Update on Levetiracetam in Infants and Children

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


Pediatr Pharm. 2018;24(7) 

In This Article

Pyridoxine to Reduce Behavioral Adverse Effects

The use of pyridoxine (vitamin B6) to prevent levetiracetam-associated behavioral adverse effects (BAEs) was initially reported more than a decade ago and has become a relatively common practice. In the cohort study by Shellhaas described earlier, 43 of the 291 patients (43%) prescribed levetiracetam as their initial AED were given pyridoxine to reduce the risk of BAEs.[2] The mechanism of pyridoxine's effect has not been determined, and the use of this combination has not been well studied.

A prospective case-control trial evaluating the use of pyridoxine to prevent or mitigate BAEs in children taking levetiracetam was published earlier this year by Marino and colleagues in the Annals of Pharmacotherapy.[11] The authors enrolled 50 patients (mean age 10.2 + 2.77 years) with focal or generalized epilepsy receiving levetiracetam as monotherapy. After 30 days, the children were randomized to levetiracetam either alone or in combination with pyridoxine 7 mg/kg/day (maximum dose 350 mg/day). Patients were evaluated monthly for 1 year with the Children's Depression Inventory (CDI). This questionnaire evaluates a wide range of BAEs including mood disorders, vegetative functions, self-esteem, social behavior, and ability to feel pleasure. Scores range from 0 to 54, with higher scores indicating greater BAEs. In addition to CDI scores, patients underwent a clinical exam and video EEG testing, as well as measurement of serum levetiracetam and pyridoxal phosphate (PLP), the active metabolite of pyridoxine.

There were no significant differences in age, seizure type, or CDI scores between the pyridoxine and control groups at baseline. All patients had normal results on MRI imaging. The mean daily levetiracetam dose was also similar between the groups: 38.6 + 2.12 mg/kg/day in the levetiracetam patients and 39.2 + 7.4 mg/kg/day in those receiving levetiracetam plus pyridoxine. Behavioral adverse effects were frequent in both groups, with the most common being irritability and aggression, followed by depression and confusion. Only 25% of the levetiracetam plus pyridoxine group and 20% of the levetiracetam group remained free of BAEs for the duration of the study. The average time to development of a BAE was 7.4 + 2.8 days and 7.68 + 2.86 days in the two groups, respectively. Seventy-six percent of the patients in the levetiracetam group discontinued treatment as the result of BAEs, compared to only 8% in the levetiracetam plus pyridoxine group (p < 0.001). Mean CDI scores at 12 months were also significantly better in the levetiracetam plus pyridoxine group, with 82% of patients having scores less than 19, compared to just 29% of the levetiracetam patients (p < 0.001). The mean length of time to resolution of BAEs after the addition of pyridoxine was 9 + 3 days. All serum levetiracetam and PLP levels were within the target range, and no adverse effects from pyridoxine were noted.