Caution Urged When Switching between Generic Antiepileptic Drugs

Caution Urged When Switching between Generic Antiepileptic Drugs [TABLE]
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[TD="width: 100%"] S. Andrew Josephson[/TD]
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The development of generic drugs has led to substantial savings for millions of patients in the United States. Generic formulations of epilepsy medications are widely used, but concerns remain among some physicians and their patients that switches from brand name to generic formulations or between generic drugs lead to increased side effects and breakthrough seizures. There are more than 150 generic antiepileptic drugs (AEDs) approved through the U.S. Food and Drug Administration (FDA) Abbreviated New Drug Application (ANDA) process; ANDA approves proposed generic formulations if it can be proven that they provide plasma concentrations similar to brand name drugs. A recent study (Krauss et al., 2011) aimed to examine the accuracy of generic AED copies in bioequivalence studies using FDA data regarding approved generic AED drugs obtained via the Freedom of Information Act.


The authors examined 141 generic AED products studied in 258 bioequivalence studies. A total of 251 of the studies (N = 7125) included demographic data demonstrating a male predominance (78%) and a mainly young age group studied, with a mean age of 31.9 years and only 44 patients (0.7%) who were >65 years. Zero patients under the age of 18 were included in these studies. Ethnic breakdown of the participants included 54% Caucasian, 26% Asian, 9.7% Black, and 3.1% Hispanic.


The authors found that the generic and brand name AED formulations had very similar total drug delivery as measured by area under the plasma concentration time curve calculated to the last measured concentration (AUC[SUB]o-t[/SUB]); this value differed by <15% in 98.8% of the studies examined. Peak drug concentrations differed by <15% in 89% of the studies examined.


The authors then examined 595 pairs of generic AED products that were tested at the same doses in order to simulate switching between 2 generic formulations of an AED. The authors found that 85 (14.3%) of these pairs had an estimated AUC[SUB]o-t[/SUB] that differed by 15”“25% and 14 (2.4%) had an estimated AUC[SUB]o-t[/SUB] that differed by >25%, indicating pharmacokinetic variability that could lead to meaningful clinical effects. Peak plasma concentration differed by >15% for 39% of the pairs. Those AEDs such as oxcarbazepine with low solubility and bioavailability exhibited the greatest variability in bioequivalence.


This interesting study has broad implications for both future research and current practice. Further studies are needed moving forward as to the effects of switching from one generic medication to another, as well as switching between brand name and generic AEDs. The studies to date are remarkably homogeneous in their populations tested and exclude the elderly, pediatric populations, and many ethnic minorities who may have distinct pharmacokinetic responses to these medications. For the clinician caring for patients taking AEDs, generic substitutions appear to be at least pharmacokinetically similar to brand name drugs, although it is key to monitor patients for side effects and breakthrough seizures when this switch is made. More importantly, patients on generic medications often are given different generic pills when they fill their prescriptions; patients should be aware that these substitutions could indeed result in distinct pharmacokinetics and clinical effects, and should therefore carefully make sure that the generic formulation they receive is identical to their previous prescription.
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[TD="class: contentReference"]Reference
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[TD="class: contentBody"]Krauss GL et al. Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol 2011;70:221.
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