PHILADELPHIA – Several different generic lamotrigine products proved pharmacologically and clinically equivalent to Lamictal, the brand-name, reference form of lamotrigine, in three separate, prospective, randomized trials run by two independent groups. These results that should lay to rest lingering concerns by physicians and patients that generic lamotrigine poses any risk to patients, agreed a panel of experts speaking at a session at the annual meeting of the American Epilepsy Society.
The findings, which confirmed the standards now set by the Food and Drug Administration for deeming generic products equivalent to their reference product, should also reassure physicians and patients more broadly about the reliability of the generic forms of most other antiepileptic drugs as well as generic drugs used for virtually all indications across the range of medical practice, the panelists said.
The results of these three new studies “show that generic drugs have the same quality as the reference-listed drugs in patients with epilepsy,” said Dr. Wenlei Jiang, acting deputy director of the FDA’s Office of Research Standards and Office of Generic Drugs. Dr. Jiang coauthored one of the new studies.
Mitchel L. Zoler/Frontline Medical News
Dr. Michel J. Berg (left) and Dr. Michael Privitera
“We were a skeptical group going into our studies,” said Dr. Michael Privitera, coprincipal investigator for the other two new studies. “We were not sure that these drugs [brand-name lamotrigine and various generic products] were really the same. We were shocked at how equivalent they were. It wasn’t that the differences [among their pharmacokinetic profiles] were small; it’s that there was no difference. We could not see any difference,” said Dr. Privitera, professor of neurology and director of the Epilepsy Center at the University of Cincinnati.
“We chose to study lamotrigine because there had been a lot of complaints [about the generic products] and because it is a drug that is very susceptible to drug-drug interactions. There is no reason I can think of why what we found would not extend to all antiepileptic drugs except for phenytoin, which has saturation kinetics and the way the FDA tests drugs in a single-dose study is not appropriate for drugs with saturation kinetics,” Dr. Privitera said in an interview. The implications of the new findings also extend beyond just drugs for epilepsy or other neurologic conditions, he added.
“When you have a very complicated disorder like epilepsy, which has the possibility for drug-drug interactions, and we could show this much quality” in the generic products, it has implications for the entire universe of generic drugs that show equivalence in FDA-mandated testing, Dr. Privitera said.
Randomized trials in epilepsy patients
One of the two studies run by Dr. Privitera and his associates used a single-dose format, and the second used a chronic-dosage format.
The EQUIGEN (Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy) Single Dose Study enrolled 48 epilepsy patients at any of six U.S. centers. All patients were on an antiepileptic drug other than lamotrigine, and the researchers randomized them to receive single doses of the brand-name reference form of lamotrigine (Lamictal), or either of two generic forms of lamotrigine. Patients received single dosages of each of the three study drugs with a 12-23 day washout period separating each dose (the preferred washout interval was 14 days), with the patients and researchers blinded to which specific product was administered at any time. The researchers selected the two FDA-approved generic products with the most widely divergent profiles based on in vitro dissolution testing and prior pharmacokinetic data supplied to the FDA. Forty-five patients received the scheduled two doses (on two different occasions) of each drug, a total of six test doses administered. The remaining three patients received a single dose of each of the three tested products.
All three products resulted in essentially superimposed concentration-time curves and area under the curve measures with no outliers or serious adverse events seen, Dr. Privitera and his associates reported in a poster presented at the meeting as well as during the session.
The EQUIGEN Chronic Dose Study compared the pharmacokinetic patterns after chronic dosing for 2 weeks with one of the two most disparate lamotrigine generic products. The study enrolled 35 patients with epilepsy at any of six U.S. centers, and 33 patients completed all four treatment periods, which involved a repeated crossover between the two study products. Patients received lamotrigine twice daily and could be on additional antiepileptic drugs or monotherapy; six patients received concomitant enzyme-inducing antiepileptic drugs during the study. The results showed that the area under the curve for both products had 90% confidence intervals of 98%-103%, compared with Lamictal, and they both had a 90% confidence interval for peak plasma concentration of 99%-105%, Dr. Privitera and his associates reported at the session. None of the enrolled patients showed unexpected adverse events, and the two generics produced similar adverse-event profiles.