Dear Pharmacist,

We are requesting your assistance in providing optimal care to your patients with epilepsy. Since medications play a major role in the treatment of epilepsy, pharmacists serve a vital role in the care of patients with this chronic condition. As such, we are alerting all US pharmacists of potential safety issues resulting from unmonitored formulation switching for patients with epilepsy taking anti-epileptic drugs (AEDs). Formulation switching includes changing from brand to generic, generic to brand and generic to generic formulations. Finding the right balance of preventing seizures and minimizing adverse effects in many patients with epilepsy is a complex and sometimes lengthy process. This balance can be affected when an AED formulation is changed. The variance in bioequivalence currently allowed by the FDA may result in the fluctuation of AED concentrations in the individual. This fluctuation can result in lower AED concentrations with resultant seizures or higher AED concentrations and subsequent toxicity in a small but significant number of epilepsy patients.

The Epilepsy Foundation strongly recommends that pharmacists contact the physician and inform the patient prior to formulation switching.

The Epilepsy Foundation released survey data today from 1,085 people with epilepsy regarding their experience with formulation switching. Among respondents that had switched from a brand-name to a generic AED, seizures
worsened for 59% of patients and medication side effects worsened for 49%. Among respondents that had switched from a generic to brand AED, seizures worsened for 15% and side effects worsened for 18%. More than 25% of respondents reported experiencing problems after switching between different generic formulations of an AED.

**Studies on the safety of unmonitored formulation Switching**

While the Foundation study is limited as patient reported data, it lends further credence to recent large scale retrospective studies on the safety of unmonitored formulation switching. The study of data from 451 physicians published in Neurology, the journal of the American Academy of Neurology (Berg, et al 2008) provides documentation of lower drug serum levels in some cases with breakthrough seizures, followed by a return to baseline after switchback; this gives significant weight to the concern that the breakthrough seizure was not coincidental, but caused by the switch.

A case-control analysis utilizing the Ingenix LabRX data sought to determine if patients who received epilepsy care in an emergency room had greater odds of having had a switch between an A rated AED in the past six months. The results, published in Epilepsia, the journal of the International League Against Epilepsy (Zachry, et al 2009) indicated 81% greater odds of exposure to generic switches in patients receiving emergency room care with an epilepsy diagnosis. These results were subsequently replicated with the PharMetrics and Marketscan databases. Each author independently estimated the attributable risk of a breakthrough seizure when switched at 5%.

The Food and Drug Administration

In response to these studies, the Food and Drug Administration (FDA) is working with the American Epilepsy Society and Epilepsy Foundation to conduct a prospective trial of AED concentrations when switching among AED's. The FDA has also amended its regulation on the submission of bioequivalence data to require applicants to submit data from all bioequivalence studies (in the past applicants needed to only submit studies demonstrating that a generic product meets bioequivalence criteria in order for the FDA to approve).

Pharmacists Can Protect Patient Safety

Given that there is not yet a way to identify which patients may be at risk for a breakthrough seizure; and given that even one breakthrough seizure could cause significant and even life-threatening consequences for the patient and others, the Epilepsy Foundation believes that pharmacists have a responsibility to protect patient safety by obtaining the agreement of the physician and informing the patient prior to formulation switching.