Drug Interaction Report

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 and/or 2C19 may increase the plasma concentrations of cilostazol and or its pharmacologically active metabolites, which are substrates of these isoenzymes. The possibility of prolonged and/or increased pharmacologic effects of cilostazol should be considered. In pharmacokinetic studies, pretreatment with a 400 mg priming dose of ketoconazole (a potent CYP450 3A4 inhibitor) one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg resulted in a 94% increase in cilostazol peak plasma concentration (Cmax) and a 117% increase in cilostazol systemic exposure (AUC). Coadministration of the less potent inhibitor erythromycin (500 mg every 8 hours) with a single 100 mg dose of cilostazol resulted in a 47% and 73% increase in cilostazol Cmax and AUC, respectively, while AUC of 4-trans-hydroxy-cilostazol (an active metabolite with 1/5 the pharmacologic activity) increased by 141% as a result of the inhibition of cilostazol metabolism via CYP450 3A4. Coadministration with 180 mg of diltiazem, a moderate CYP450 3A4 inhibitor, decreased cilostazol clearance by 30% and increased its Cmax by 30% and AUC by 40%. In contrast, cilostazol metabolism was not significantly affected when coadministered with omeprazole, a potent CYP450 2C19 inhibitor, but the systemic exposure to 3,4-dehydro-cilostazol (the most active metabolite of cilostazol) was increased by 69%.

MANAGEMENT: A 50% dosage reduction of cilostazol (i.e., 50 mg twice a day) should be considered when used with potent or moderate CYP450 3A4 and/or 2C19 inhibitors. Close clinical and laboratory monitoring is advised whenever the inhibitor is added to or withdrawn from therapy, and the cilostazol dosage adjusted as necessary. Patients should be advised to contact their physician if they experience adverse effects of cilostazol such as dizziness, nausea, diarrhea, bleeding, or irregular heartbeat.

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of cilostazol. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Until more information is available, the manufacturer recommends avoiding consumption of grapefruit juice during cilostazol therapy. Orange juice is not expected to interact with cilostazol.