Update on Levetiracetam in Infants and Children

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS

Disclosures

Pediatr Pharm. 2018;24(7) 

In This Article

Efficacy and Safety

Two recent meta-analyses have assessed the efficacy of levetiracetam in children. Zhang and colleagues performed a meta-analysis of 13 randomized controlled trials comparing levetiracetam to placebo or other AEDs as monotherapy or adjunctive therapy in 1,013 pediatric patients.[3] Eleven studies enrolled patients between 2 and 16 years of age, while the other two included infants. Levetiracetam was initiated at doses of 5–20 mg/kg/day and titrated to a maximum of 30–60 mg/kg/day. Five of the studies compared levetiracetam to oxcarbazepine, three to valproate, three to placebo, one to carbamazepine, and one to sulthiamine, an AED not available in the United States. Several of the studies included a placebo control group. The primary outcome for the studies was defined as a 50% or greater reduction in seizure frequency.

Levetiracetam was found to produce a response rate similar than that of the comparators (RR 1.08, 95% CI 1.01–1.16), p = 0.35). The percentage of seizure-free patients was also similar among the AEDs studied (RR 1.16, 95% CI 1.03–1.31, p = 0.3). The authors found a lower incidence of adverse effects with levetiracetam, but the difference did not reach statistical significance (RR 0.9, CI 95% 0.77–1.06, p = 0.22). The most commonly reported adverse effects were irritability and somnolence. The majority of adverse effects were classified as mild and did not require discontinuation.

Earlier this year, Rosati and colleagues published a meta-analysis of AED use in children categorized by seizure type.[4] They included 46 randomized clinical trials with a total enrollment of 5,652 children and adolescents. Comparators included 22 different AEDs as well as placebo. Carbamazepine and lamotrigine were found to produce higher response rates (a seizure frequency of 50% or greater) in the initial treatment of focal seizures, but the differences among the AEDs were not statistically significant. Nine studies of refractory focal epilepsy were included. In these trials, only levetiracetam and perampanel were found to produce a higher response rate than placebo (OR 3.3, 95% CI 1.3–7.6 and OR 2.5, 95% CI 1.1–5.8, respectively).

Another recent paper has added to our understanding of the efficacy of levetiracetam in pediatric patients with refractory epilepsy. Muramatsu and colleagues analyzed the cases of 49 children and adolescents (mean age 10.6 + 5 years) with multidrug refractory epilepsy lasting more than 2 years.[5] Following treatment with a mean levetiracetam dose of 38 mg/kg/day (range 8–87 mg/kg/day) for a minimum of 6 months, eighteen patients (37%) achieved a 50% or greater reduction in seizure frequency, with 13 becoming seizure-free. Nine patients improved on treatment, but had a less than 50% reduction in seizure frequency. Twenty patients (41%) had no response to levetiracetam, and two patients experienced a worsening of their seizure frequency.

The patients were further classified according to the presence of MRI abnormalities, including cerebral atrophy, leukoencephalopathy, congenital malformations, and focal cortical dysplasia, or the diagnosis of intellectual disability, defined as documented neurologic impairment or an IQ < 70. Of the 19 children with MRI abnormalities, 5 (26%) experienced a 50% or greater reduction in seizures. Among the 36 patients with intellectual disability, nine (25%) had a greater than 50% reduction. Levetiracetam was well tolerated, with the majority of patients (78%) having no significant adverse effects. Seven patients (14%) were found to have increased drowsiness, while one experienced irritability. The authors concluded that levetiracetam can be of benefit in children with multidrug refractory seizures, and may be useful even in patients with central nervous system lesions or significant neurologic impairment.

In contrast to these reports, the role for levetiracetam in preventing seizures within the first week after traumatic brain injury (TBI) remains unclear. A recent prospective observational study by Chung and O'Brien found that levetiracetam administration failed to effectively prevent early seizures following moderate to severe traumatic brain injury in children. A total of 34 patients (median age 6 years, range 5 days-16 years) received levetiracetam prophylaxis with a median dose of 20 mg/kg/day. Six patients (17%) had clinical seizures despite prophylaxis, with another two having non-convulsive seizures. The authors found that the prevalence of seizures in this cohort was similar to that reported in patients not receiving an AED, and higher than in previous reports using phenytoin (2-15%). Larger controlled studies are needed to determine the true efficacy of levetiracetam in pediatric TBI.

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