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Original Investigation
August 2017

Bioequivalence Between Generic and Branded Lamotrigine in People With EpilepsyThe EQUIGEN Randomized Clinical Trial

Author Affiliations
  • 1Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York
  • 2College of Pharmacy and Health Sciences, Drake University, Des Moines, Iowa
  • 3School of Pharmacy and Department of Neurology, University of Wisconsin–Madison
  • 4Department of Biostatistics, The University of Kansas Medical Center, Kansas City
  • 5Department of Neurology, University of Alabama at Birmingham
  • 6Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 7Department of Neurology, University of Pennsylvania, Philadelphia
  • 8Zeeh Pharmaceutical Experiment Station, University of Wisconsin–Madison
  • 9Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, MD
  • 10SuccinctChoice Medical Communications, Chicago, Illinois
  • 11Department of Neurology, University of Cincinnati Medical Center, Cincinnati, Ohio
JAMA Neurol. 2017;74(8):919-926. doi:10.1001/jamaneurol.2017.0497
Key Points

Question  Are branded-to-generic and generic-to-generic lamotrigine switches bioequivalent in people with epilepsy?

Findings  In this randomized clinical trial involving 50 adults with epilepsy, bioequivalence between branded and generic lamotrigine products was established for 2 key pharmacokinetic measures (area under the concentration–time curve and maximal concentration).

Meaning  Branded and generic lamotrigine products can be substituted with an expectation of bioequivalence.

Abstract

Importance  Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs.

Objective  To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products.

Design, Setting, and Participants  The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses.

Interventions  Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected.

Main Outcomes and Measures  The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%).

Results  Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76).

Conclusions and Relevance  This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs.

Trial Registration  clinicaltrials.gov Identifier: NCT01733394

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