Adverse effects of AEDs remain a major cause of morbidity and sometimes mortality in the course of treatment of epilepsy and hence considerably impact the QoL of people with epilepsy, pe
Trang 1Address for correspondence:
Dr Gagandeep Singh,
Department of Neurology,
Dayanand Medical College,
Ludhiana - 141 001, India
E-mail: gagandeep_si@yahoo.co.uk
Received : 25-01-2011
Review completed : 25-01-2011
Accepted : 25-01-2011
Do no harm – But first we need to know more: The case of adverse drug reactions with antiepileptic drugs
Gagandeep Singh
Department of Neurology, Dayanand Medical College, Ludhiana, India
Topic of the issue: Review Article
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DOI:
10.4103/0028-3886.76859
Epilepsy is one of the most common neurological
disorders The mainstay of treatment of epilepsy is
antiepileptic drugs (AEDs), often for a long duration The
primary goals of treatment of epilepsy include complete
seizure remission, improvement in the the quality of
life (QoL), and do no harm, i.e., to avoid, minimize and
amend any adverse effects that might occur as a result of
treatment with AEDs Adverse effects of AEDs remain a
major cause of morbidity and sometimes mortality in the
course of treatment of epilepsy and hence considerably
impact the QoL of people with epilepsy, perhaps as
much as the seizure burden.[1] The exact incidence of
adverse effects of AEDs has not been determined as most people with epilepsy are managed as outpatients and are not hospitalized for either the epilepsy or for the adverse effects It is easy to estimate adverse effects in hospitalized patients and in patients who are hospitalized for the serious adverse effects However, the majority of adverse effects to AEDs are mild and
do not require admission In the outpatient setting, many of the mild adverse effects are either not reported
or not recorded; hence, it is difficult to determine the accurate incidence of adverse effects of AEDs One way
of evaluating the impact of adverse effects is to determine the proportion of patients who discontinue treatment (also referred to as treatment failure), for which there can be two reasons: (1) failure of the AED to control seizures adequately and (2) the occurrence of adverse effects during AED treatment It has been estimated that adverse effects of AED account for about 40% of treatment failures of AEDs in people with epilepsy.[2]
In a survey of selected patients with epilepsy, over 80%
Abstract
An adverse drug reaction (ADR) is defined by the World Health Organization as a noxious, unintended, and undesired drug effect, when used for therapeutic purposes in humans ADRs to anti-epileptic drugs (AEDs) significantly impact the quality of life of people with epilepsy and account for a little less than half of all recorded treatment failures with AEDs Hence prevention and early recognition of ADRs constitute an important aspect
of management of epilepsy Recent developments have improved our ability to predict and hence potentially prevent the occurrence of some of the serious ADRs to AEDs One example is the potential prediction of the risk of severe cutaneous hypersensitivity reactions including Stevens Johnson syndrome and toxic epidermal necrolysis by testing for expression
of HLA B*1502 allele in people of Asian origin who are prescribed carbamazepine The association between HLA B*1502 expression and carbamazepine skin reactions has been documented in India but the role of HLA testing in Indian populations needs to be clarified
in larger studies across different ethnic groups within the country
Key words: Adverse drug reaction, anti-epileptic drugs, Stevens Johnson syndrome, carbamazepine, HLA B*1502
Trang 2had reported at least one adverse event and the majority
had more than one adverse event.[3]
Definitions
The definition of an adverse drug reaction (ADR)
by the World Health Organization (WHO) is “any
noxious, unintended and undesired effect of a drug,
which occurs at doses used in humans for prophylaxis,
diagnosis or therapy” (World Health Organization,
1966) On the other hand, an “adverse event” refers
to any untoward experience that occurs during drug
treatment but which does not necessarily have a causal
relationship to the treatment.[4] The precise incidence of
ADRs in the community has never been estimated as
it is an onerous task due to inadequate documentation
and reporting It is easy to estimate the incidence of
ADRs in hospitalized patients In a meta-analysis of
ADRs to any medication, the overall incidence of ADRs
leading to hospitalization and in hospitalized patients
was 6.7% (95% CI 5.2–8.2%) and of fatal ADRs was
0.32% (95% CI 0.23–0.41%).[5]
The sources for determining ADRs in humans can be
many Prior to approval, pharmaceutical agents are
subjected to controlled clinical trials These clinical
trials, although rigorously regulated, might not bring
to light all possible ADRs as these are conducted for
short periods of time and in highly selected patient
populations While in the post-marketing phase, when
the drugs are used in much larger and unrestricted
patient population and often for unapproved
indications, several of the ADRs not reported in the
clinical trials come to light This underscores the
importance of meticulous and careful reporting of
adverse effects observed in the clinical practice as in
four of the case reports in this issue of the journal.[6-9]
The United States Food and Drug Administration (FDA)
has in place a well-established system, the FDA Safety
Information and Adverse Events Reporting Program
(also known as MedWatch), to which ADRs can be
reported in writing, telephonically or electronically
by prescribing physicians, other health-care workers,
patients and pharmaceutical companies (http://www
fda.gov/Safety/MedWatch) Each report is made in
a standard format and entered into a computerized
database and then analyzed by experts in order to
establish the causality A review of adverse event
reporting to the FDA from 1969 through 2002 revealed
about 2.3 million reports.[10] Likewise, in India, the
National Pharmacovigilance Advisory Committee
(NPAC) set up a system in 2004 to monitor safety of
medicinal products in India The committee has so
far appointed two zonal, five regional and about 25
peripheral pharmacovigilance centers ADRs can be
reported to the NPAC either directly or through one of the appointed centers (www.pharmacovigilance.co.in)
Antiepileptic Drugs – Incidence of Adverse Drug Reactions
The precise incidence of adverse effects to AEDs ideally needs to be determined in the community setting, but this apparently is an arduous task It might be possible to obtain community-based data from databases of general practices (e.g., the General Practice Research Database
in the UK) linked to pharmacy databases, but the information obtained thereof is likely to be incomplete
as many adverse effects are not reported and/or recorded It has been shown that systematic screening for adverse effects to AEDs using standardized and validated adverse effects profile-questionnaire provides
a greater yield of adverse effects experienced by the patients in comparison to spontaneous reporting by patients as is the usual practice in clinics.[11] Not only this, it results in better rationalization of AED treatment
as well as better QoL experienced by people with epilepsy The adverse effect profile-questionnaire is
a 19- or 21-item validated questionnaire, in which all items are scored on a 4-point scale (1 – never or rarely experienced adverse effect; 4 – common adverse effect)
by the patient.[11]
Systematic screening in pre-regulatory clinical trials results in a greater yield of adverse effects On the other hand, post-marketing studies might underestimate the magnitude of adverse effects to AEDs, but it is possible that new and hitherto unknown adverse effects come to light during this phase A large multicenter survey undertaken in Europe with over 5000 patients determined that 88% of the patients experienced at least one adverse effect and about one-third reported change of the AEDs in the previous one year on account
of adverse effects.[12]
Classification of Adverse Drug Reactions and Determination of Causality
In order to understand better the impact of ADRs, so frequently reported in many scientific journals, it is pertinent to review various classifications of ADRs The original Rawlins and Thompson’s classification (1977) of ADRs into Type A (augmented) and Type
B (bizarre) has been expanded to Types A through F [Table 1].[4,13] Other classifications are based on the frequency [Table 2] and severity of the ADRs An important concern is the assessment of causality of the reported ADRs Many standardized qualitative
or semi-quantitative approaches toward causality determination and classification are available
Trang 3Table 1: Classification of ADRs [4]
Type A Predictable, dose-related ADRs With most AEDs (with some interindividual variations between AEDs and patients): sedation,
somnolence, fatigue, tiredness, dizziness, unsteadiness, depression, agitation, nervousness, blurred vision, diplopia, ataxia, headache
With specific AEDs: leukopenia (carbamazepine), thrombocytopenia and deranged coagulation profile (valproate), hyponatremia (carbamazepine, oxcarbazepine), tremors (valproate), hypohiderosis (topiramate, zonimsamide), anxiety (levetericetam), paresthesiae (topiramate) Type B Unpredictable, idiosynchratic ADRs Skin rash both-, benign and anticonvulsant hypersensitivity syndrome (phenytoin,
carbamazepine, phenobarbital, lamotrigine, zonisamide) Aplastic anemia (phenytoin, carbamazepine, felbamate), angle closure glaucoma (topiramate), liver failure (valproate, felbamate, carbamazepine, phenytoin)
Type C Chronic, cumulative ADRs Osteomalacia and osteoporosis (phenytoin, carbamazepine, phenobarbital, valproate), gingivial
hyperplasia (phenytoin), hirsutism (phenytoin), weight gain (valproate, pregabalin, gabapentin), visual field loss (vigabatrin)
Type D Delayed ADRs Carcinogenesis (unproven in most cases, e.g., phenytoin-induced myeloma and lymphoma),
teratogenesis Type E ADRs evident only after withdrawal of drug NA
Type F Therapeutic failure of drug NA
Table 3: Assessment of causality of reported ADRs (adapted from Reference 2)
Category Explanation
Certain An ADR (clinical or laboratory) with definite time
relationship to drug administration, with appropriate response to drug withdrawal and documented by re-challenge with the drug The occurrence of the event cannot be explained by the underlying disease or other drugs
Probable An ADR (clinical or laboratory) with definite time
relationship to drug administration, with appropriate response to drug withdrawal but not documented by re-challenge with the drug The occurrence of the event cannot be explained by the underlying disease or other drugs
Possible An adverse event with plausible time relationship to
drug administration but might also be explained by the underlying disease or another drug Information on response to drug withdrawal is lacking
Unlikely An adverse event without plausible time relationship to
drug administration and which might be explicable by underlying disease or other drugs
Unclassified/
unclassified
A reported adverse event for which more data are required for causality assessment or not available
Table 2: Classification of ADRs to AEDs based on the frequency
of occurrence
Category Frequency (%) Examples
Very
common
>10 Dizziness, fatigue, tiredness, difficulty
in concentration
depression Uncommon 0.1–1 Ataxia, somnolence, skin rash
nephrolithiasis (topiramate) Very rare <0.01 Aplastic anemia (phenytoin), glaucoma
(topiramate)
[Table 3].[4,14] The assignment of causality is mostly
based on the temporal relationship of the adverse event
to drug administration, plausibility of its occurrence,
absence of a better explanation and consistency with
other reports of similar ADRs with the drug Going
by the above listed criteria, the ADRs reported in four
case reports in this issue of the journal are very rare
ADRs with a frequency of less than 0.01%.[6-9] With
the exception of the report of refractory hiccups due
to phenytoin therapy, in which case re-challenge with
phenytoin led to reappearance of hiccups, the ADRs
in the case reports might be classified as probable
inasmuch as re-challenge was not undertaken in the
patients.[9]
Patterns of Adverse Drug Reactions to
Antiepileptic Drugs
It remains unclear whether certain AEDs are more often
associated with ADRs Some adverse effects such as
dizziness, unsteadiness, sleepiness and tiredness occur
with nearly equal frequency during the use of any of the
conventional AEDs.[12] Other adverse effects such as hair
loss and weight gain are more specifically associated with
only certain AEDs such as valproate-sodium Attempts
to classify ADRs according to whether certain effects segregate along with certain others have generally not yielded any concrete pattern In one study of patients with refractory epilepsy, certain adverse effects tended to
go along with each other, e.g., restlessness with disturbed sleep, depression with nervousness or agitation, memory problems with difficulty in concentrating and sleepiness with tiredness.[3] The authors of this study classified ADRs to AEDs into five groups using factor analysis: disturbances of cognition and co-ordination, disorders of mood and emotion, sleep disturbances, weight changes and adverse effects related to the skin and mucosa The most common Type A (dose-related) adverse effects
do not vary much in their frequency of occurrence at
Trang 4least among the conventional AEDs (carbamazepine,
valproate, phenytoin and phenobarbital) Certain ADRs
(especially, certain Type B adverse effects) are AED
specific (e.g., weight gain with certain AEDs including
valproate-sodium, pregabalin and gabapentin) It is
generally believed that the second- and third-generation
AEDs produce lesser adverse effects than the conventional
AEDs In the Standard and New Antiepileptic Drugs
(SANAD) trial, while carbamazepine was found to be
significantly better than lamotrigine in terms of efficacy,
the latter was found better than the former in terms of
tolerability On the other hand, in people with either
generalized or unclassified seizures, valproate-sodium,
though significantly better than lamotrigine (a
second-generation AED) in terms of efficacy, was also superior
to another second-generation AED, topiramate, in terms
of tolerability In addition, certain newer AEDs have
been shown to have very serious and severe adverse
effects For instance, felbamate was approved by the
FDA in 1993 for use in patients with refractory partial
epilepsy with or without secondary generalization and
in children with Lennox Gastaut syndrome Within 1
year, following the reports of about 10 cases of aplastic
anemia and another 10 of hepatic failure (of which four
cases were fatal), the approval was withdrawn.[15,16] At
that time, an estimated 10,000–15,000 patients were on
treatment with the drug in the United States Hence,
letters were sent to several physicians warning them
about these potentially fatal adverse effects At present,
felbamate is approved for use only in those conditions
in which the benefit of administration far outweighs
the risks Another second-generation AED, vigabatrin,
was available in several countries for use in children
with infantile spasms and adults with complex partial
seizures not responding to other AEDs However,
post-marketing use in these countries revealed irreversible
peripheral visual field defects inasmuch as 30% of the
patients using the AED.[17] Hence, approval for use in
the United States by the FDA was withheld till as late as
2009 Hence, it might not be true that the newer AEDs
have lesser adverse effects than the conventional AEDs
The incidence of adverse effects is expected to vary
according to the patient population Hence, a recent
study in a cohort of patients with epilepsy, 50% of
whom were on more than one AED, revealed that 83%
experienced two or more adverse effects, and in this
subgroup, the mean number of adverse effects was seven.[3]
However, in a different study, with a cross-sectional
design, the frequency and pattern of ADRs did not differ
among patients on monotherapy and polytherapy.[18]
Hence, although it might be theoretically plausible that
polytherapy leads to more ADRs than monotherapy in
patients with refractory epilepsy and this contention
might be supported by data from pre-approval clinical
trials, in the pragmatic situation involving routine clinical
practice, polytherapy might not be disadvantageous in comparison to monotherapy in terms of adverse effect profiles at least in patients with refractory epilepsy
The Special Case of Carbamazepine Hypersensitivity Among People of Asian Origin
An unrelated but important issue concerns the occurrence
of severe hypersensitivity reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) among people of Asian origin The association between the HLA B*1502 allele and the occurrence
of carbamazepine-associated severe hypersensitivity reactions was first reported in the Hans Chinese in a controlled study from Taiwan.[19] In this report, the HLA B*1502 allele was expressed in all of the 44 cases with carbamazepine-induced severe hypersensitivity reactions, and in comparison, in only 3% of 101 carbamazepine-tolerant patients and 9% of 93 healthy, unexposed controls The odds ratio for the association was very high (2504; 95% CI 126–49,522) Similar associations, albeit less strong, were found among people
of Chinese origin from mainland China, Hong Kong, and among Thai and Malaysian patients.[20-22] One small study
of eight patients with carbamazepine-associated Stevens Johnson Syndrome from Gujarat in India also revealed HLA B*1502 expression in six.[23] However, no significant association was demonstrated in studies in Japanese and Caucasian (from Europe) people.[24,25] The FDA recently issued recommendations for screening of all people of Asian origin for the HLA B*1502 allele before initiating treatment with carbamazepine.[26] It recommended that those Asians who tested positive for the allele should avoid exposure to carbamazepine
Although not based on reliable comparative data, the frequency of carbamazepine-induced severe hypersensitivity reactions appears to be higher among people of Asian origin in comparison to Caucasians Furthermore, the strength of association between carbamazepine hypersensitivity and HLA B*1502 expression apparently depends on the background frequency of expression of this allele in the general population The highest frequencies of expression on the allele outside India have been reported among Filipinos (from Philippines), Chinese from Taiwan, mainland China and Hong Kong and among the Thai and Malaysians, in whom background rates are in the order of 10–20% Apparently, HLA B*1502 expression
is of very low order among Europeans In concordance with the background rates of allele expression, the association between HLA B*1502 and carbamazepine hypersensitivity is strongest among the Hans Chinese (from Taiwan), other Chinese, Thai and Malaysians
Trang 5Within India, in the ethnic population from Kandhesh
Pawra in Maharashtra in Western India, the frequency
of expression of this allele is as high as 6% In North
Indian populations from Delhi and Punjab, the frequency
of expression is about 1%.[23,26,27] Since India comprises
a very large and multiethnic population, the frequency
of expression of the allele is likely to be highly variable
Accordingly, the strength of association between HLA
B*1502 expression and carbamazepine hypersensitivity
is expected to vary by ethnic regions within India
Can the Impact of Adverse Drug Reactions be
Reduced?
Most Type A adverse effects are dose related Hence,
the incidence of Type A ADRs can be reduced by
keeping the dose of the required AED as low as possible,
whilst not compromising its efficacy At the same
time, although unproven, tolerance often develops
to many of the dose-related adverse effects of many
of the AEDs, such as dizziness, tiredness, fatigue and
sedation It makes sense, therefore, to slowly titrate
the doses of AEDs while initiating treatment, i.e., go
slow, keep low Even for certain Type B adverse effects,
for instance, lamotrigine-induced skin rash and
topiramate-induced glaucoma, slow upward titration of
doses helps In addition, recognizing patient subgroups
that are more predisposed to a particular adverse
effect is an important aid in reducing the incidence
of adverse effects For instance, valproate-induced
hepatotoxicity appears to be more common among
children <2 years of age, on AED polytherapy and
with underlying mental retardation and developmental
delay indicative of organic brain disease or inborn errors
of metabolism Hence, valproate should be started with
caution in such individuals Likewise, levetericetam
administration leads to psychiatric adverse effects
in some patients Careful analysis of these cases has
led to the understanding that psychiatric adverse
events appear to be more common among individuals
with prior psychiatric conditions or a family history
of psychiatric disease Hence again, levetericetam
should be started with caution in individuals with
prior or family history of psychiatric disorders A more
definitive example where screening helps in avoiding
untoward effects has been hitherto described – the
case of carbamazepine-induced hypersensitivity in
association with HLA B*1502 expression Finally, it
is most crucial to counsel patients and their families
regarding the possibility of occurrence of adverse
effects, their early recognition, the time frame in which
these are expected to occur and the importance of
reporting these adverse effects to the physician early,
while at the same time reassuring her/him that most
side effects are uncommon or rare
Conclusions
What do we learn and conclude from the contained case reports in this issue of the journal[6-9] and the limited data available on the association between HLA B*1502 allele expression and carbamazepine hypersensitivity from India? In the first place, we learn that as responsible physicians involved in the care of people with epilepsy,
we are justifiably obliged to report as completely as possible any suspected adverse event occurring during treatment with AEDs to the appropriate authority This will go a long way to ensure safety of the people with epilepsy that we care for Secondly, it is desirable to have multicenter studies from across the country on the association between HLA B*1502 expression and carbamazepine hypersensitivity The association studies might be extended to include a large number of single nucleotide polymorphisms that might be related to ADRs
to AEDs These are the take-home messages
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Source of Support: Nil, Conflict of Interest: None declared.
Trang 7not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use.