absorption, distribution, metabolism, and excretion speed. Some drugs are hepatically metabolized, and some are excreted by the kidneys,” he said. “If the level drops down, you are open to the risk of seizure. If the level is too high, you can be vulnerable to drug toxicity.”
Dr. Meador pointed out that consistency in dosage levels becomes even more crucial for patients on low doses of AEDs, such as female patients who want to become pregnant. If a dip in drug levels leads to breakthrough seizures, the implications are serious. “If you have a seizure, you may get injured, lose your driver's license for six months, or even die,” said Dr. Meador.
Several commonly used brand-name AEDs have already had their patents expire and are available in generic forms, including phenytoin (Dilantin), carbamazepine (Tegretol), zonisamide (Zonegram), lamotrigine (Lamictal), and valproate (Depakote).
Dr. Meador has seen a few cases of breakthrough seizures and toxicity in patients who had AEDs switched to generic without their knowledge. “We asked them to bring in the prescription bottles, and we found the drug had been changed,” he said.
Dr. French said she has a young patient whose mother pays $800 every three months to refill her AED prescription with a name-brand medication rather than with the generic formulation, which costs $30. “She's thinking, ‘If I am not willing to pay this money and I switch to generic and something happens, how will I forgive myself?’”
The AAN board of trustees approved a position paper in November 2006 opposing generic substitution of AEDs without the knowledge and consent of the treating physician and patient (Neurology 2007;68:1249–1250).
“We are not anti-generic,” said Kore Liow, MD, the lead author of the AAN position paper and a member of the AAN State Affairs committee, which sponsored the AED position statement. “We are for generics in the proper situation, and we are for cost savings,” said Dr. Liow, a clinical associate professor in internal medicine at the University of Kansas School of Medicine in Wichita. “But we need to be clear that epilepsy is different from other conditions. Patients who are switched to generics without their knowledge or their physician's knowledge are at an extreme disadvantage.”
AAN officials decided to develop a position statement on AED switching after hearing “a lot of concern” from members about the issue, said AAN Chief Health Policy Officer Rod Larson.
The AAN does not hire lobbyists, but has conducted grassroots lobbying and advocacy to educate policymakers about the pros and cons of AED legislation. “We work through state neurology societies and groups of physicians who organize on the state level on letter-writing campaigns,” Larson said. “When the issue comes up in states, we alert our members and provide them with background information and resources.”
As a membership-dues organization, the AAN does not accept external funding for its advocacy efforts and clinical practice guidelines development. The organization's guidelines do permit grants from the pharmaceutical industry for its annual meeting, some educational events, and other programs, including guideline dissemination, according to Larson.
The FDA stands by its review of generic drugs. “The FDA has not seen persuasive evidence that switching to generic drugs causes seizures and the FDA believes each generic is equivalent to the brand-name drug it copies,” said Sandy Walsh, of the FDA Office of Public Affairs in an e-mailed statement to Neurology Today. The statement said the agency “is aware” of the concerns of epilepsy groups and monitors reports of potential inequivalence. “The FDA recommends conducting a thorough study in this area.”
There are challenges to designing an appropriate study, according to Dr. French. A randomized study comparing patients who stayed on the name-brand drugs and patients who switched to a generic equivalent might not attract many subjects. “If you're already on the name brand, you may not be interested in the possibility that you'd be given the generic,” she said.
One solution, she said, may be to mandate that patients get the same generic every time they refill their prescription. However, the logistics of that may be difficult, because pharmacy-purchasing patterns are generally based on the cheapest generic available at a given time.
The FDA encourages people with epilepsy and physicians to report breakthrough seizures resulting from generic switching to the FDA's MedWatch program at www.fda.gov/medwatch or 1-800-FDA-1088.