Therapeutic Basis of Generic Substitution of Antiseizure Medications

Abstract

More than thirty antiseizure medications (ASMs) are available for treating epilepsy. ASMs differ in their potency and efficacy in controlling seizures by acting on diverse targets in the brain, often with variable pharmacokinetics. Moreover, nearly 30% of people with epilepsy have drug-resistant or intractable seizures. Generic substitution of ASMs is a complex issue. It is thought that generic substitution in people with epilepsy may cause problems because FDA rules allow too much variability across products. The standard bioequivalence range (80% to 125%) appears too broad for many ASMs, especially those exhibiting little separation between therapeutic and toxic levels. Hence, sub-therapeutic concentration may lead to therapeutic failure with seizure recurrence, which could be life threatening. A supra-therapeutic level could result in adverse effects or compliance issues. There are reported issues with generic substitutions of phenytoin, topiramate, levetiracetam, carbamazepine, and lamotrigine. There is discussion in the epilepsy community about additional guidelines, including designation of generic ASMs as Narrow Therapeutic Index (NTI) drugs and how patient education plays a role in generic substitution. Overall, based on the published evidence on specific generic ASMs, FDA bioequivalence standards are not the cause of problems with generic ASM substitution. Rather, it is imperative that physicians and pharmacists provide adequate patient education on what to expect when switching to generic ASMs, including changes in medication shape, color and consequences. Another suggestion would be to consider that all ASMs be considered for inclusion in NTI class to prevent the clinical outcome issues associated with generic ASM switching. SIGNIFICANCE STATEMENT  There are critical aspects to consider when switching from a brand name antiseizure medication (ASM) when a generic becomes available or switching between generics. Generic ASMs are interchanged with little consideration of differences in therapeutic equivalence and other clinical factors. This article describes key issues on generic substitution of ASMs and highlights critical pharmacotherapeutic issues associated with generic ASMs including adverse clinical consequences.Many therapeutic issues can be mitigated if all ASMs are categorized as NTI drugs.

Breakthrough Seizures in Patients Switched from Brand to Generic Antiseizure Medications

“…The active medicinal components used in branded goods are also present in generic versions of ASMs. If the maximum plasma drug concentration (Cmax) ratios of both products fall within the range of 80-125% with 90 percent confidence intervals, the bioequivalence of generic medicines is authorized (3) .…”

“…According to the FDA, a generic medicine is one that has the same dosage form, safety, strength, administration method, quality, performance attributes, and intended use as a brand-name drug (3) .…”

“…For patients who are without health insurance or who are economically disadvantaged, the cost of generic ASMs is crucial. Generic drugs and go into a distinct tier that is more patient-affordable, while brand drugs fall into a tier that raises expense to patients (3) .…”

Generic substitutions of antiseizure medications: recommendations issued by the Israeli Chapter of the International League Against Epilepsy

“…Products for which the following recommendations apply include: (1) all preparations of carbamazepine, clobazam, clonazepam, ethosuximide, gabapentin, perampanel, phenobarbital, phenytoin, primidone, rufinamide, and valproic acid; (2) switches between different formulation types of any ASMs (i.e., liquid oral formulations versus solid immediate-release products versus modified-release products); (3) switches across modified-release formulations; (4) any other switch which involves non-bioequivalent products. Exemptions may apply as per case.…”

“…Recent issues related to supply discontinuation in Israel (e.g., a need to switch phenobarbital tablets to a solution) have called for questions, often asked by physicians in the community, patients and caregivers, to be addressed, related to safety of switching and precise details of the switch. Our recommendations are based upon relevant literature [2][3][4], ASM solubility and permeability, their half-life in plasma, and the narrow therapeutic index of several ASMs (carbamazepine, phenytoin, and valproic acid) [2]. Modifiedrelease ASM preparations consist a distinct group; values values for the area under the curve (AUC) and maximal concentration (Cmax) of many generic modified-release products are close to those of the brand product in healthy volunteers [5].…”