Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the oral bioavailability and plasma concentrations of itraconazole and ketoconazole. In vitro studies have shown that CYP450 3A4 is the major enzyme involved in their metabolism, and pharmacokinetic studies as well as case reports have demonstrated decreases in itraconazole and ketoconazole systemic exposure (AUC) by at least 80% and sometimes even to undetectable levels when coadministered with potent CYP450 3A4 inducers such as rifampin or phenytoin, including reports of treatment failure.

MANAGEMENT: Concomitant use of itraconazole or ketoconazole with potent CYP450 3A4 inducers should generally be avoided. Some authorities recommend avoiding coadministration of potent CYP450 3A4 inducers from 2 weeks before and during treatment with these azole antifungal agents unless the benefits outweigh the risk of potentially reduced antifungal efficacy. If coadministration is required, clinical response and antifungal activity should be closely monitored and the itraconazole or ketoconazole dosage increased as necessary.

GENERALLY AVOID: Excessive use of alcohol or products containing alcohol together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole. Hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no obvious risk factors for liver disease. In addition, use of alcohol or products containing alcohol during ketoconazole or levoketoconazole therapy may result in a disulfiram-like reaction in some patients. Symptoms of disulfiram-like reaction include flushing, rash, peripheral edema, nausea, and headache.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of ketoconazole or levoketoconazole. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. 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.

When administered to healthy volunteers with a high-fat meal (875 calories; 62% fat), levoketoconazole systemic exposure (AUC) increased by 30% while peak plasma concentration (Cmax) did not change and the time to reach Cmax (Tmax) was delayed from 2 to 4 hours, compared to fasted conditions.

MANAGEMENT: Levoketoconazole may be administered with or without food. Excessive consumption of alcohol should generally be avoided during ketoconazole or levoketoconazole therapy. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during ketoconazole or levoketoconazole therapy. Patients receiving ketoconazole or levoketoconazole should be instructed to contact their doctor immediately if they experience swelling, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage.