ARTICLE IN BRIEF
Several new studies are comparing bioavailability and bioequivalence data on brand name lamotrigine and generic forms in patients with epilepsy.
Two FDA-sponsored patient studies could help answer the much-debated question of whether there are bioequivalence differences between generic and name brand versions of antiepileptic drugs (AEDs) that could be problematic for patients who switch among products from various manufacturers.
The studies are different from the usual bioequivalent testing of generics because the research involves evaluation of drugs in epilepsy patients rather than healthy subjects. One study involves the evaluation of two generic versions of lamotrigine. The other is comparing the name-brand product for lamotrigine (Lamictal) to a commonly used generic substitute for the drug.
While there are many documented and anecdotal reports of patients experiencing poor seizure control or side effects when switching from one version of an AED to another, whether or not generics can be problematic for epilepsy patients remains an unanswered question.
The US Food and Drug Administration (FDA) has been considering the possibility of establishing tighter bioequivalence standards for drugs considered to have a “narrow therapeutic index,” meaning there is not much leeway between a therapeutic dose and one that causes side effects or toxicity.
Currently generic drugs must, in bioequivalence testing, produce a blood level of 80 to 120 percent of the level produced by the brand drug, a range that some experts believe is too wide for certain AEDs.
“Many of the concerns raised by professional societies about generic substitution of antiepileptic drugs were supported by anecdotal evidence, so these FDA-funded studies...were designed in collaboration with the National Institutes of Health and the epilepsy community to provide a set of well-controlled data to move the discussion forward,” Kristofer Baumgartner, an FDA spokesperson, told Neurology Today. “The FDA will use the results of the studies to evaluate whether there should be any changes to our bioequivalence recommendations for antiepileptic drugs.”
Some preliminary findings related to the bioequivalence research were presented at the American Epilepsy Society (AES) annual meeting in December in Washington, DC. The topic was also the subject of a town hall meeting at the conference.
Michael Privitera, MD, professor of neurology and director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute, told Neurology Today that the investigators hope that the research being conducted at his institution and elsewhere using epilepsy patients will provide more of a real-world look at the issue of patients switching from one version of an AED to another.
“The FDA's position has been that all these drugs are bioequivalent and interchangeable. So if a patients gets a generic and the next time they go to the pharmacy they get a different generic, the two drugs are equivalent and they don't have to worry,” said Dr. Privitera, who is vice president of the American Epilepsy Society. “But that's not what we have heard from patients and doctors.”
Dr. Privitera study will evaluate two generic versions of lamotrigine that were identified in laboratory and human testing as being at the high and low end of the range for content, uniformity, and dissolution.
Edmund J. Elder, Jr., PhD, a registered pharmacist and director of the Zeeh Pharmaceutical Experiment Station in the School of Pharmacy at the University of Wisconsin, Madison, was one of the researchers who did the laboratory testing, which involved seven different suppliers of lamotrigine and two strengths, 25 mg and 100 mg. In some cases, multiple lots of the same generic product were tested. The goal was to identify the two most different products so they could then be further evaluated in the patient study.
“All the products met the specification for (bioequivalence) laboratory testing in terms of content, uniformity and dissolution,” Dr. Elder said, but there was variability within the acceptable range. The research, funded by the FDA, Epilepsy Foundation, and the AES, even found some variability from lot to lot of a manufacturer's product, he said.
He said there was variability in the time it took the drugs to initially dissolve. As for content, “the products varied from 91 to 110 percent of labeled amount (strength),” all within the allowable range of 90 to 110 percent, he said.
Dr. Elder said lamotrigine is a drug that needs to be carefully dosed because there is “a fine line between the effective dose and the level at which you start seeing side effects.”
Dr. Privitera said some epilepsy patients are outright afraid of taking generics, perhaps unnecessarily so. His two studies, which are ongoing at six different sites, have slightly different designs. The single-dose study, modeled after the FDA's current requirements for generic manufacturers, is testing two different generic products and the brand product in 54 people with epilepsy. Every two weeks for six periods, each participant receives a single dose of either the brand or one of the two generic products, followed by an intense pharmacokinetic sampling of 19 blood levels over 12 hours.
In the chronic dose study, 36 participants take a different generic version of lamotrigine each day for two weeks followed by the pharmacokinetic sampling. The study will determine if people with epilepsy, often taking multiple medications, differ from normal volunteers in their response to generic medication.
“If the drugs are found not to be bioequivalent then there would be a reason to revisit approval criteria used by the FDA to determine bioequivalence,” James E. Polli, PhD, professor and Ralph F. Shangraw/Noxell endowed chair in industrial pharmacy and pharmaceutics at the University of Maryland School of Pharmacy, told Neurology Today.
IS THERE A NOCEBO EFFECT?
Tricia Ting, MD, associate professor of neurology and director of Investigational Drug Trials in Epilepsy at the University of Maryland, said that using epilepsy patients for the bioequivalence study, rather than healthy volunteers, was key to the research because it mimicked real-world clinical circumstances.
The research team is also interested in the “nocebo effect,” that is, that a patient may report experiencing a bad reaction from a drug simply because they anticipate that they might have one.
In a poster presentation at the AES meeting, Dr. Ting and colleagues reported on the case of a man who dropped out of the brand-versus-generic study because he said he was experiencing adverse mood effects and increased focal seizures.
“Throughout the study, the subject exhibited an active awareness to switching between band and generic, albeit not an accurate one,” the researchers reported in their poster presentation.
“Whether a nocebo phenomenon accounts for other epilepsy patients' reported sensitivity to product switching should be considered in further assessments of generics equivalence,” they said.
In another presentation at the AES meeting, researchers from Cincinnati Children's Hospital Medical Center reported on the results of a survey that focused on pharmacists' awareness of issues related to switching AEDs.
Lisa Garrity, PharmD, lead author of the study, told Neurology Today that the research found some positive trends. Of the 30 Cincinnati-area retail pharmacists who responded to the survey, 80 percent said they tried to keep the same antiepileptic drug manufacturer in stock for patients and 87 percent told their patients when a manufacturer was changed. Only about 13 percent, however, reported that they informed prescribers when a manufacturer has been changed.
Dr. Garrity said it's important for patients to be informed about drug switches, but not in a way that suggests there is going to be a problem.
“We don't want to create fear and more anxiety for patients,” she said, “because we know anxiety can be a trigger for seizures.”