Evaluating the Bioequivalence of Generic Lamotrigine for Epilepsy
Patients with epilepsy may resist switching to a generic for fear of breakthrough seizures.
Generic versions of the antiepileptic drug (AED) lamotrigine were found to be bioequivalent to the brand-name version of the drug, according to results of the Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) study, published in JAMA Neurology.1 EQUIGEN was a single-dose, crossover, prospective, sequence-randomized, replication pharmacokinetic study sponsored by the US Food and Drug Administration (FDA) to assess bioequivalence in cost-effective generic AEDs.
A total of 50 patients were enrolled from 5 academic epilepsy centers across the United States (mean age, 46 years; 57% men; 86% white). They were each randomly assigned to 1 of 3 sequences made up of 6 study periods of 96 hours each. The participants had baseline blood samples drawn before being given a single 25-mg dose of a study drug at 20-minute intervals for 4 hours, and then at multiple times up to 12 hours and daily draws up to 96 hours after dosing for a pharmacokinetic (PK) profile of each drug in each patient.
The comparison drugs included a branded form of immediate-release lamotrigine and 2 disparate generics from different manufacturers. The study protocol was designed to assess each of the 3 study drugs twice in each patient; 46 patients completed all 6 assessments, and 3 more completed the first 3 assessments.
The investigators observed "essentially identical PK values" in the cohort across all 3 agents tested and noted specifically that the differences in bioavailability between the brand-name drug and the 2 generics was <5%, which is well within the acceptable range for narrow-therapeutic index drugs. Bioequivalence was established because the 90% CIs of relative bioavailabilities were between 80% and 125% equivalence limits. Consistency across the 46 replicated studies indicated a lack of significant variations in per patient pharmacokinetic response to the 3 drugs.
In an editorial,2 Gregory M. Krauss, MD, observed that the issue of generics in epilepsy is of particular concern to patients who have to weigh fears of breakthrough seizures or significant adverse effects against the burden of high-cost brand-name drugs such as Trileptal, at $14.81 per tablet, where a version generic costs only 90 cents. Dr Krauss reported that the percentage of patients who switch back to brand-name agents from generics is unusually high, at 20% to 44%.3
The current study indicated that the 2 generics tested should provide the same level of efficacy and safety as the original brand-name agent. "This reassurance might reduce 'nocebo' responses in patients who are anxious about losing seizure control," Dr Krauss wrote.
- Berg M, Welty TE, Gidal BE, et al. Bioequivalence between generic and branded lamotrigine in people with epilepsy: the EQUIGEN randomized clinical trial [published online June 27. 2017]. JAMA Neurol. doi:10.1001/jamaneurol.2017.0497
- Krauss GL. Potential influence of FDA-sponsored studies of antiepilepsy drugs on generic and brand-name formulation prescribing [published online June 27, 2017]. JAMA Neurol. doi:10.1001/jamaneurol.2017.0497
- LeLorier J, Duh MS, Paradis PE, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology. 2008;70:2179-2186.