Safety, Efficacy, and Favorability of Utilizing Levetiracetam for Busulfan-Induced Seizure Prophylaxis in Pediatric Patients Undergoing Hematopoietic Cell Transplant (HCT)

Intravenous Busulfan is a common conditioning agent for children undergoing HCT. A potential adverse effect of Busulfan is seizures thus anti-convulsant prophylaxis is standard. Phenytoin is no longer preferred given its potent inhibition of cytochrome P450 hepatic enzymes and benzodiazepenes also have significant side effects that may prohibit use. One promising alternative is Levetiracetam, a second-generation antiepileptic with lower side effect profile and limited drug interactions including Busulfan. We evaluated the incidence, safety, and efficacy of Levetiracetam for short-term anti-seizure prophylaxis in pediatric patients receiving Busulfan as part of HCT conditioning.

Retrospective chart review was done on patients who received Busulfan prior to HCT from 2007 to 2012.  A total of 95 patients with a malignant or non-malignant diseases, and autologous or allogeneic donors were included. First line anti-convulsant therapy was Lorazepam (0.2mg/kg IV/PO every 6 hours). Those patients who had documented or new adverse reactions to Lorazepam, who were already taking Levetiracetam, or who had increased baseline risk factors for seizures, received alternative prophylaxis with Levetiracetam (10-15mg/kg IV/PO every 6 hours).

Of the 95 patients who received Busulfan-based conditioning, 33 (35%) received Levetiracetam instead of institutional standard Lorazepam. Thirteen of the 33 patients (30%) were either previously on Levetiracetam due to a prior seizure or received it preemptively due to increased risk of seizures. Twenty-three of these 33 patients (70%) were switched to Levetiracetam due to prior (n=10) or development of new (n=13) adverse reaction to Lorazepam. Levetiracetam was extremely well tolerated with no adverse events. There were no Busulfan-induced seizures or neurotoxicity in either cohort.

Our findings indicate that one-third of analyzed patients required Levetiracetam instead of the institutional standard of Lorazepam for anti-convulsant prophylaxis during Busulfan administration. Overall, Levetiracetam was efficacious in preventing Busulfan-induced seizures with no documented side effects, whereas Lorazepam was not as well tolerated. Notably, a significant number of patients developed adverse reactions to Lorazepam mid-chemotherapy creating interruptive and unpleasant side effects, the most common being over-sedation, irritability and hyperactivity. Practically and economically, Levetiracetam is also attractive given its less frequent dosing and available low-cost generic formulation.

Current practice is to use benzodiazepines to prevent Busulfan-induced seizures. Our findings substantiate early data showing that not only is Levetiracetam safe, effective, and feasible in preventing Busulfan-induced seizures during pediatric HCT, but also may actually be favorable due to lower side effect profile and ease of administration.