Patients with epilepsy may have a higher risk of seizures if they switch from their brand-name medication to generic anti-epileptic drugs (AEDs). This is the message often heard from clinicians when expressing their concern over generic versions of narrow therapeutic index (NTI) drugs, one class of which is those used to manage the symptoms of epilepsy.
Anecdotal evidence, case reports, editorials and press reports are used to back this assertion and, if true, pose implications not only for the patient, but also for the clinician and the healthcare system too.
Epilepsy is successfully treated with AEDs in ~70–80% of patients [1], but loss of this seizure control can have considerable implications for the patient, including medical, financial and social. Several AEDs have reached the end of their patent protection and generic versions have been approved. This has had the result of bringing the debate concerning the interchangeability of brand-name and generic AEDs to the fore and has become somewhat controversial with several states in the US requiring signed informed consent forms from both the prescriber and the patient, and in Europe some countries, such as Sweden, have excluded this class of drugs from automatic generic substitution [2].
Kesselheim’s latest research into generic and brand-name AEDs
GaBI Online has recently reported on the excellent research performed by the team of Professor Kesselheim of the Brigham and Women’s Hospital in Boston, USA [3-8]. In this research, Kesselheim et al. performed a systematic search of the peer reviewed literature for studies comparing the clinical endpoints achieved with brand-name cardiovascular drugs and their generic counterparts. Despite a similar situation where anecdotal evidence and cautionary editorials act to dissuade against generic substitution, especially with NTI drugs, their meta-analysis uncovered no evidence for the superiority of brand-name cardiovascular medication over generic versions.
Curious to see if this above conclusion also applies to AEDs, Kesselheim’s team has recently published a report of their systematic evaluation of trials and observational studies assessing seizure control with brand-name and generic AEDs [9].
Randomised clinical trials investigating generic versus brand-name AEDs
This study has provided a comprehensive overview of the available evidence and identified nine randomised clinical trials (RCT), one prospective non-randomised trial and six observational studies that had been published between 1984–2009 and which compared seizure events or seizure-related outcomes between a brand-name AED and at least one generic version. Seven RCTs involving three types of AEDS—phenytoin (Dilantin), carbamazepine (Tegretol), and valproic acid (Depakene)—were finally included in the meta-analysis. The results indicated that there was no difference between the brand-name or generic in terms of seizure control or safety concerned.
Non-interventional trials with generic and brand-name AEDs
The observational studies, on the other hand, identified trends in the utilisation of drugs or health services which their authors attributed to any reported changes in seizure control. However, three observational studies based their conclusions on the observed switchback rates from generic AEDs, compared to non-AED drugs. In this case, although switchback rate can be attributed to adverse clinical events with the generic AED, Kesselheim et al. propose that there are other possible alternative hypotheses [9]. These can be, for example, simply that the neurologists may be more likely to allow the patient to switchback than general physicians, even in the absence of any adverse clinical outcome, due to concerns about generic AEDs from media sources or from anecdotal evidence. Other conclusions made by these observational studies could also have had alternative, and equally viable, explanations.
Conclusion
In conclusion, this novel research by Kesselheim’s team has shown that at least three brand-name AEDs are not superior to their generic counterparts for maintaining control of seizures. Although the non-interventional studies do suggest that switching from a brand-name AED to a generic form may lead to higher switchback rates and an increased use of health services, these studies were limited in their design, including a number of unmeasured confounders. Data from such observational studies should thus be carefully considered before basing any clinical decisions on them.
Editor’s comment
Professor Kesselheim proposes a series of prospective studies that would be worthwhile conducting in the future to obtain a better picture. These include identifying whether there are any groups of high-risk patients with epilepsy for whom switching between versions of AED may be dangerous. These future studies should focus not only on generic versus brand-name, but also take into consideration any differences in manufacturing processes. Observational studies should also help identify specific subpopulations of patients at risk.
Please feel free to share your thoughts via email to editorial@gabionline.net or in the comments section below.
It is evident that more research is needed in this field. What are your ideas for further investigation? Where would you like more research to be undertaken and to answer which questions?
If you are interested in contributing a research article in a similar area to the GaBI Journal, please send your submission to science@gabi-journal.net.
Related articles
Switching from a brand-name antiepileptic drug to a generic is not associated with a higher risk of seizures
Epilepsy: medical concerns of prescribing generics
References
1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9.
2. Krämer G, Biraben A, Carreno M, Guekht A, de Haan GJ, Jedrzejczak J, et al. Current approaches to the use of generic antiepileptic drugs. Epilepsy Behav. 2007 Aug;11(1):46-52.
3. GaBI Online - Generics and Biosimilars Initiative. Generic or brand-name drugs for cardiovascular disease? Does the evidence match current opinion? [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 Aug 19]. Available from: www.gabionline.net/Generics/Research/Generic-or-brand-name-drugs-for-cardiovascular-disease-Does-the-evidence-match-current-opinion/
4. GaBI Online - Generics and Biosimilars Initiative. The clinical equivalence of brand-name beta-blockers and their generic counterparts? [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 Aug 19]. Available from: www.gabionline.net/Generics/Research/The-clinical-equivalence-of-brand-name-beta-blockers-and-their-generic-counterparts/
5. GaBI Online - Generics and Biosimilars Initiative. Are generic diuretics clinically equivalent to their brand-name counterparts for the management of cardiovascular disease [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 Aug 19]. Available from: www.gabionline.net/Generics/Research/Are-generic-diuretics-clinically-equivalent-to-their-brand-name-counterparts-for-the-management-of-cardiovascular-disease/
6. GaBI Online - Generics and Biosimilars Initiative. The clinical equivalence of generic and brand-name calcium channel blockers [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 Aug 19]. Available from: www.gabionline.net/Generics/Research/The-clinical-equivalence-of-generic-and-brand-name-calcium-channel-blockers/
7. GaBI Online - Generics and Biosimilars Initiative. The therapeutic equivalence of antiplatelet agents, ACE-inhibitors, statins and alpha-blockers [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 Aug 19]. Available from: www.gabionline.net/Generics/Research/The-therapeutic-equivalence-of-antiplatelet-agents-ACE-inhibitors-statins-and-alpha-blockers/
8. GaBI Online - Generics and Biosimilars Initiative. The therapeutic equivalence of brand-name and generic narrow therapeutic index (NTI) cardiovascular drugs [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 Aug 19]. Available from: www.gabionline.net/Generics/Research/The-therapeutic-equivalence-of-brand-name-and-generic-narrow-therapeutic-index-NTI-cardiovascular-drugs/
9. Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, Lee JL, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010 Mar;70(5):605-21.
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