Generic Antiepileptic Drug Switches: Be Cautious

Generic medications are a source of major cost savings in pharmacotherapy. In this era of rapidly rising medical costs and insurance-related problems, this is no small matter. Most of the time, no adverse consequences arise as a result of generic substitution. However, there is some evidence that persons with epilepsy taking antiepileptic drugs (AEDs) may be more likely to experience problems with switches to, from, and between generic AED formulations. I do note that rather anecdotal evidence exists supporting both sides of the generic AED substitution debate.

Almost 20 years ago, the American Academy of Neurology (AAN) recommended caution with generic substitution of AEDs. This was well before the advent of any of the newer AEDs, and long preceded the availability of generic formulations of same. More recently, the AAN advocated access to all available AEDs, and opposed mandatory substitution and Prior Authorization programs. In an accompanying article, Berg et al comment on substantial evidence of loss of seizure control due to generic substitution, according to a survey of neurologists.

Well controlled data on generic AED substitution are scarce. However, recently Zachry et al looked at ambulance and ED visits, as well as inpatient admissions, associated with "A rated" (therapeutically bioequivalent) medication switches. This could be a switch to a generic from a brand name drug, from a generic to branded, or between generic formulations. This paper was real science: The authors tested a specific hypothesis: Patients who sought inpatient or emergency care for epilepsy would have greater odds of a recent prior switch between A-rated AED alternatives. The method was a case/control analysis of data from a large medication claims database. A particular 12 month period was selected, partially based on the advent of generic zonisamide shortly prior to the period. Many previous analyses had preceded the availability of a generic formulation of this agent. A 1:3 case/control ratio was used, resulting in 416 cases and 1,248 controls available for analyses. In the six months prior to their index events, 11.3% of patients and 6.2% of controls (OR 1.92) were switched between A rated drug formulations. Zonisamide formulation changes were more frequent than other AEDs. The majority of patients, 54.7%, were switched within 2 months of their index event (out of a possible 6 month period). The proximity of drug switch to index event supports the association between the two.

In the discussion, the authors emphasize that prescribers likely underestimate the frequency of generic substitution. They are also concerned that cost savings data do not take into account ancillary costs and outcomes such as ED visits.

Limitations include the inability to show causation: An association, but not causation, was demonstrated. Also, persons seeking care in the ambulatory setting were not captured. One material confounding issue is that three of 4 authors were Abbott Laboratories employees. However, valproic acid and divalproex (AEDs made by Abbott) were not major topics in this paper. The major strength of this analysis is that a specific hypothesis was tested with a clear statistical methodology. Most other data on AED substitution are case reports or prescriber surveys, lacking scientific rigor.

Generic substitution of medications can save considerable sums. However, there may be situations, such as with persons with epilepsy, where extra caution is warranted. This paper contributes to the evidence that this may be the case. Caveat emptor.