Drug Interactions between thiotepa and Tuinal

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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.

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.