Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new‐onset epilepsy: A randomized double‐blind clinical trial

Abstract

SUMMARYPurpose: To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in newonset epilepsy. Methods: Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure. Results: At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047). Conclusion: This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

“…60–63 The prevalence of AEs with phenytoin use has been shown to be dose-related and independent of concomitantly administered medications. 64 In one study, 86% of patients with toxicity had phenytoin-free levels >2 μg/mL.…”

Evidence-Based Guideline: Management of an Unprovoked First Seizure in Adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society

“…30 For example a study of patients with new-onset epilepsy found initial AED monotherapy with either phenytoin or topiramate was associated with AEs leading to AED discontinuation in only 7% to 13% of patients. 32 Another in a mixed group of patients with epilepsy initially treated with AEDs found that AEs were no more likely to occur than in untreated controls and proposed that this was because the drugs were typically started as monotherapy and at low doses. 31 Conclusion.…”

Evidence-based guideline: Management of an unprovoked first seizure in adults

“…30 For example, a study of patients with new-onset epilepsy found that initial AED monotherapy with either phenytoin or topiramate was associated with AEs leading to AED discontinuation in only 7% to 13% of patients. 32 Another study in a mixed group of patients with epilepsy initially treated with AEDs found that AEs were no more likely to occur than in untreated controls and proposed that this was because the drugs were typically started as monotherapy and at low doses.…”