Substitution of Different Formulations of Antiepileptic Drugs for the Treatment of Epilepsy

Adopted January 25, 2016
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The American Epilepsy Society (AES) recognized that well-designed, prospective studies of generic antiepileptic drug (AED) substitution were needed and collaborated with the Epilepsy Foundation and the Food and Drug Administration to initiate several studies. These studies have been completed. Three studies demonstrated bioequivalence of generic products in patients with epilepsy taking concomitant AEDs.1-3 Additionally, an analysis of Abbreviated New Drug Application (ANDA) data suggests that generic products of branded modified-release products (e.g., extended release, delayed release) are bioequivalent and safely interchangeable.4 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 bioequivalence are appropriate for patients with epilepsy.

The AES offers it support of the following principles concerning the continuity of AEDs for adults and children with epilepsy:

  1. The AES acknowledges that drug formulation substitution with FDA-approved generic products usually reduces cost, and does not compromise efficacy.
  2. 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 AEDs in adults and children.
  3. When dispensing medications to patients, healthcare professionals should ensure that a bioequivalent FDA-approved generic product is substituted for the brand or another generic AED. For example, an immediate-release generic product should not be dispensed as a substitute for a delayed-release or an extended-release product.
  4. Based on data showing that 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.5,6
    1. 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.
    2. 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.

References

  1. 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.
  2. Privitera MD, Welty TE, Gidal BE, et.al. Generic-to-generic lamotrigine switches in people with epilepsy: A randomized, controlled trial. Lancet Neurology. In press.
  3. Berg M, Privitera M, Diaz F, et.al. Equivalence among generic AEDS (EQUIGEN): Single-dose study. American Epilepsy Society. 2015; Abstract 2.267.
  4. Johnson EL, Chang YT, Davit B, et.al. Assessing bioequivalence of generic modified release antiepilepsy drugs. Neurology. In press.
  5. Kesselheim AS, Misono AS, Shrank WH, et.al. Variations in pill appearance of antiepileptic drugs and the risk of nonadherence. JAMA Intern Med. 2013;173(3):202-208.
  6. Espay AJ, Norris MM, Eliassen JC, et.al. Placebo effect of medication cost on Parkinson disease a randomized double-blind study. Neurology. 2015;84(8):794-802.