Drug Interactions between fosphenytoin and Thioplex

GENERALLY AVOID: Coadministration with strong CYP450 3A4 inducers may decrease plasma concentrations of thiotepa and increase concentrations of its active metabolite triethylenephosphoramide (TEPA). Thiotepa is a prodrug that is primarily converted to TEPA by the isoenzyme. In a study involving a 42-year-old male with relapsing germ-cell cancer, the pharmacokinetics of thiotepa and its active metabolite (TEPA) were assessed during two high-dose chemotherapy courses (cyclophosphamide 1500 mg/m2/day, thiotepa 120 mg/m2/day, and carboplatin), with phenytoin initiated five days before the second course for seizure management. In the second course, TEPA exposure increased by 115% and thiotepa exposure decreased by 29%, resulting in a thiotepa dose reduction of nearly 40% on day 3 due to the increased risk of toxicity from higher TEPA exposure.

MANAGEMENT: Given the increased risk of toxicity, concomitant use of thiotepa with strong CYP450 3A4 inducers should generally be avoided. If coadministration with a strong CYP450 3A4 inducer is required a dose reduction may be considered. Patients should also be more closely monitored for thiotepa-related toxicities such as myelosuppression, cutaneous toxicity, and neurotoxicity. Pretreatment and subsequent blood counts may be used to guide dose adjustments in accordance with product labeling.