Drug Interactions between Docivyx and posaconazole

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may significantly increase the plasma concentrations of docetaxel, which is a substrate of the isoenzyme. Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg/m2) reported that docetaxel AUC increased by 65% compared with the AUC target of 1.96 mg*h/L and clearance decreased by 63%, with a 71% reduction in the patient's neutrophil count. In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months. Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%.

MANAGEMENT: The use of docetaxel in combination with grapefruit and grapefruit juice should generally be avoided. If concomitant use is required, a reduced dosage of docetaxel should be considered, particularly if used with large amounts of grapefruit juice, and therapeutic drug monitoring of docetaxel considered per local treatment protocols. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

ADJUST DOSING INTERVAL: Food significantly increases the absorption of posaconazole from the oral suspension but only modestly from the delayed-release tablet. Following single-dose administration, posaconazole mean peak plasma concentration (Cmax) and systemic exposure (AUC) are approximately 2.5 to 3 times higher when the oral suspension is given with a nonfat meal or a nutritional supplement (14 grams of fat) than when given under fasting conditions, and approximately 3.5 to 4 times higher when given during or 20 minutes after a high-fat meal (50 grams of fat) than under fasting conditions. Acidic beverages may also increase posaconazole absorption. In 12 healthy volunteers, administration of a single 400 mg dose of posaconazole suspension with 12 ounces of ginger ale increased posaconazole Cmax by 92% and AUC by 70% compared to administration after fasting. In contrast, the Cmax and AUC of posaconazole increased by just 16% and 51%, respectively, when posaconazole tablets were given as a single 300 mg dose to healthy volunteers after a high-fat meal relative to a fasted state.

GENERALLY AVOID Concomitant use of alcohol and posaconazole administered in the form of delayed-release oral suspension may lead to a faster release of posaconazole. An in vitro dissolution study determined a potential for alcohol-induced dose-dumping with the delayed-release oral suspension of posaconazole.

MONITOR: In 5 study subjects, posaconazole Cmax decreased by 27% to 53% and AUC decreased by 33% to 51% when the oral suspension was administered via a nasogastric tube as opposed to orally.

MANAGEMENT: Posaconazole tablets should be taken with food, whereas posaconazole oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance bioavailability. Patients who cannot eat a full meal should take the suspension with a liquid nutritional supplement or an acidic carbonated beverage such as ginger ale. In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking another formulation of posaconazole, alternative antifungal therapy should be considered; otherwise, monitor patients closely for breakthrough fungal infections. Patients receiving posaconazole via a nasogastric tube should also be closely monitored due to increased risk of treatment failure associated with lower plasma exposure. Administration of alcohol with posaconazole from the delayed-release oral suspension formulation is not recommended.