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Neurology India, Vol. 59, No. 1, January-February, 2011, pp. 53-58 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 Date of Submission: 25-Jan-2011 Code Number: ni11012 PMID: 21339660 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.Keywords: 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 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% had 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],[7],[8],[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 ( http://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 [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],[7],[8],[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 least 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],[21],[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. Within 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],[7],[8],[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. References
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