ARTICLE IN PRESS

european journal of paediatric neurology xxx (2008) 16

Official Journal of the European Paediatric Neurology Society

Special contribution

The use of generic medication in epilepsy: A review

of potential issues and challenges
Wim Van Paesschena,*, Henri Haumanb, Lieven Lagaec
a

Department of Neurology, University Hospital Leuven, Leuven, Belgium

Epilepsy Centre, Duffel, Belgium
c
Department of Pediatric Neurology, University Hospital Leuven, Leuven, Belgium
b

article info

abstract

Article history:

Changing from brand name to generic antiepileptic drugs (AEDs) is increasingly being

Received 15 July 2008

advocated by the authorities, principally for budgetary reasons. However, caution should

Accepted 15 July 2008

be exercised since AEDs may have a narrow therapeutic margin, the regimen with AEDs
may be complex, the consequences of uncontrolled seizures may be severe, and risk of side

Keywords:

effects is relatively high, particularly when seizures are difficult to control. This article

Epilepsy

focuses on the possible problems that can arise from the substitution of AEDs formula-

Antiepileptic drugs

tions, such as loss of seizure control and emergence of new side effects. We would advise

Generics

that patients stay on the same formulation of the first AED, whether a brand name or

Generic substitution

generic AED. Switching AED formulations should always be done with the necessary

Overview

caution and under the physicians supervision. Closer follow-up during the transitional
period is necessary, and dosage adjustment may be required. The patient should be given
full and correct advice about risks involved in switching AED formulations.
2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

1.

Introduction

Epilepsy is a common and chronic disorder with a prevalence

of between 0.5% and 1%.1 Lifelong treatment is often
required.2 Around 70% of patients obtain seizure remission
with the help of antiepileptic drugs (AEDs), enabling them to
lead a normal life.1 Caution must be exercised when considering the generic substitution of AEDs in patients who are
stabilized on their treatment.2 This article discusses the
potential risks of generic substitution of AEDs in the treatment
of epilepsy.

2.

Generic products definitions

A generic product is described as a product which has the same

qualitative and quantitative composition in active substances
and the same pharmaceutical form as the reference medicinal
product, and whose bioequivalence with the reference
medicinal product has been demonstrated by appropriate
bioavailability studies (Directive 2004/27 of the European
Parliament; Directive 2001/83).
Bioavailability can be described as the rate and extent to
which the active ingredient becomes available at the site of
drug action.3,55 Most bioavailability studies are based on

* Corresponding author. Department of Neurology, University Hospital Leuven, 49 Herestraat, B-3000 Leuven, Belgium. Tel.: 32 16 344
332; fax: 32 16 348 434.
E-mail address: Wim.vanpaesschen@uz.kuleuven.ac.be (W. Van Paesschen).
1090-3798/$ see front matter 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpn.2008.07.007

Please cite this article in press as: Van Paesschen W et al., The use of generic medication in epilepsy: A review of potential issues
and challenges, European Journal of Paediatric Neurology (2008), doi:10.1016/j.ejpn.2008.07.007

ARTICLE IN PRESS
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european journal of paediatric neurology xxx (2008) 16

plasma drug concentrations.4 In practice the area under the

curve (or AUC) (which is equivalent to the quantity of drug
available to the body) and the peak concentration (Cmax) are
usually measured to compare the bioavailability of different
products.5,58

Particular attention is warranted if the original brand name

drug has a narrow therapeutic index or a non-linear pharmacokinetic profile, such as phenytoin.

4.
3.
Generic products pharmacological
considerations
For bioequivalence to be demonstrated the area under the curve
(AUC) must lie within 80% and 125% of the reference preparation with 90% reliability.6 When bioequivalence of the generic
agent with the brand name drug is established, usually in
single-dose studies, it is generally assumed that the generic
product also has therapeutic equivalence in clinical use,
although these bioequivalence studies are conducted in healthy
volunteers and usually in a limited number of study subjects.
In patients with epilepsy the bioavailability of a drug can
vary markedly as a result of differences in age, comorbidities,
and the simultaneous use of potentially interacting medications. As a result the bioavailability of a given drug in patients
with epilepsy can vary from 74 to 142%.5 It is important to note
that an even greater variation in pharmacokinetic parameters
can occur when patients switch between different generic
formulations than when a generic is substituted for the brand
name drug or vice versa. It is theoretically possible for a patient
to have a 50% increase in serum concentration when changing
from a generic with low bioavailability (e.g. 80% of that of the
brand name drug) to a generic with high bioavailability (e.g.
120% of the brand name drug) (see Fig. 1).6 In the same
example, switching the generic with high bioavailability of
120% to one with low bioavailability of 80% will result in a 33%
fall in serum concentration.6

Generic medication can also differ in other ways from the

original brand name product, such as shelf life5 or general
appearance (color, form and taste). This can result in confusion and concern in the patient.1,7
Generic products can also use a different salt or ester of the
active substance.8 Different salts, esters, isomers, mixtures of
isomers, complexes or derivatives of an active substance are
considered to be the same active substance, unless they differ
significantly with regard to safety or efficacy (Directive 2004/
27 of the European Parliament; Directive 2001/83).9 Nevertheless, different salts of the same active substance can
exhibit different chemical and biological properties. Also,
excipients in the tablet may not always be considered as
inactive or inert, and can differ from one generic to another4
and affect the pharmacokinetics of the active substance.
Different manufacturers market different generic equivalents of the same brand name drug.1 It is possible, therefore,
that patients receive a different generic preparation each time
with the same prescription if the drug is prescribed on the
basis of the generic name of the AED.6

5.
Other formulations of brand name drugs
a similar problem
The problem of substitution does not just arise with generic
forms of AEDs. The same problem can occur when a company
markets a different formulation of the original antiepileptic,
as happened with oxcarbazepine (Trileptal). A new formulation of oxcarbazepine (Trileptal) resulted in acute side
effects such as diplopia, dizziness, dysarthria and ataxia in
patients who had been taking oxcarbazepine for years without
any side effect. The new oxcarbazepine formulation was
absorbed more rapidly and had a higher bioavailability than
the old one and resulted in a mean increase in the oxcarbazepine concentration of more than 400%. Oxcarbazepine is
a prodrug of the monohydroxy derivative (MHD). The mean
serum concentration of MHD increased by more than 40%
following the introduction of the new formulation. We,
therefore, argue for the same approach to new formulations of
brand name drugs as to generics.10 In this case, however, the
new formulation was not bioequivalent with the previous
formulation.

6.
Fig. 1 Illustration of a brand name and two generic drugs
that meet the criteria of bioequivalence. Reproduced with
permission: Feely et al. Risk management in epilepsy:
generic substitution and continuity of supply, EJHP
Science, Volume 11, 2005, issue # 4, Pharma Publishing &
Media Europe bvba.

Generic products considerations

Risk categories

On the basis of these facts it has been proposed to exclude

certain patient groups from generic substitution.11 This
concerns disorders in which patients have a higher risk of an
unfavorable outcome, in which potentially serious complications can occur, polymedication is administered, and
medication with complex dosage regimens, a narrow

Please cite this article in press as: Van Paesschen W et al., The use of generic medication in epilepsy: A review of potential issues
and challenges, European Journal of Paediatric Neurology (2008), doi:10.1016/j.ejpn.2008.07.007

ARTICLE IN PRESS
european journal of paediatric neurology xxx (2008) 16

therapeutic index or a high risk of interactions. Although

there are convincing reasons to recommend excluding AEDs
from generic substitution, there are probably more justified
reasons for considering epilepsy itself a critical disease. The
impact of a breakthrough seizure can be dramatic for
a patient, particularly in terms of stigmatization and loss of
confidence, and can even have irreversible consequences.2

7.
Generic substitution for AEDs potential
risks
The primary aim of AED treatment is the remission of seizures
with no side effects.12 When considering generic substitution,
it is important to assess the possible clinical consequences of
over- or undertreatment. Studies have shown that regaining
seizure control after recurrent seizures can be a long-term
process and may not be obtained.13 Breakthrough seizures can
reduce the extent to which someone can find or hold a job.14
At the same time a breakthrough seizure can mean that the
patient loses his or her driving license. Seizures can have an
important impact on cognitive development in children.15 The
child can be absent from school for a long time and can fall
behind as a result. As well as cognitive impairment, epilepsy
in children is often associated with a higher risk of behavioral
and other psychiatric disorders.15 Breakthrough seizures can
also cause serious injuries, such as burns or drowning.6,12 The
most serious consequence of a breakthrough seizure is death,
and studies have shown that the relative risk of sudden
unexpected death in epilepsy (SUDEP) is increased after
breakthrough seizures. Tomson et al.16 reported that the
relative risk of SUDEP is 23 times higher in patients who had
experienced at least 1 attack in the past year compared to
seizure-free patients.
Poor treatment compliance with consequent failure of AED
treatment can be promoted by generic substitution, particularly if the patient is worried or suspicious of the new
packaging. In contrast to brand name drugs, identifying
features are not always marked on the pack, which can
confuse the patient.6,17 When a sudden, unexpected loss of
seizure control is observed, lack of treatment compliance, an
inappropriate dosage, drug interactions, comorbidity, or
malabsorption are often considered, but rarely generic
substitution. It is, however, important not to overlook generic
substitution as a cause, particularly as the frequency of
generic substitution is usually seriously underestimated.18

8.
Economic factors involved in generic
substitution of AEDs
In addition to the potential consequences for the patient, the
pharmacoeconomic implications of generic substitution
should also be considered. Generic substitution can produce
direct savings in costs, but can also entail indirect costs from
the need to tackle treatment failure or side effects.17,1921 A
breakthrough seizure may mean that the patient can no
longer live independently, suffers injuries, has to be hospitalized or even dies, which is associated with enormous
implications for the patient and their family and for the

community (Therapeutics and Technology Assessment

Subcommittee of the American Academy of Neurology).14,22
24
The costs of these complications may be difficult to
calculate.

9.
Clinical experience with generic
substitution of AEDs
Studies among general practitioners in the UK identified 2285
patients with epilepsy treated with carbamazepine, phenytoin
or sodium valproate.25 Nineteen percent of participants had
changed medication in the previous 2 years, 29% of whom
reported problems (including reduced seizure control or more
side effects).25 Patients who had switched from a brand name
drug to a generic product, or from one generic product to
another (88%) reported most problems.
In a Canadian study in 83 epilepsy patients, 17% switched
from a brand name drug to a generic alternative.7 Fourteen
percent of these reported problems after the change. Interestingly, 22% of these patients did not know that they had
been switched from a brand name drug to a generic
alternative.
A large, international survey of patients and their opinions
on generic AEDs was conducted in Canada, the UK, Germany,
France and Spain.26 Of the 974 patients, around half of them
were aware of the term generic (52%). Further in the survey
the term generic was described as a less expensive and
clinically equivalent alternative for a brand name drug.
However, 58% said they would not feel happy if they were
prescribed a generic AED.
Around one in four patients attributed breakthrough
seizures to generic AEDs.
The literature describes individual case reports confirming
problems with generic AEDs,6 such as phenytoin,27,57 carbamazepine,2831,52,53,56valproate32 and primidone,33 with some
authors attributing this to reduced bioavailability of the
generic AED. Case studies also report serious side effects after
changing to a generic anticonvulsant.28,30 In an open-label,
cross-over study, 14 patients treated for at least 35 days with
the brand name drug carbamazepine were switched to
a generic alternative. Nine of the 14 patients developed side
effects, including dizziness, nausea, ataxia, diplopia and
nystagmus. Severe side effects occurred in seven patients. The
side effects were associated with an increased Cmax and AUC
of carbamazepine and its active metabolite, carbamazepine10,11-epoxide, following the change to the generic product.30
The problems associated with generic substitution of AEDs
are probably underreported and underestimated. An appeal,
therefore, appeared in Neurology for physicians to actively
report to the competent authorities all breakthrough seizures
and/or side effects that occurred after switching to a generic
product.34
A recent published analysis of medical resource utilization
in patients with epilepsy switched from branded treatment to
generic treatment in Canada, demonstrated not only that the
switchback rates from generic to branded drugs were significantly higher for AEDS compared to other classes of drugs (e.g.
antidepressants or antihyperlipidemics), but also that patients
on generic treatment received higher average daily dose, and

Please cite this article in press as: Van Paesschen W et al., The use of generic medication in epilepsy: A review of potential issues
and challenges, European Journal of Paediatric Neurology (2008), doi:10.1016/j.ejpn.2008.07.007

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european journal of paediatric neurology xxx (2008) 16

increased utilization of both other AED and non-AED products,

compared to patients on branded drugs. They also analyzed
medical resource utilization, and found that the use of generic
products may lead to unfavorable clinical consequences,
including longer inpatient length of stay, increase in number of
outpatient visits, and higher dosing regimens. Based on their
findings, the authors question the therapeutic equivalence in
practice, of generic AEDs compared to their branded
counterparts.35,36

10.
Recommendations of international
societies
On the basis of the above data and because of the concern of
doctors and patients, neurological societies have issued
recommendations. The official standpoint of Epilepsy Action
(the British association for epilepsy) on the reliability of AEDs
is as follows37:
It is the view of Epilepsy Action that for the epilepsy
patient, consistency of supply is important. Epilepsy
patients should receive the same version of AEDs whenever they get a repeat prescription unless their clinician
prescribes otherwise. It should be from the same manufacturer, and indeed from the same country of
manufacture.
MIMS is a periodical guide for doctors in England that
publishes recommendations about the use of generic AEDs
form:38
Loss of seizure control may occur when switching
between different preparations of the same AED because of
differences in bioavailability between them. It is recommended that AEDs should be prescribed by brand name
and also that patients are not switched from one preparation to another without reassessment and retitration.
NICE (UK National Institute for Health and Clinical Excellence) states that substitution of AEDs is not recommended:39
Changing the formulation or brand of any AED is not
recommended because different preparations may vary in
bioavailability or have different pharmacokinetic profiles
and, thus, increased potential for reduced effect or excessive side-effects.

AEDs in the pharmacy without prior consent of the physician

and the patient.
The AAN supports legislation that would require informed
consent of physicians and patients before generic substitutions of AEDs are made by the pharmacist.
The AAN believes that the use of AEDs in the treatment of
epilepsy should be distinguished from the use of AEDs in
treating other disorders. The AAN recognizes that other rules
may apply.
Unlike other diseases, a single breakthrough seizure due to
change in delivered medication dose can have devastating
consequences, including loss of drivers license, injury, and
even death.
The Ligue Francaise Contre LEpilepsie has also recently
associated itself with this approach and spoken out against
generic substitution with AEDs. It underlines the need for
clear information from the physician to their patients if
changing brand name to generic AEDs (http://www.lfceepilepsies.fr/docs/pdf/affsaps_fiche_presse_antileptique.
pdf).51

11.

The opinion of public bodies

In the light of the potential risks of generic substitution,

a number of public bodies in Europe have issued rules to limit
or even prohibit the generic substitution of AEDs. The MPA
(Medical Products Agency) in Sweden specified that the firstand second-generation AEDs lamotrigine, carbamazepine,
phenytoin, valproic acid and gabapentin cannot be replaced
by a generic version.40,41 While a few approved generics can be
used, the generic versions of AEDs are not included in the list
of substitutable products. The Finnish National Agency for
Medicines42 also banned the substitution of AEDs because no
AEDs are included in the list of drugs considered for generic
substitution. The Danish Medicines Agency (DMA) also introduced more stringent legislation for generic products
containing lamotrigine in 2005 in respect of bioavailability.
Under these new regulations studies must demonstrate that
the quantity of generic product absorbed and the absorption
rate is 90%110% of that of the original product with a probability of more than 90%.43 In Canada, Canada Health released
in June 2006, a guidance document for pharmaceutical
industry titled Bioequivalence Requirements: critical dose
drugs. In this document, narrow therapeutic ranges are
proposed for certain drugs, including some AEDs.44

The American Academy for Neurology (AAN) also published recommendations on generic substitution:45

12.

AEDs differ from other classes of drugs in several ways that

make generic substitution problematic.
For AEDs, small variations in concentrations between namebrands and their generic equivalents can cause toxic effects
and/or seizures when taken by patients with epilepsy. The
AAN believes that the authorities should give complete
physician autonomy in prescribing AEDs.
The AAN opposes policies that would result in arbitrary
switching among AEDs. It also opposes generic substitution of

Because of the implications of breakthrough seizures for

patients with epilepsy, numerous neurological and epilepsy
societies have advised against the generic substitution of
brand name AEDs. The apparent economic benefits must be
weighed against the risks resulting from loss of seizure
control, particularly in seizure-free and stabilized patients.
We would advise that patients stay on the same formulation
of the first AED, whether a brand name or generic AED.
Switching AED formulations should always be done with the

Conclusion

Please cite this article in press as: Van Paesschen W et al., The use of generic medication in epilepsy: A review of potential issues
and challenges, European Journal of Paediatric Neurology (2008), doi:10.1016/j.ejpn.2008.07.007

ARTICLE IN PRESS
european journal of paediatric neurology xxx (2008) 16

necessary caution and under the physicians supervision.47

Closer follow-up during the transitional period is necessary,
and dosage adjustment may be required. Patient should be
given full and correct advice about risks involved in switching
AED formulations, and obtaining informed consent may be
advisable.

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and challenges, European Journal of Paediatric Neurology (2008), doi:10.1016/j.ejpn.2008.07.007

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Please cite this article in press as: Van Paesschen W et al., The use of generic medication in epilepsy: A review of potential issues
and challenges, European Journal of Paediatric Neurology (2008), doi:10.1016/j.ejpn.2008.07.007