Drug Interaction Report

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.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.