SEATTLE – Different generic versions of lamotrigine had essentially the same pharmacokinetics, safety, and efficacy in controlling seizures in a randomized, head-to-head cross-over trial reported at the annual meeting of the American Epilepsy Society.
“There is all this worry about generics, even though the FDA [Food and Drug Administration] says, ‘We do rigorous testing, and these generics are beautiful, and you don’t have to worry, and you don’t have to measure blood levels of anything,’” lead investigator Dr. Michael D. Privitera commented in an interview. And pharmacies often switch patients with epilepsy between generic antiepileptic drug products with little or no notice.
Dr. Michael D. Privitera
“What we tried to do here was sort of a worst-case scenario [comparison] with two different generics that would be the most different, and we demonstrated that they were extremely close,” he said. “Although there are other studies that you need to look at too, from this study, I would say that the risks of switching from generic to generic are probably less than one might anticipate from reading the nonrigorous studies that are out there in the literature.”
To capture real-world conditions, Dr. Privitera and his colleagues of the EQUIGEN (Equivalence Among Generic AEDs) study group designed a practical trial using repeated dosing among epilepsy patients who could be taking other medications. “The FDA does all their studies in normal volunteers using single doses, never people with epilepsy, never somebody taking a drug,” he noted.
In the study, the investigators chose for comparison the two generic lamotrigine products on the market having the most disparate dissolution and content characteristics based on testing, and the most disparate pharmacokinetic profiles based on data submitted to the FDA by the manufacturers for approval. For the latter, the products had the lowest and highest values for the total drug exposure as assessed from the area under the curve (AUC) and for the peak blood concentration (Cmax) that still fell within the permitted 90% confidence interval of 80% to 120% relative to the brand-name drug.
Study participants were 35 adults with epilepsy, with or without comorbidities, who were receiving lamotrigine in a dose that was a multiple of 100 mg, with equal morning and evening doses, as either monotherapy or polytherapy. The sample was enriched in that five of the patients reported experiencing troubles when switching between generics in the past.
“In general, these were not people with high seizure frequency because we really wanted them to be stable and compliant, because compliance is the single most important thing in getting these kinds of numbers,” noted Dr. Privitera, professor of neurology at the University of Cincinnati and director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute.
After randomization to the order of products, patients took the low and high generic products on a blinded basis for four alternating 2-week periods. Compliance was assessed with tablet counts, patient diaries, and computerized compliance caps on bottles. Pharmacokinetics were assessed in each period with serial blood measurements.
Results presented in a poster session showed that none of the patients experienced adverse events or lost seizure control, as assessed from self-reported seizure frequency, when switching between the two generic products, reported Dr. Privitera, who disclosed that he had no relevant conflicts of interest.
Additionally, the two products did not differ significantly in pharmacokinetics, meeting the FDA standards for bioequivalence for both the ratio of their AUC values (90% confidence interval, 98%-103%) and the ratio of their Cmax values (90% confidence interval, 99%-105%). “We didn’t find any outlier group here,” he added.
Findings were essentially the same after controlling for concomitant use of enzyme-inducing antiepileptic drugs, sex, dose, and missing data.
Dr. Privitera speculated that reported difficulties after switches of generic antiepileptic drugs have been because of compliance issues and not the drug products. That is, the differing appearance of various generics may confuse patients, causing them to stop taking the medication, as suggested by recent research (JAMA Intern. Med. 2013;173:202-8), or to take too much.
“The FDA actually wants generic drugs [from different manufacturers] to look different,” he noted. But there has recently been a push from clinicians “to say look, if you are making generic lamotrigine, no matter who manufactures it, it should all look the same, and then people won’t get confused when they go from a blue triangle to a white round to a yellow round.”
The investigators are conducting a similar trial that is comparing brand name drug lamotrigine (Lamictal) with generic versions in patients with epilepsy, but using single doses.