National Journal of Physiology, Pharmacy and Pharmacology

RESEARCH ARTICLE
The pattern of adverse drug events to antiepileptic drugs: A cross-sectional
study at a tertiary care teaching hospital

Bharat M Gajjar1, Amit M Shah2, Pragna M Patel3

Department of Pharmacology, Pramukhswami Medical College, Karamsad, Gujarat, India, 2Department of Pharmacology,
1

GMERS Medical College, Gandhinagar, Gujarat, India, 3Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat, India

Correspondence to: Amit M Shah, E-mail: dr_amit84@yahoo.co.in

Received: July 15, 2016; Accepted: August 13, 2016

ABSTRACT

Background: The goal of antiepileptic therapy is to achieve complete seizure control with minimum adverse effects
impacting negatively on the quality of life. The drugs available in the market for the treatment of epilepsy have their own
new and unique adverse drug reaction profile. Aims and Objective: To study the pattern of adverse drug events (ADEs)
to antiepileptic drugs (AEDs) in a tertiary care teaching rural hospital in India. Materials and Methods: Data of all the
patients visited the Outpatient Department of Neuromedicine, Neurosurgery, and Paediatric Department of the Shree
Krishna Hospital in the study duration and who received AEDs as treatment, irrespective of diagnosis, age or sex were
collected after obtaining written informed consent from the patients. All the adverse events reported spontaneously as
well as founded by researcher during the interview at each visit were recorded in the case record form with all necessary
information. Results: Total 112 ADEs were reported from 58 (36.25%) patients in 6-month follow-up. Central nervous
system was most frequently affected with 68 (60.71%) ADEs followed by the gastrointestinal system (68, 60.71%).
Phenytoin was most commonly suspected AEDs (with 39 cases) followed by carbamazepine (in 23 cases). Causality
assessment by the WHO-UMC criteria most common association was possible in 75 (66.96%) cases, probable 21
(18.75%), certain 6 (5.36%), and conditional/unclassified 10 (8.93%). Similar result was obtained by Naranjo’s criteria
as possible 84 (75.00%), probable 22 (19.64%), and definite 6 (5.36%). 91 (80.36%) ADEs were not preventable by
modified Schumock and Thornton scale. Severity assessment by Hartwig’s criteria showed 79 (70.53%) ADEs as mild.
Number of AEDs given per patient had a statistical correlation with ADEs. Conclusions: There are higher chances of
development of ADEs in patients taking AEDs. However, at individualized regimens, the burden of ADEs is likely to
be related more to individual responsiveness, type of AEDs/AED combinations chosen, and physician treatment skills,
intensive therapeutic surveillance, education about epilepsy and the importance of drug compliance, and psychosocial
interventions.

KEY WORDS: Adverse Drug Events; Antiepileptic Drugs; Causality Assessment; Preventability; Severity Assessment

Access this article online INTRODUCTION

Website: www.njppp.com
DOI: 10.5455/njppp.2016.6.0823013082016
Quick Response code
Antiepileptic drugs (AEDs) have a narrow therapeutic index,
and their adverse effects can affect any organ and system;
their widespread use has significant safety implications.
Overall, 10-30% of people with epilepsy discontinue their
initially prescribed AED due to intolerance.[1] Adverse effects

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2016 | Vol 6 | Issue 6      National Journal of Physiology, Pharmacy and Pharmacology 616
Gajjar et al.
of AEDs can be divided into acute and chronic. Acute effects
can be dose/serum concentration related or idiosyncratic.
Most AEDs have a narrow therapeutic window – a small range
of serum concentrations within which seizure prevention
is achievable without significant toxicity or side effects.
This concept applies primarily to dose-related, reversible,
short-term side effects. Concentration-dependent effects are
common and troublesome but not usually life-threatening.
However, the risk of idiosyncratic effects such as allergic
reactions and organ damage must also be considered. Serious
idiosyncratic effects are rare but can be life-threatening. They
generally occur within several weeks or months of starting
the drug, tend to be dose-independent, and unpredictable.[2,3]
AEDs differ in the type and severity of adverse effects,
mostly during initiation and early treatment. The ability of
patients to tolerate initiation of AED can be a function of
several factors, including how rapidly a dose is escalated, the
length of time needed to develop tolerance to early toxicity
and the rate at which blood levels of a drug increase, as well
as complexity of the titration schedule. For some AEDs,
initiation with a small dose given at bedtime, followed by
slowly increasing the dose, or dividing a total daily dose
into multiple small portions taken throughout the day, and
may allow a patient to develop tolerance but increases the
complexity of the regimen. Patients will often adapt to a
regimen over a period.[4]
The goal of antiepileptic therapy is to achieve complete
seizure control with minimum adverse effects impacting
negatively on the quality of life. The drugs available in the
market for the treatment of epilepsy have their own new
and unique adverse drug reaction (ADR) profile.[5] Hence,
this study was planned with the aim to study the pattern of
adverse drug events (ADEs) to AEDs in our hospital setup.
MATERIALS AND METHODS
This was a prospective observational study conducted
between February 2010 and October 2011, in Shree Krishna
Hospital, a tertiary care teaching rural hospital attached
to Pramukhswami Medical College, Karamsad, Gujarat,
India. The study was approved by the Institutional Ethical
Committee.
Data of all the patients visited the Outpatient department
(OPD) of Neuromedicine, Neurosurgery, and Paediatric
Department of the Shree Krishna Hospital in the study
duration and who received AEDs as treatment, irrespective
of diagnosis, age or sex were collected after obtaining
written informed consent from the patients. The important
information was collected from their case sheet, discard card
to complete case record form. Each patient enrolled in the
study was followed up for next 6 months. At each follow-up
visit, all patients were asked about ADRs as well as other
617          National Journal of Physiology, Pharmacy and Pharmacology
Adverse drug events to antiepileptic drugs
problems with these drugs use. They were interviewed
according to a questionnaire about the presence of adverse
events associated with the AED.
All the adverse events reported spontaneously as well as
founded by researcher during the interview at each visit
were recorded in the case record form with all necessary
information. Data were analyzed according to the following
parameters: (i) Frequency of patients developing ADEs
during follow-up; (ii) age and sex distribution of reported
ADEs; (iii) system wise distribution of reported ADEs; (iv)
causality assessment by the WHO-UMC scale and Naranjo’s
probability score and comparison in between two scores;[6,7]
(v) preventability of ADEs using criteria of Schumock and
Thornton modified by Lau et al., 2003;[8] (vi) severity of
ADEs using scale of Hartwig and Siegle.[9]
Statistical Analysis
All data obtained from 160 patients were analyzed with
the help of SPSS version 17 software. Data were presented
in frequency and percentage. Chi-square test was used in
analysis and P < 0.05 considered as significant.
RESULTS
Out of 160 patients enrolled in this study, total 131 patients
have completed total 6-month follow-up in the study because
27 patients lost to follow-up, 1 patient died in course of
1-month follow-up due to brain tumor metastasis, and
1 patient was operated for the reason for which AED was
prescribed; therefore, there was no more need of AED and
physician stop AED. Even though the ADE analysis was done
in 160 patients who enrolled in this study and was considered
intention to treat.
Out of total 160 patients, 58 (36.25%) patients developed
ADEs. Total 112 different ADEs were observed in 58 patients
with average incidence of ADEs per patients was 1.92. The
most of the patients fell within the age range of 18-65 years
(46, 5.17%) followed by that of more than 65 years (9,
15.52%). 40 (68.97%) patients were male and 18 (31.03%)
patients were female who were observed of having ADEs
during the study period.
The majority of ADEs had affected central nervous system
(68, 60.71%), followed by the gastrointestinal system
(15, 13.39%) (Table 1). The most commonly suspected
AED for development of ADE was phenytoin followed by
carbamazepine and oxcarbazepine (Table 2).
The analysis using the WHO-UMC scale[6] showed that, in
majority of the cases, a causality assessment was falling
in the category of the possible (75, 66.96%) and probable
(21, 18.75%), whereas in 6 (5.36%) cases, it was found
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Gajjar et al. Adverse drug events to antiepileptic drugs

to be certain, and in 10 (8.93%) cases, it was conditional/ (84.75%) and probable (22, 19.64%) categories. In both these
unclassified. Causality was also assessed by Naranjo’s methods, possible was common category (Table 3).
algorithm,[7] which is objective questionnaire-based method
of evaluation. The common association was of possible The preventability assessment of ADEs was carried out using
modified Schumock and Thornton scale[8] for all the reports
including the serious cases. It was evident that majority of
Table 1: System wise distribution of ADEs (N=112) ADEs were not preventable (90, 80.36%). 21 (18.75%)
System and type of ADEs Number of patients (%) ADEs were probably preventable. Only one ADR which
Central nervous system was definitely preventable was bleeding caused by aspirin/
Headache 13
warfarin in the patient who had history of deranged hepatic
enzyme system which metabolizes phenytoin and oral
Sedation 13
contraceptive pills.
Ataxia 11
Memory impairment 7 Out of 112 ADRs, 79 (70.53%) were mild adverse events. In
Tremor 7 24 (21.43%) cases, they were moderately severe, whereas in
Giddiness/vertigo 6 9 (8.03%) cases, they were severe in nature (Table 4). Most
Tiredness/weakness 4 of the adverse events (64, 57.14 %) were seen after 3 months
Pseudoseizures 2 of initiation of therapy followed by after 1-3 months
Cognitive impairment 2 (22, 19.64%).
Tingling in limbs 1
Of all factors; age, sex, number of concurrent conditions,
Hypertonia 1
and number of non-AEDs had not shown any statistically
Insomnia 1
significant association with ADEs occurrence (P > 0.5).
Total 68 (60.71) Number of AEDs taken was significantly associated with
Gastrointestinal system
Vomiting 6
Table 2: Suspected causal AEDs for adverse drug event
Change in appetite 6
Suspected AED for ADEs Number of ADEs in which
Gastritis 2 it involved
Indigestion 1 Phenytoin 39
Total 15 (13.39) Carbamazepine 23
Skin Oxcarbazepine 22
Acneiform skin eruption 3 Valproic acid 15
Rash 3 Clobazepam 12
Hair loss (Alopecia) 2 Pregabalin 11
Itching 2 Topiramate 7
Total 10 (8.93) Lamotrigine 7
Metabolic Clonazepam 5
Weight gain 3 Phenobarbitone 2
Weight loss 1
ADEs: Adverse drug events, AEDs: Antiepileptic drugs
Hyponatremia 1
Total 5 (4.46)
Table 3: Causality assessment of AEDs
Ophthalmic condition
Causal association WHO Naranjo’s
Diplopia 2
assessment association
Yellow vision 1 criteria criteria
Uprolling of eyeballs 1 N (%) N (%)
Total 4 (3.57) Certain/definitive 6 (5.36) 6 (5.36)
Oral condition Probable 21 (18.75) 22 (19.64)
Gingival hypertrophy 2 Possible 75 (66.96) 84 (75.00)
Oral ulcer 1 Unlikely 0 0
Total 3 (2.68) Conditional/unclassified 10 (8.93) NA
Other 7 (6.25) Unassessable/unclassifiable 0 NA
Total 112 (100) Total 112 (100) 112 (100)
ADEs: Adverse drug events AEDs: Antiepileptic drugs, NA: Not applicable

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Gajjar et al.
Table 4: Severity assessment of adverse drug events
according to Hartwig scale[11] (N=112)
Severity Level Number of events (%)
Mild 1 45 (40.18)
2 34 (30.35)
Total 79 (70.53)
Moderate 3 22 (19.64)
4a 0 or different types of geographic prevalence of diseases in our
4b 2 (1.79)
Total 24 (21.43)
Severe 5 1 (0.89)
6 8 (7.14)
7 0
Total 9 (8.03)
ADEs (P = 0.017). Out of 113 patients taking single AEDs,
35 patients developed ADEs, whereas 18 patients developed
ADEs out of 41 patients taking dual AEDs therapy and 5 out
of 6 patients observed to had ADEs who were on triple AED
therapy.
DISCUSSION
Adverse effects of AEDs are common, can have a considerable
impact on quality of life and contribute to treatment failure
in up to 40% of patients. The adverse effect profiles of AEDs
differ greatly and are often a determining factor in drug
selection because of the similar efficacy rates shown by most
AEDs. The most common adverse effects are dose-dependent
and reversible.[10]
In our study, 36.25% (58 out of 160) patients developed ADEs
during 6-month follow-up and total 112 ADEs were reported.
In Mathur et al. study in Hyderabad, Pal et al. study in
Cuttack, and Roopa et al. study in India, it was found that only
4.67%, 16.28%, 10.27% patients were suffering from ADEs,
respectively.[11,12] Adverse events reported by us were more
than other Indian studies because follow-up and surveillance
were done by us for 6 months to find adverse events. We had
also used questionnaire of checklist to identify ADEs along
with spontaneously reported ADEs by patients themselves.
In our study, the majority of patients having ADEs were fell
in the age group of 18-65 years which is similar to findings of
the study done by Seha et al.[13] More male (68.97%) patients
were affected with ADEs than female (31.03%) patients. This
is opposite to that reported in Perucca et al.[14] and Pal et al.[15]
Central nervous system side effects were at the top with
60.71% followed by gastrointestinal system 13.39% in this
study. Literature also shows that neurotoxic adverse effects are
encountered commonly and may include sedation, dizziness,
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Adverse drug events to antiepileptic drugs
blurred, or double vision, difficulty with concentration and
ataxia.[2] Headache (11.63%) and sedation (11.63%) were
commonly encountered ADEs. Soha et al. study in Iran had
similar finding with most frequent detected adverse reactions
to AEDs as sedation (7.29%) and amnesia (6.35%).[13] All
ADEs occurrence in our study was identical to the other
studies except headache. The reason for frequent occurrence
of headache in our population may be different AEDs
utilization pattern in our study as compared to other studies,
study population, or may be different or higher number of
concurrent medicine prescribed in our study population and
chances of drug-drug interaction are higher.
Phenytoin was the most frequently associated with ADEs
occurrence followed by carbamazepine in our study.
Phenytoin was also was frequently suspected in studies done
by Roopa et al.[12] and Arul Kumaran et al.[16] Older AEDs
were suspected for more number of ADEs occurrence than
newer generation in our study.[17]
In the present study, causality assessment of ADEs was done
by the WHO-UMC score[6] as well as Naranjo’s scale.[7]
Finding of both the scales was almost similar; majority of
ADEs fell in the category of “possible” by both WHO
(66.96%) and Naranjo’s scale (75.00%). The study by Pal et
al. in Cuttack, India showed majority of ADEs as probable
(53.48%), WHO-UMC score.[15] Anther study by Roopa et
al. in India showed probable in 65.62%.[12] More number
of ADEs was classified as possible category in our study
than another Indian study, may be because more number of
concomitant medicine and comorbid condition associated
with our study population which might explain ADEs. A
comparative study of causality assessment scales used in the
analysis of spontaneously reported events showed that there
is no difference between the two scales, but Naranjo’s scale is
more time-consuming as compared to the WHO scale.
Establishing the preventability status of the ADEs is essential
to adopt appropriate strategies to prevent the occurrence of
similar ADEs in the future. In of our study, majority (80.36%)
ADEs were not preventable. The rate of preventable ADRs
was 57%, as reported by Soha study in Iran using the same
scale.[13] Literature also suggested that 30-70% ADEs are
preventable.[18] Our result was inconsistent with other study
and literature; reason for dissimilarity may be most of the
patients were prescribed drugs in a rational way; or it is
the nature of the drugs to produce ADEs like dizziness by
clonazepam or clonazepam (pharmacodynamic property
of drug at therapeutic dose and unavoidable); maximum
recommended dose of the drug required to treat disease might
cause development of ADEs. Standard treatment guidelines
had been prepared and followed in our hospital; usual protocol
to mention drugs causing allergic reaction and similar drugs
which might cause allergic reaction in case sheet of patients
who visit the hospital.
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Gajjar et al.
It is necessary to access the severity of ADEs as treatment of
ADEs is highly dependent on it. In the present study, out of
112 events reported, 79 (70.53%) were scored at level 2 or
less on Hartwig’s scale and by definition requires no change
in treatment with the suspected drug or only withhold/
discontinue the suspected drug, but no specific intervention
is required. The study conducted in OPD by Pal in Cuttack et
al. found that mild (39.53%), moderate (32.55%), and severe
(27.90%) ADEs by applying the same scale for severity
assessment.[15] According to Soha et al. study in Iran, only
8 (0.76%) ADRs were identified as serious by applying the
WHO severity criteria.[13] The difference is seen in severity
of ADEs in our study than other studies may be because
of different criteria applied for the assessment; or different
type of ADEs occurred in the study population; or due to
different methods of identifying ADEs were applied, i.e., if
we apply questionnaire checklist even mild ADEs are also
reported which never even disturb routine life of the patient,
or by applying spontaneously reporting system by patient
themselves only report that ADEs that disturb routine life of
the patient and therefore seek intervention.
In our study, the majority (57.14%) of ADEs were appeared
after 3 months of starting the therapy. Literature search
suggests that most of the ADEs appear during initiation and
early treatment.[4] Contradictory finding is due to low initial
dose and slow titration of doses of AEDs in this study.
In the present study, high ADEs occurred in patients taking
more number of AEDs (P = 0.017). Soha et al. study in Iran
also showed polytherapy was associated with more ADRs
than monotherapy (P = 0.039).[13] Roopa et al. study in India
showed a higher incidence of ADEs with polytherapy but
no statistical correlation between polytherapy and ADEs
occurrence.[12] Canevini et al. study in Italy and Mei et al.
study in Brazil showed no correlation between monotherapy
and polytherapy of the AEDs.[19,20] However, it is well
understood that many of the AEDs inhibit/induce hepatic
microsomal enzymes system and have narrow therapeutic
index, so chances of drug-drug interactions are higher, which
will lead to increase chances of occurrence of ADEs.
Some of the limitations of this study may be as follows:
(i) We have collected data from only one institute; therefore,
population is relatively homogenous. Large studies involving
heterogeneous population are required. (ii) We have enrolled
only patients from outpatients department, studies needed to
evaluate prescription pattern and adverse events for inpatients
department. (iii) We have followed up all enrolled patients
only for 6 months, not whole treatment span, further studies
needed having follow-up of whole treatment span. (iv)
Evaluation of AEDs will be further studied in other disorders
than epilepsy with recommended doses. (v) Irrespective of
methods of causality assessment of ADEs, assignment of a
causality link between the reported ADEs and the prescribed
medication relies on subjective judgment.
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Adverse drug events to antiepileptic drugs
Despite this limitation, we believe that the strength of our
data is such that it has revealed several important aspects of
the ADEs with AEDs. After considering all these factors, it is
evident that there should be prescribing guidelines for AEDs,
and it must be strictly adhered by prescribing physician for
better heath outcome and improvement in the quality of life
of patients suffering from epilepsy and who are taking AEDs.
CONCLUSION
In conclusion, the present study demonstrated the higher
chances of development of ADEs in patients taking AEDs.
However, at individualized regimens, the burden of ADEs
is likely to be related more to individual responsiveness,
type of AEDs/AED combinations chosen, and physician
treatment skills, intensive therapeutic surveillance, education
about epilepsy and the importance of drug compliance, and
psychosocial interventions.
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How to cite this article: Gajjar BM, Shah AM, Patel PM. The
pattern of adverse drug events to antiepileptic drugs: A cross-
sectional study at a tertiary care teaching hospital. Natl J Physiol
Pharm Pharmacol 2016;6(6):616-621.
Source of Support: Nil, Conflict of Interest: None declared.
2016 | Vol 6 | Issue 6