Drug Interactions between Fiorinal and thiotepa

MONITOR: Coadministration with CYP450 3A4 and/or 2B6 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 these isoenzymes. 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. Clinical data for thiotepa use in combination with other less potent CYP450 3A4 inducers or with CYP450 2B6 inducers are not available.

MANAGEMENT: Caution and closer monitoring for adverse effects is advised when thiotepa is used concurrently with CYP450 3A4 and/or 2B6 inducers. Patients should be more closely monitored for thiotepa-related toxicities such as myelosuppression, cutaneous toxicity, and neurotoxicity. A dosage reduction of thiotepa may be necessary. Pretreatment and subsequent blood counts may be used to guide dose adjustments in accordance with product labeling.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.