Drug Interactions between Equetro and Tepadina

GENERALLY AVOID: Coadministration with carbamazepine may result in decreased plasma concentrations of cyclophosphamide and thiotepa, while concentrations of their main active metabolites increase. The proposed mechanism is carbamazepine induction of CYP450 2B6 and 3A4, the isoenzymes responsible for the bioactivation of cyclophosphamide and thiotepa to 4-hydroxycyclophosphamide and tepa, respectively. In one study, pharmacokinetics of the prodrugs and their active metabolites were determined in a 52-year-old female patient with metastatic breast cancer receiving three 4-day courses (4 weeks apart) of high-dose chemotherapy with cyclophosphamide (1000 mg/m2/day), thiotepa (40 mg/m2 twice a day), and carboplatin. The patient used carbamazepine and vigabatrin for epilepsy during cycles 1 and 2, but anticonvulsant treatment was discontinued after the second cycle due to severe nausea and vomiting that made it difficult for the patient to ingest the medications. Compared to day 1 of cycle 3, plasma exposure (AUC) to cyclophosphamide and thiotepa on day 1 of the first two cycles was reduced 40% and 43%, respectively, while exposure to 4-hydroxycyclophosphamide and tepa was increased by 58% and 75%, respectively. The effect of carbamazepine appeared to diminish after the first day, presumably because cyclophosphamide itself is also an inducer of CYP450 2B6 and 3A4 and may have had the same effect as carbamazepine during subsequent days of cycle 3. Thus, the overall AUCs were only moderately affected by carbamazepine in this case, and it is possible that the interaction may be more clinically relevant in single-dose administrations of the antineoplastic agents.

MANAGEMENT: Given the potential for interaction and the high degree of interpatient variability with respect to hepatic enzyme activities, the use of cyclophosphamide or thiotepa in combination with carbamazepine should be avoided if possible. Anticonvulsants with no significant effects on CYP450 hepatic enzymes such as valproic acid, lamotrigine, or gabapentin may be appropriate alternatives. If carbamazepine is required, consideration should be given to dosage reduction of the chemotherapeutic agents. In addition, plasma levels of the active metabolites should be monitored to guide further dosing.

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