Abstracts

Rationale: Long-term adherence to antiepileptic drugs (AEDs) is a critical element in management of seizures in patients with epilepsy or other psychological disorders. An ideal AED should have high potency and tolerability over the long term. In 2010, the U.S. Food and Drug Administration (FDA) issued a black box warning against the use of lamotrigine because of its adverse effect of aseptic meningitis. Some studies with small sample sizes suggest that other AEDs may be safer, but the comparative risk of aseptic meningitis associated with individual second-generation AEDs remains unclear. This study compares the risk of aseptic meningitis associated with the five most frequently prescribed AEDs to that of lamotrigine. Methods: This retrospective cohort study followed patients in a large nationally representative administrative claims database between 2006 and 2011. The sample consisted of Medicaid, Medicare and Commercial patients continuously enrolled with both medical and pharmacy benefits for one year prior to the index fill for an AED. Patients were included in the analysis if they: (a) were aged two years or older; and (b) were new monotherapy users of the five AEDs (no prior AED use in previous 90 days). Eligible patients were followed up to 12 months after the index date. Cox proportional hazard model was used to assess the risk of aseptic meningitis. Multivariate analysis was used to compare difference in time to aseptic meningitis event, adjusting for age, gender, region, index year and comorbidity. Results: The analysis included 719,749 new users of AEDs. Children comprised 8.3% (N=60,011, female=50.1%, age=13.0 [ 4.2]) and adults 91.7% (N=659,738, female=64.5%, mean age=57.1 [ 17.8]). Compared to patients prescribed lamotrigine, patients prescribed gabapentin, levetiracetam and topiramate had higher risk to develop aseptic meningitis (HR=1.80, 95% CI: 1.20-2.70, p=0.0047; HR=10.22, 95% CI: 6.69-15.61, p<0.0001; and HR=2.65, 95% CI: 1.71-4.10, p<0.0001 respectively). The median time to outcome was significantly shorter for children than adults (44.0 vs. 77.0 days, t=-2.73, p=0.0065). Patients treated with levetiracetam were quicker (29.5 days) to develop aseptic meningitis compared to those treated with lamotrigine (83.0 days) (t=-3.25, p=0.0012), but there was no difference in time to outcome in patients prescribed gabapentin and topiramate compared to lamotrigine.Conclusions: Rare but serious adverse effects resulting from treatment with AEDs are an important consideration in evaluating the risk vs. benefit of various treatment options. Despite the FDA black box warning for lamotrigine, this large sample retrospective cohort analysis showed three other commonly prescribed second-generation AEDs were associated with greater risk of developing aseptic meningitis. These new findings should be considered in weighing treatment options for patients with seizures.