The Value of Specifying Brand-name Antiepileptic Drugs

Abstract

T HE PATENT LIVES OF most of the newergeneration antiepileptic drugs (AEDs) have either expired or come close to expiration. This is despite occasional attempts by the pharmaceutical industry to extend patent lives by creating a variation of an existing compound/AED, often in the form of an extendedrelease version, eg, Lamictal XR and Keppra XR. Inevitably the question of generic substitution of our patients’ AEDs arises, usually prompted by the paying insurance companies whose main interest is the bottom line, though it is not infrequently prompted by the (self-paying) patients or their families. This brief commentary will not attempt to be a comprehensive review of this topic, which have already been written. There is a saying in the management of epilepsy that most of us who treat such patients are well aware of: “If it ain’t broke, don’t fix it.” That simply means of course that if our patients were seizure free and without any (significant) adverse effects, we would not change their medication regimen (with the exception of trying to reduce or even discontinue treatment with AEDs in a successfully treated patient). In this scenario, there should be no reason to change from one AED to another. I am not going to argue whether or not the generic form of an AED is the same as the brand form, though I think even the most ardent supporters of generic substitution will grant that there are differences between brand-name AEDs and generic drugs and among the multiple generic forms themselves. If cost were not an issue, there would be no contention at all (at least in this scenario of a successfully treated patient). Substitution of brand-name AEDs with generic AEDs can and does lead to breakthrough seizures. Unlike other diseases, a single breakthrough seizure due to change in delivered medication (dose) may lead to dire consequences, including loss of one’s driver’s license, injury (to self and others), loss of employment, hospitalization, or even death. Patients with epilepsy are not simply dealing with minor adverse effect profile changes when their AED is substituted for a generic form, though they are not exempt from other comorbidities associated with such change. In a study of the generic substitution of lamotrigine in patients with epilepsy, the most prevalent comorbidity was high blood pressure, followed by depression, asthma, diabetes, and angina. It has been shown that the switch-back rates of patients who were substituted generic for brandname drugs were substantially higher for AEDs than non-AEDs. This was likely the result of increased toxicity and/or loss of seizure control associated with the use of generic AEDs. There was a dramatic, recent case report of a 29-year-old man who had been taking high-dose (800-mg/d) Lamictal, which was abruptly substituted with 800-mg/d generic lamotrigine. He developed anticonvulsant hypersensitivity syndrome. As a consequence, the Danish licensing authority now reimburses the cost difference between generic and proprietary forms of lamotrigine for all patients with epilepsy taking high doses of lamotrigine ( 30 μmol/L) to eliminate the risks associated with the arbitrary switching among types of this drug. The risks of generic substitution can be life-threatening, even independent of breakthrough seizures. None of these adverse reactions should be surprising. Generic forms of AEDs or any drugs are not the same as the propriety form. Two reviews conducted by the Food and Drug Administration showed that the average difference between area under the curve and maximum concentration of the reference and generic compounds was about 3% to 4% (standard deviation, about 3%). Notably, in 13 (5.8%) of 224 bioequivalence studies, there was a 10% or greater difference in the mean areas under the curve. One obvious problem is that the in vivo bioequivalence testing is typically done in 24 to 36 healthy adults, who are usually different than most of our patients with epilepsy. Another problem is the large numbers of different generic medications for 1 particular branded product. These many forms are of course not only different than the proprietary form but from each other. Two years after the Zonegran patent expired, there were 17 approved generic manufacturers of zonisamide. Pharmacies are currently not only substituting branded AEDs for generic Author Affiliation: Division of Pediatric Neurology, Barrow Neurological Institute/St Joseph’s Medical Health Center, Phoenix, Arizona.