Reassurance on Generic Lamotrigine Bioequivalence

July 07, 2017

Reassurance as to the bioequivalence of generic formulations of the antiepileptic drug lamotrigine with the branded product, Lamictal (GlaxoSmithKline), has come from a new study sponsored by the US Food and Drug Administration (FDA).

The study showed that two disparate lamotrigine products – selected as the two products available that were most different from the brand name product, as determined on the basis of laboratory tests – were bioequivalent to Lamictal when tested in patients with epilepsy who were taking concomitant antiepileptic drugs.

"We went into this project with uncertainty about the generics, as there had been a lot of concern raised about them. Our study has satisfied me that there isn't an issue with generic lamotrigine," lead author Michel Berg, MD, University of Rochester School of Medicine and Dentistry, New York, told Medscape Medical News.

"Because of all the concerns raised, I used to be reluctant to prescribe this drug generically, but I'm not anymore. I now prescribe this drug generically, and everyone saves money as a result.

"There is the odd patient who I would still prescribe the brand name drug – those that are allergic to fillers or dyes used in other formulations, or occasionally a patient is psychologically completely dependent on having exactly the same tablet and gets very confused if it looks different ― but these are only a handful of individuals," he added.

The study was published online June 26 in JAMA Neurology.

For the six-way crossover study, 50 patients received single doses of Lamictal (25 mg immediate release) and the two generic formulations. Replicate testing was performed to evaluate underlying variability in absorption. Maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were compared.

Results showed that the three drug products were bioequivalent, because the 90% confidence intervals (CIs) were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC, 96.9% and 101.9%).

Dr Berg pointed out that they studied single doses, which is thought to be the most sensitive method to discern problems regarding bioavailability, and to reflect real-world situations, they studied the drugs in patients with epilepsy who were concomitantly taking other medications.

"One of the criticisms that has been leveled at the FDA is that they only require bioequivalence studies in healthy volunteers, so we wanted to address that," he said.

The researchers conducted a replication study – each formulation was given twice several weeks apart. Interestingly, they found very large differences in bioavailability between exactly the same drug in the same patient – a 15% variation in Cmax, and an 8% difference in AUC.

"This is the normal biological difference in each individual person and may account for some of the concerns raised. This was a surprise to me, but it shows how biological processes vary within the same individual at different times," said Dr Berg.

Findings "Reassuring"

In an accompanying editorial, Gregory L. Krauss, MD, Johns Hopkins University, Baltimore, Maryland, notes that two other FDA-sponsored studies have been conducted on generic lamotrigine formulations. One study evaluated bioequivalence during long-term dosing with Lamictal and two generic lamotrigine formulations and found that the steady state concentrations for the generic and brand name formulations were nearly identical.

The other study showed that for patients with brittle epilepsy, defined as epilepsy associated with seizures or possible adverse drug effects during lamotrigine therapy, lamotrigine concentrations were similar during long-term dosing with a generic lamotrigine formulation and Lamictal and that seizures or adverse drug effects were the same with generic and brand name treatments.

The three studies together are "reassuring" and "suggest most patients with epilepsy can safely be treated with inexpensive generic lamotrigine formulation rather than the brand name formulation," Dr Krauss notes.

However, he points out that lamotrigine is among the most well-absorbed and well-tolerated antiepileptic medications, and the FDA studies did not include drugs with more problematic pharmacologic properties, such as low solubility (carbamazepine), nonlinear kinetics (phenytoin), prodrug features (oxcarbazepine), and narrower ranges of tolerated and effective concentrations (all three of these drugs).

Dr Krauss also suggests that other generic lamotrigine products that were not tested in these studies may have different bioequivalence ranges.

Dr Berg responded that he believes the results can be applied to all generic lamotrigine formulations.

"We very deliberately attempted to identify the two generic formulations that were the most different based on independent laboratory tests on dissolution, chemical assay, etc. We purchased all the various different generics ourselves, so the manufacturers didn't have any control. However, we were constrained somewhat by what was available at the time," he said.

"Although there are said to more than 30 different generics approved, we could only source around 10 to 12 at the time of the study. This happens with generics – they are not all available all the time. I don't think it is necessary to restrict our conclusions to just those two products. It wouldn't be practical to do that.

"We would have liked to have studied all the different antiepileptic drugs and all the different generic formulations of each one, but you have to be practical. We studied lamotrigine because it is a popular antiepileptic agent, and this was the drug that was causing concerns regarding generics. The complaints were anecdotal and included reports of increased seizures on switching to generic, increased healthcare utilization, and patients switching back to the branded product," he added.

Asked what the reason could have been for the concerns regarding generic lamotrigine, given that this study revealed no problems regarding bioequivalence, he said, "There's always been a history of brand manufacturers raising concerns about generics. This is probably no different."

This study was funded by the FDA, the Epilepsy Foundation, and the American Epilepsy Society. Dr Berg is a site investigator for industry-sponsored research by Upsher-Smith Laboratories, Sunovion, Neuropace, Lundbeck, Pfizer, King Pharmaceuticals, Sage Therapeutics, and Acorda Therapeutics. Dr Krauss has disclosed no relevant financial relationships.

JAMA Neurol. Published online June 26, 2017. Abstract, Editorial

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