Drug Interactions between gepirone and Noxafil

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.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations and effects of gepirone. The proposed mechanism is inhibition of CYP450 3A4 mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. For example, when subjects who were at steady state on the strong CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) received a single dose of gepirone (36.3 mg), the maximum plasma concentration (Cmax) and systemic exposure (AUC) of gepirone increased by approximately 5-fold. Similarly, when subjects who were at steady state on the moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily) received a single dose of gepirone (18.2 mg), the maximum plasma concentration (Cmax) and systemic exposure (AUC) of gepirone increased by approximately 2.6-fold. In general, the effects of grapefruit products are concentration-, dose-, and preparation-dependent and can vary widely among both brands and individual patients. Some preparations have demonstrated strong CYP450 3A4 inhibition, while others have demonstrated moderate inhibition.

ADJUST DOSING INTERVAL: Food enhances the bioavailability of gepirone and its major active metabolites (3'-OH-gepirone and 1-PP). The magnitude of the effect is dependent on the fat content of the meal, but the systemic exposure of gepirone and its major metabolites was consistently higher under fed conditions as compared to the fasted state. The peak plasma concentration (Cmax) of gepirone after intake of a low-fat (about 200 calorie) breakfast was 27% higher, after a medium-fat (about 500 calorie) breakfast was 55% higher, and after a high-fat (about 850 calorie) breakfast was 62% higher than the Cmax achieved in the fasted state. Likewise, the systemic exposure (AUC) of gepirone was about 14% higher after a low-fat breakfast, 22% higher after a medium-fat breakfast, and 32% to 37% higher after a high-fat breakfast when compared to the AUC achieved in the fasted state. The effect of varying amounts of fat on the AUC and Cmax of 3'-OH-gepirone and 1-PP were similar to that of gepirone.

MANAGEMENT: Coadministration of gepirone with grapefruit products should be avoided. If grapefruit juice is consumed, monitoring for adverse effects (e.g., QT prolongation, serotonin syndrome, dizziness, nausea, insomnia, abdominal pain, and/or dyspepsia) should be considered. Gepirone should be taken orally with food at the approximately the same time each day. Tablets should be swallowed whole.