The American Epilepsy Society (AES) collaborated with the Epilepsy Foundation and the U.S. Food and Drug Administration to initiate well-designed, prospective studies of generic antiseizure medication (ASM) substitution. Four studies of lamotrigine demonstrated bioequivalence of generic products in patients with epilepsy taking concomitant ASMs.1-4 Additionally, an analysis of Abbreviated New Drug Application (ANDA) data determined that generic products of branded modified-release products (e.g., extended-release, delayed release) are bioequivalent with minor variability for a large majority of clinical study participants and therefore are safely interchangeable.5 Results from these studies have shown no difference in bioequivalence when switching from a brand to generic product or between multiple generic products. These studies confirm that the United States Food and Drug Administration (FDA) standards for determination of bioequivalence are appropriate for patients with epilepsy.
The AES offers its support of the following principles concerning the continuity of ASMs for adults and children with epilepsy:
- The AES recognizes that drug formulation substitution with FDA-approved generic products usually reduces cost and the most rigorous and reliable studies that have been performed to date have found no evidence of a compromise to efficacy.
- The AES supports ongoing research by the FDA to study factors (e.g., extended-release products, tablet or capsule color and shape, nocebo effect) related to the generic substitution of ASMs in adults and children.
- When dispensing medications to patients, healthcare professionals should ensure that a bioequivalent FDA-approved generic product is substituted for the brand or another generic ASM. For example, an immediate-release generic product should not be dispensed as a substitute for a delayed-release or an extended-release product without the knowledge of the prescribing provider.
- Based on data showing that changes to tablet or capsule color or shape and that statements about drug products impact patient adherence and drug response, healthcare professionals should exercise the highest standards of care when substituting generic products.6,7
- Patients or caregivers should be informed when substitution of a drug product results in a change in color or shape, and drug products that differ in color or shape should not be mixed in the same prescription vial. These measures will help to avoid confusion on the part of the patient or caregiver.
- Descriptions of generic products to patients and caregivers should indicate that generic products are equivalent to the brand product. Patient counseling should not include descriptions of generic products that imply they are of lower quality or less effective versions of the brand product.
- Providers may consider obtaining plasma ASM levels while a patient is taking a stable dose of a branded ASM and repeating a level at the same time point during stable dosing with the generic equivalent to help allay concerns.
6. Consideration for product excipients and manufacturer compliance with current Good Manufacturing Practice regulations should be evaluated when substituting generic products. Risk assessment of potential toxicity of excipients should be conducted.8,9 Heightened caution is warranted for medically complex patients at highest risk for seizures.10 Patients receiving concomitant nonpharmacological therapies, as well as those using the ketogenic diet, may need more rigorous assessment for potential formulation-specific considerations (i.e., propylene glycol and other carbohydrate content) to minimize risk for potential adverse drug effects.9, 11-14
- Ting TY, Jiang W, Lionberger R, et al. Generic Lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015;56(9):1415-1424. doi:10.1111/epi.13095
- Privitera MD, Welty TE, Gidal BE, et al. Generic-to-generic lamotrigine switches in people with epilepsy: The Randomized Controlled Equigen trial. The Lancet Neurology. 2016;15(4):365-372. doi:10.1016/s1474-4422(16)00014-4
- Berg M, Welty TE, Gidal BE, et al. Bioequivalence between generic and branded lamotrigine in people with epilepsy. JAMA Neurology. 2017;74(8):919. doi:10.1001/jamaneurol.2017.0497
- Fang L, Li Z, Kinjo M, et al. Generic lamotrigine extended-release tablets are bioequivalent to innovator drug in fully replicated crossover bioequivalence study. Epilepsia. Jan 2023;64(1):152-161. doi:10.1111/epi.17438
- Johnson EL, Chang Y-T, Davit B, Gidal BE, Krauss GL. Assessing bioequivalence of generic modified-release Antiepileptic Drugs. Neurology. 2016;86(17):1597-1604. doi:10.1212/wnl.0000000000002607
- Kesselheim AS, Misono AS, Shrank WH, et al. Variations in pill appearance of antiepileptic drugs and the risk of Nonadherence. JAMA Internal Medicine. 2013;173(3):202. doi:10.1001/2013.jamainternmed.997
- 7. Espay AJ, Norris MM, Eliassen JC, et al. Placebo effect of medication cost in Parkinson disease: A randomized double-blind study. Neurology. 2015;84(8):794-802. doi:10.1212/wnl.0000000000001282
- Rayavarapu S, Braithwaite E, Dorsam R, et al. Comparative risk assessment of formulation changes in generic drug products: A pharmacology/toxicology perspective. Toxicological Sciences. 2015;146(1):2-10. doi:10.1093/toxsci/kfv074
- Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. The Journal of Pediatric Pharmacology and Therapeutics. 2014;19(4):277-282. doi:10.5863/1551-6776-19.4.277
- Privitera MD. Generic Antiepileptic Drugs: Current controversies and Future Directions. Epilepsy Currents. 2008;8(5):113-117. doi:10.1111/j.1535-7511.2008.00261.x
- McGhee B, Katyal N. Avoid unnecessary drug-related carbohydrates for patients consuming the ketogenic diet. Journal of the American Dietetic Association. 2001;101(1):87-101. doi:10.1016/s0002-8223(01)00021-9
- Lebel D, Morin C, Achim N, Laberge M, Carmant L. The carbohydrate and caloric content of concomitant medications for children with epilepsy on the ketogenic diet. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques. 2001;28(4):322-340. doi:10.1017/s0317167100001542
- Kossoff EH, Turner Z, Bluml RM, Pyzik PL, Vining EPG. A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins Diet. Epilepsy & Behavior. 2007;10(3):432-436. doi:10.1016/j.yebeh.2007.01.012
- Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018;3(2):175-192. doi:10.1002/epi4.12225