Optimal Prevention of Seizures Induced by High‐Dose Busulfan

Abstract

High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.

Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease

“…For seizure prophylaxis, clonazepam (1 mg) was administered on the days surrounding test dose administration and three times a day throughout conditioning (evening of day −7 through day −2) [18]. Acetaminophen was prohibited during busulfan administration.…”

Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children

“…Furthermore, it needs to be examined whether the outcome and the incidence of side effects such as acute graft-versus-host disease (aGvHD) and SOS correlate with the existence of GST polymorphisms. In addition, especially when giving busulfan orally, co-medications like phenytoin, metronidazole, and azole antifungals, which are prescribed for seizure and infection prophylaxis (33), have been shown to influence busulfan clearance although they do not play a major role when busulfan is administered intravenously. Intravenous formulations of busulfan are given with more priority to reduce the high PK variability (34).…”

A Case of posterior reversible encephalopathy syndrome in a pregnant woman with sickle cell anemia

“…4,6,19 Other antiepileptics drugs can be used while considering the patient's coexisting medical disorders and prescribed drugs. 30 While long-term follow-up studies are limited, seizure recurrence or epilepsy appears to be rare. In one case series of 127 patients who had recovered from an episode of RPLS, unprovoked seizures occurred in 8 patients over a median 3.2 years of follow up.…”