Although generic versions of Topamax will soon be available, some neurologists are concerned that the new formulations might be dangerous for patients at high risk of seizure complications.

The Food and Drug Administration approved the marketing of generic topiramate for seizure disorders on April 1, and maintains that generic formulations of any drug must be bioequivalent to the brand formulation. But the agency's accepted bioequivalence range of 80%-125% could put some patients who switch at risk for breakthrough seizures or increased side effects, Dr. Michael Privitera said.

“The FDA's bioequivalence requirements are not based on any strong evidence,” said Dr. Privitera, professor of neurology at the University of Cincinnati and director of the Cincinnati Epilepsy Center. “There are no studies that say people with epilepsy will do well within that range. The FDA could be correct in saying that generic formulations will fall within that range, but there is no way of knowing if that range is good for our patients.”

Generic antiepileptic drugs (AEDs) certainly have a valuable place in medicine, with the potential to save patients thousands of dollars per year while providing excellent seizure control and adverse effect profiles. But the lack of extant data makes it difficult to decide which patients might be the best candidates for a generic formulation, and which might face an unacceptable risk of poor outcomes if they switch, said Dr. Privitera, who disclosed that he has served on advisory boards, consulted, and/or received honoraria and research support from a range of companies that manufacture AEDs, including Ortho-McNeil Neurologics, the manufacturer of Topamax.

Dr. Stuart Black, medical director of the Dallas Headache Association, agreed that the lack of evidence clouds the issue of which patients might experience problems if switched to a generic formulation. “We don't have any data at all on the similar comparison of using a generic antiepileptic for migraine as opposed to a nongeneric,” said Dr. Black, who is also the medical director of neurology and codirector of the Neuroscience Center at Baylor University Medical Center, Dallas.

However, migraine patients have less at stake in the case of a negative outcome, he said. “The consequences of a poor response would be a migraine as opposed to a grand mal seizure. I would personally recommend prescribing brand name AEDs for a patient with a history of epilepsy. In treating patients with migraine, I would inform the patient of the pros and cons of generic versus brand name and include the patient in the decision making process,” said Dr. Black, who said that he has no relevant conflicts of interest.

American Epilepsy Society recommends that generic AEDs should not be substituted for a brand formulation without both physician and patient approval.

The FDA has approved generic topiramate formulations from 17 different companies. Each company has had to show that its formulation is bioequivalent to the original, said Barbara Davit, FDA's acting director of the Division of Bioequivalence 2 in the Office of Generic Drugs. The testing, usually performed in about 40 healthy adult subjects, addresses the new formulations' maximum plasma concentration (Cmax) and area under the plasma concentration time curve (AUC). Both measurements must be within 20% of the original formula; 90% of all the study's pharmacokinetic ratios of generic to brand name compound must fall within the 80%-125% range, she said.

This doesn't mean, however, that the generic drugs' bioequivalence can vary up to 45% from the reference compound. Instead, the ratio is going to be much lower. “We have shown repeatedly that because we are looking at the confidence interval, and not the mean ratio, it forces the reference ratio to be close to 1,” she said in an interview.

In a 2008 review Dr. Privitera wrote on the topic and quoted two FDA reviews of bioequivalence studies, one in 1987 and one in 1997. The papers concluded that the mean difference between the original and generic compounds was 3.5%-4.0% for Cmax and AUC. That difference may be enough to initiate breakthrough seizures or increased adverse events in sensitive patients, he said, especially if the patient is switching between generics—a distinct possibility. Because pharmacies buy large lots of the least expensive generic, patients aren't assured of getting the same generic with each refill. “You might get a medication one month that's stronger than what you get the next month,” he said.

The FDA asserts that there is no conclusive evidence showing that any patient has experienced a lack of seizure control or increased side effects from an AED switch. “That's probably true because if someone has a problem, the doctor is not going to do a full pharmacokinetic study on that one patient. So there is no way of absolutely proving the problem,” Dr. Privitera said.

However, reports of such problems do occur in the literature, he said. “More than 60% of physicians in a 2004 survey believed that they have seen patients experience toxicity or breakthrough seizures with a change to generic” (Epilepsy Behav. 2004;5:995-8).

In his review article (Epilepsy Curr. 2008;8:113-7), Dr. Privitera cited several other studies, including case reports, physician surveys, and a study examining switchback rates after the Canadian Health System approved a number of generic drugs. Among 1,354 patients who took generic lamotrigine, 13% switched back to the brand formulation; the switchback rate for other antiepileptics in the study (clobazam and valproate) approached 20% (Epilepsia 2007;48:464-9). Other studies document increased side effects from generic AEDs.

Although none of these studies examined topiramate, they show that while generic formulations may fulfill the FDA's bioequivalence requirements, they may not be therapeutically equivalent to the original formulation, Dr. Privitera said.

He and other epilepsy experts are working on the protocol for a controlled trial of patients who have been taking the drugs, which he predicts will include about 50 patients for each AED that has a generic equivalent. “We have a contract with the National Institutes of Health to identify people who have problems with these generic formulations and do a rigorous pharmacokinetic study to see if their levels fall within those FDA goal posts,” he said.

The results might lead the FDA to reconsider its requirements for generic AEDs, but might also bolster the use of generics in epilepsy treatment. “A lot of people who might be appropriate candidates for them are not getting them because we don't understand who is and is not at risk when a switch is made.”