Drug Interaction Report

GENERALLY AVOID: Coadministration with strong CYP450 3A4 inhibitors may increase plasma concentrations of thiotepa, and decrease concentrations of its active metabolite triethylenephosphoramide (TEPA). Thiotepa is a prodrug that is primarily converted to TEPA by the isoenzyme. A pharmacokinetic study evaluating six breast cancer patients receiving high-dose chemotherapy (cyclophosphamide 1,500 mg/m2/day, thiotepa 120 mg/m2/day, and carboplatin AUC 5 mg min/mL/day) with the moderate CYP450 3A4 inhibitor aprepitant (125 mg one day before chemotherapy, then 80 mg daily during and for three days after) showed a 15% increase in total thiotepa exposure, a 33% decrease in TEPA formation, and 20% reduction in TEPA exposure. Although clinical evidence is limited, strong CYP450 3A4 inhibitors may more significantly increase thiotepa exposure and reduce TEPA exposure, potentially resulting in more thiotepa-related adverse effects and reduced efficacy.

MANAGEMENT: The use of thiotepa in combination with strong CYP450 3A4 inhibitors should generally be avoided. If concomitant use of a strong CYP450 3A4 inhibitor is required, it is recommended that patients be carefully monitored for reduced efficacy and thiotepa-related toxicities such as myelosuppression, cutaneous toxicity, and neurotoxicity.

ADJUST DOSING INTERVAL: Food may reduce the systemic bioavailability of amprenavir from fosamprenavir oral suspension. The mechanism of interaction has not been described. According to the product labeling, administration of fosamprenavir oral suspension (1400 mg single dose) with a high-fat meal (967 kcal, 67 g fat, 33 g protein, 58 g carbohydrate) reduced amprenavir peak plasma concentration (Cmax) by 46% and systemic exposure (AUC) by 28% compared to administration in a fasted state. The time to reach peak plasma level (Tmax) was delayed by 0.72 hours. In contrast, the same high-fat meal did not affect the pharmacokinetics of amprenavir from fosamprenavir tablets.

MANAGEMENT: Fosamprenavir suspension should be administered on an empty stomach in adults, but with food in pediatric patients to aid palatability and compliance. If emesis occurs within 30 minutes after dosing the suspension, the dose should be repeated. Fosamprenavir tablets may be taken with or without food.