Topic of the issue: Review Article 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 Abstract Address 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 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 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 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 Access this article online Quick Response Code: Website: www.neurologyindia.com PMID: *** DOI: 10.4103/0028-3886.76859 Neurology India | Jan-Feb 2011 | Vol 59 | Issue 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 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% 53 Singh: Antiepileptic drugs – Adverse drug reactions had reported at least one adverse event and the majority had more than one adverse event.[3] reported to the NPAC either directly or through one of the appointed centers (www.pharmacovigilance.co.in) Definitions Antiepileptic Drugs – Incidence of Adverse Drug Reactions 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 54 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; – 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 Neurology India | Jan-Feb 2011 | Vol 59 | Issue Singh: Antiepileptic drugs – Adverse drug reactions Table 1: Classification of ADRs[4] Type Description Type A Predictable, dose-related ADRs Type B Type C Type D Type E Type F Examples 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) 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) Chronic, cumulative ADRs Osteomalacia and osteoporosis (phenytoin, carbamazepine, phenobarbital, valproate), gingivial hyperplasia (phenytoin), hirsutism (phenytoin), weight gain (valproate, pregabalin, gabapentin), visual field loss (vigabatrin) Delayed ADRs Carcinogenesis (unproven in most cases, e.g., phenytoin-induced myeloma and lymphoma), teratogenesis ADRs evident only after withdrawal of drug NA Therapeutic failure of drug NA Table 2: Classification of ADRs to AEDs based on the frequency of occurrence Category Very common Common Uncommon Rare Very rare Frequency (%) Examples >10 1–10 0.1–1 0.01–0.1