Drug Interaction Report

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ibrexafungerp, which is primarily metabolized by the isoenzyme in vitro. In healthy subjects receiving the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 15 days), ibrexafungerp peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.5-fold and 5.8-fold, respectively. Increased plasma concentrations of ibrexafungerp may increase the risk for adverse effects such as diarrhea, nausea, abdominal pain, dizziness, and vomiting.

MANAGEMENT: The manufacturer recommends a dose reduction of ibrexafungerp to 150 mg approximately 12 hours apart (e.g., in the morning and in the evening) for one day when used concomitantly with potent CYP450 3A4 inhibitors.

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: Coadministration with grapefruit juice may increase the plasma concentrations of ibrexafungerp. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In healthy subjects receiving the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 15 days), ibrexafungerp peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.5-fold and 5.8-fold, respectively. Increased plasma concentrations of ibrexafungerp may increase the risk for adverse effects such as diarrhea, nausea, abdominal pain, dizziness, and vomiting.

When administered to healthy volunteers with a high-fat meal (800 to 1000 calories; 50% fat), ibrexafungerp Cmax and AUC increased 32% and 38%, respectively, compared to fasted conditions.

MANAGEMENT: Ibrexafungerp may be administered with or without food. However, avoiding consumption of grapefruit or grapefruit juice during treatment with ibrexafungerp may be advisable.

The recommended maximum number of medicines in the 'antifungal agents' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'antifungal agents' category:

• Brexafemme (ibrexafungerp)
• posaconazole

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.