Drug Interaction Report

ADJUST DOSING INTERVAL: Coadministration with thiotepa may significantly decrease the conversion of cyclophosphamide to its active metabolite, 4-hydroxycyclophosphamide (4-OHCP), which may reduce the efficacy of cyclophosphamide. The proposed mechanism is inhibition of CYP450 2B6 metabolism by thiotepa which is the enzyme responsible for the conversion of cyclophosphamide to its active form. The effect of thiotepa on cyclophosphamide appears to be sequence dependent with a greater reduction in the conversion to 4-OHCP when thiotepa is administered 1.5 hours prior to the intravenous administration of cyclophosphamide, although clinical drug interaction studies are not currently available. Additionally, using thiotepa and cyclophosphamide concomitantly may result in additive toxicities due to similar mechanisms of action and adverse effect profiles.

MANAGEMENT: It is recommended that the administration of thiotepa occur after the completion of cyclophosphamide therapy to avoid the potential for interaction. If coadministration is required, patients should be monitored for signs of reduced efficacy of cyclophosphamide and plasma levels of the active metabolite, 4-OHCP should be monitored to guide further dosing. Patients should also be monitored for increased adverse effects including myelosuppression, hepatic veno-occlusive liver disease, and pulmonary toxicity.