Recommendations of the Italian League Against Epilepsy Working Group on Generic Products of Antiepileptic Drugs

Abstract

Summary: The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years. In view of the importance of the issue, the Italian League against Epilepsy (LICE) set up an ad hoc working group whose task was to assess available evidence on the efficacy and safety of generic AEDs in the treatment of epilepsy and to produce recommendations on their use. A careful review of the literature revealed no adequately powered randomized controlled trials that assessed the risk/benefit ratio of generic substitution. Although there have been reports of loss or worsened seizure control, or appearance of adverse events, following the switch from brand products to generics, a critical assessment of the evidence generally does not allow us to establish a cause–effect relationship between the switch and a change in clinical status. Overall, the working group concluded that generic AEDs meeting current regulatory criteria for bioequivalence represent a valuable choice in the management of epilepsy by allowing a substantial reduction of treatment costs, particularly in patients initiating monotherapy or adjunctive treament and in those with persistent seizures. The working group considered that in patients who achieved seizure freedom a modest change in plasma drug levels, which may occasionally occur even after substitution of products that meet bioequivalence criteria, could in rare cases lead to seizure breakthrough. Therefore, generic substitution is not recommended in patients who achieved seizure remission. Switches between a particular generic and another generic should also be preferably avoided. Finally, sustained‐release AED formulations should not be used interchangeably with immediate‐release brand or generic products. Patients need to be informed about the stringent criteria that currently govern the approval of generic products and about the implications of the use of generic AEDs, and their opinion should be taken into consideration at the time of prescribing.

Requirements for generic antiepileptic medicines: a clinical perspective

“…This rule implies that the difference could be as much as a 56% increase or 36% decrease in bioavailability when switching a patient from one generic to another generic formulation. Perucca et al [35] pointed out that even with this definition of bioequivalence the AED plasma level can change as much as 45% compared to a branded product, although this may not be the case in most instances. However, two reviews conducted by the FDA showed, that the average difference between mean AUC and C max of the reference and generic compound is between 3 and 4% [27,34].…”

“…For example, the guidelines developed by the German Chapter of the International Liga against Epilepsy recommend to consider a low cost generic brand when first initiating treatment but a switch from a brand to generic drug in a well-controlled patient is not recommended [29]. In concordance with this are the Italian guidelines which state that in patients who achieved complete seizures remissions, switching is not recommended [35]. Similarly, the Swedish Medicinal Product Agency states that a switch between formulations is considered to carry a risk of unstable seizures control.…”

Neue Bioäquivalenzkriterien der Europäischen Arzneimittelagentur

“…Einige epileptologische Fachgesellschaften haben daher darauf hingewiesen, dass für Antiepileptika mit unterschiedlicher Galenik, auch wenn sie den bisherigen Standards der EMA für eine Bioäqui-valenz genügen, eine therapeutische Äqui-valenz im Einzelfall nicht als gesichert angesehen werden kann [11,14]. Ähnlich ist auch die Einschätzung der American Epilepsy Foundation [8].…”

An update of the Hong Kong Epilepsy Guideline: consensus statement on the use of antiepileptic drugs in Hong Kong

“…There appears to be a divide in the positional statements and guidelines between countries with public-funded health care and those with private health care. Many associations, including the Italian League Against Epilepsy, 112 American Academy of Neurology, 114 and the French Chapter of ILAE 113 have expressed concerns about generic substitution of AEDs, emphasising the uniqueness of epilepsy as a class of disease in which generic substitution is problematic when carried out for this indication. The latest position statement from the American Epilepsy Society acknowledges the bioequivalence of brand and FDA-approved generic products and the fact that substitution may reduce cost without compromising efficacy.…”