Stricter bioequivalence rules may be needed for generic antiepilepsy treatments

Ongoing studies may lead FDA to stiffen its bioequivalence rules for generic antiepileptic drugs (AEDs) and others with so-called narrow therapeutic indices, according to research presented at the American Epilepsy Society (AES) annual meeting recently in Washington, D.C., according to MedPage Today.

“The findings presented at the meeting were small projects related to the Equigen project, which is a series of studies funded by FDA, Epilepsy Foundation, and American Epilepsy Society on the switch-ability and bioequivalence of currently approved generic antiepileptic drugs in people with epilepsy,” explained Michael Privitera, MD, of the University of Cincinnati and the AES’s vice president, who is leading some of the new studies.

The Equigen project required researchers to first identify the most disparate generic drugs that are currently approved by FDA (based on pharmacokinetic parameters). There are two ongoing Equigen studies comparing the “low range” versus “high range” versus brand in people with epilepsy.

“The studies presented showed the results of our analysis of tablet content and variability of many different generic products of lamotrigine, and the method we established on how to identify the ‘most disparate’ for the Equigen studies,” he said.

FDA is funding 2 studies, both involving lamotrigine (Lamictal): One will examine single-dose pharmacokinetics of 2 different generic versions in 54 patients with epilepsy, and the other will test 2 generic versions in 36 patients when dosed daily for approximately 2 weeks.

Lamotrigine was a reasonable choice, apparently because it has been the source of many physician and patient complaints about generic equivalence.

All the approved generic lamotrigine products (10 different 100-mg products and eight different 25-mg products) were within FDA’s current regulatory range for number of milligrams of medication in the tablet, but did range from approximately 91 mg to 107 mg for a 100-mg tablet.

“Combining the ANDA data from FDA with our independent laboratory analysis allowed us to choose generic products for the Equigen studies,” Dr Privitera said.

More than 1 million tablets of generic antiepileptic medication are taken daily by people in the United States, according to Dr Privitera.

“FDA regulations allow pharmacies to switch these products at any time, so a patient may find his or her generic manufacturer was switched at any refill,” he said. “There are many reports in the medical literature of problems with loss of seizure control or adverse effects when patients are switched, but these have not been documented by rigorous studies. The Equigen studies are testing the switch-ability of multiple products under highly rigorous scientific conditions.”

These are the first studies to combine multiple different tests of generic products to determine the two generic products that may be the most risky to switch. “The ongoing Equigen study will better analyze these risks,” he said. 


“Generic antiepileptic drugs are safe and effective for the majority of patients,” Dr Privitera said. “We are testing whether the current regulations for antiepileptic drug generic approvals are sufficiently rigorous to protect all people with a serious disease like epilepsy. So far we are finding moderate variability among these generic products, but the Equigen study will answer these questions more completely.”