Evaluation of adverse drug reaction profile of antiepileptic drugs in persons with epilepsy: A cross-sectional study

Highlights

• Among 1011 persons with epilepsy on antiepileptic drugs (AEDs), 1990 adverse drug reactions (ADRs) were encountered.

• Anger and aggression and somnolence were the most common ADRs encountered in this study.

• Newer vs. conventional AEDs did not differ in ADRs profile except higher serious ADRs with conventional AEDs.

• Monotherapy vs. polytherapy had differences in ADRs related to nervous system, skin, and subcutaneous tissue.

• Adverse drug reactions lead to dose modification in about 49% of persons with epilepsy.

Abstract

Introduction

Newer antiepileptic drugs (AEDs) are preferred over conventional AEDs with the perception of better safety profile and efficacy though there is a lack of confirmatory evidence. The present study assessed the adverse drug reactions' (ADRs) profile of AEDs prescribed in persons with epilepsy (PWE) as per the System Organ Class (SOC) and compared them on the basis of demographics and treatment pattern.

Material and methods

This prospective, cross-sectional, and observational study was conducted in PWE attending Neurology Outpatient-Department from February 2016 to April 2019 who were presented with any ADR. World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale was used for the causality assessment of suspected ADRs.

Results

Among the 1011 PWE on AEDs, male:female ratio was 622:389, adult:pediatric ratio 736:275, and conventional:newer AEDs ratio 624:387. Among monotherapy PWE (47.1%), commonly used AEDs were levetiracetam (34.4%), valproic acid (22.9%), carbamazepine (18.3%), phenytoin (11.9%), and other AEDs (12.5%). A total of 1990 ADRs (1.96 ADRs per PWE) were reported as per SOC; among them, newer vs. conventional AEDs did not reveal any significant difference; however, monotherapy vs. polytherapy showed differences in nervous system disorders (p = 0.01) and skin and subcutaneous tissue disorders (p = 0.005). Causality assessment revealed 0.3% certain, 27.3% probable, 61.3% possible, and 11.1% unlikely association of ADRs with AEDs. Depending on the ADRs, there was either withdrawal of AED (0.9%), reduction in dose (48.4%), or continuation in the same dose as before (50.7%).

Conclusion

The ADR analysis showed that newer AEDs were associated with a similar trend of ADRs as that of conventional AEDs. Thus, the choice among newer and conventional AEDs should preferably focus on the experience of better efficacy in addition to safety data.

Introduction

Epilepsy is defined by International League Against Epilepsy as a disease of the brain with at least two unprovoked seizures occurring more than 24 h apart or one unprovoked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures, occurring over the next 10 years, or diagnosis of an epilepsy syndrome [1]. As per a recent study, 70 million people had epilepsy worldwide, and among them, 90% live in developing regions [2]. It is estimated that there are more than 12 million persons with epilepsy (PWE) in India. Its prevalence is about 1% in our population [3]. Epilepsy treatment often requires long-term antiepileptic drugs' (AEDs) use, and adverse drug reactions (ADRs) related to AEDs account for considerable economic burden to the subject, healthcare providers, and society. World Health Organization (WHO) defined ADR as “A response which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.” [4]. The incidence of ADR-related hospital admissions was 5–10% [5]. The proportion of serious and fatal ADRs among patients admitted in hospital is 6.7% and 0.32%, respectively [6]. Sometimes, ADR-related costs, such as surgery, lost productivity, and hospitalization, exceed the medications' cost [7]. Currently, more than 25 AEDs for the treatment of epilepsy were in the market, with similar efficacy but different tolerability profile. Various ADRs are seen in long-term treatment in 60% of PWE, which requires a change of AEDs in 33% of PWE [8]. The psychiatric and behavioral adverse effects occurred in 17.2% of PWE, and the highest association was with levetiracetam (LEV) [7]. The idiosyncratic reactions may manifest as simple rashes as well as fatal reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Chronic effects include hirsutism, gingival hyperplasia, and weight gain [9]. Antiepileptic drugs are effective in epilepsy treatment to the extent that about 70% of PWE can be seizure-free, but poor compliance to medication is a major concern [10]. One of the major reasons for poor compliance is AED-related adverse effects and cost of treatment [11]. Polytherapy can lead to a higher risk of adverse drug effects compared with monotherapy. A recent study has shown a higher prevalence of polytherapy than monotherapy [12], which could be due to increased use of second-generation AEDs as add-ons. However, several other studies have highlighted a contradictory opinion where monotherapy was prescribed to the majority of PWE (70–96%) in India [13,14].

The AEDs' associated adverse effects are highly specific and highly individual. Some adverse effects like carbamazepine (CBZ)-induced SJS have been correlated with human leukocyte antigen (HLA) (HLA-B ∗ 15:02 allele) [15]. So, the choice of AEDs was based on individual PWE and drug characteristics [16]. Though in current practice, newer drugs are preferred over conventional AEDs, there is a lack of confirmatory comparative trials expressing superiority of newer AEDs. The present study assessed the ADRs' profile of AEDs prescribed in PWE as per the System Organ Class (SOC) and compared them on the basis of demographics and treatment pattern. This will help in rationalizing AEDs' treatment in PWE with supportive evidence.