Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of erythromycin, which is primarily metabolized by the isoenzyme. The use of erythromycin has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. In a population-based retrospective study of 1476 cases of confirmed sudden death from cardiac causes, concurrent use of erythromycin and a CYP450 3A4 inhibitor (mostly verapamil or diltiazem) was associated with a marked increase in the risk of sudden death from cardiac causes as compared to nonuse of CYP450 3A4 inhibitors, erythromycin, or amoxicillin; concurrent use of amoxicillin and CYP450 3A4 inhibitors; use of CYP450 3A4 inhibitors without erythromycin or amoxicillin; and concurrent use of erythromycin and calcium channel blockers that do not significantly inhibit CYP450 3A4 (e.g., nifedipine). In fact, the risk was five times as high as that for nonuse of CYP450 3A4 inhibitors, erythromycin, or amoxicillin. In addition, erythromycin may increase the plasma concentrations of drugs that are substrates of CYP450 3A4.

MANAGEMENT: Concomitant use of erythromycin with potent CYP450 3A4 inhibitors should generally be avoided.

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Coadministration with erythromycin has been shown to increase the oral bioavailability of fexofenadine. The proposed mechanism is erythromycin inhibition of the intestinal efflux of fexofenadine via P-glycoprotein transporter. In addition, erythromycin may decrease biliary excretion of fexofenadine. In 24 healthy volunteers, coadministration of fexofenadine 120 mg twice a day and erythromycin 500 mg every 8 hours resulted in a 82% and 109% increase in the steady-state fexofenadine peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of fexofenadine alone. However, no increase in adverse effects or QTc interval were noted. No studies have been performed using clarithromycin or troleandomycin, but similar results are possible given their similarities to erythromycin. Fexofenadine had no effect on the pharmacokinetics of erythromycin.

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Coadministration with ketoconazole has been shown to significantly increase the oral bioavailability of fexofenadine. The proposed mechanism is ketoconazole inhibition of the intestinal efflux of fexofenadine via P-glycoprotein transporter. In 24 healthy volunteers, coadministration of fexofenadine 120 mg twice a day and ketoconazole 400 mg once a day resulted in a 135% and 164% increase in the steady-state fexofenadine peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of fexofenadine alone. However, no increase in adverse effects or QTc interval were noted. No studies have been performed using other azole antifungal agents, but similar results are possible given their similarities to ketoconazole. Fexofenadine had no effect on the pharmacokinetics of ketoconazole.

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ADJUST DOSING INTERVAL: Food may variably affect the bioavailability of different oral formulations and salt forms of erythromycin. The individual product package labeling should be consulted regarding the appropriate time of administration in relation to food ingestion. Grapefruit juice may increase the plasma concentrations of orally administered erythromycin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In an open-label, crossover study consisting of six healthy subjects, the coadministration with double-strength grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of erythromycin (400 mg) by 52% and 49%, respectively, compared to water. The half-life was not affected. The clinical significance of this potential interaction is unknown.

MANAGEMENT: In general, optimal serum levels are achieved when erythromycin is taken in the fasting state, one-half to two hours before meals. However, some erythromycin products may be taken without regard to meals.

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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.

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GENERALLY AVOID: Coadministration with large amounts of certain fruit juices, including grapefruit, orange and apple, may decrease the oral bioavailability of fexofenadine. The proposed mechanism is inhibition of drug efflux via intestinal organic anion transporting polypeptides (e.g., P-glycoprotein), of which fexofenadine is a substrate. In a five-way crossover study with 10 healthy volunteers, 1/4-strength grapefruit juice, grapefruit juice, orange juice and apple juice (300 mL with drug administration and 150 mL every 1/2 hour for up to 3 hours, total volume 1.2 L) reduced the mean area under the plasma concentration-time curve (AUC) of a 120 mg dose of fexofenadine by 23%, 67%, 72% and 77%, respectively, compared to water. Mean peak plasma concentration (Cmax) was similarly affected. The clinical significance of these changes is unknown. However, results from studies using histamine-induced skin wheals and flares found that the size of wheal and flare was significantly larger when fexofenadine was administered with either grapefruit or orange juices compared to water.

MANAGEMENT: To maximize plasma levels and therapeutic effects, fexofenadine should be taken with water. In addition, patients should refrain from consuming large amounts of grapefruit, orange, or apple juice.

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Ethanol, when combined with erythromycin, may delay absorption and therefore the clinical effects of the antibiotic. The mechanism appears to be due to slowed gastric emptying by ethanol. Data is available only for erythromycin ethylsuccinate. Patients should be advised to avoid ethanol while taking erythromycin salts.

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