Drug Interaction Report

ADJUST DOSE: Coadministration of protein-bound sirolimus intravenous suspension with moderate or weak inhibitors of CYP450 3A4 may increase the systemic exposure to sirolimus, which is primarily metabolized by the isoenzyme and also a substrate of the P-glycoprotein (P-gp) efflux transporter. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. However, significant increases in systemic exposure have been reported for oral sirolimus coadministered with moderate dual inhibitors of CYP450 3A4 and P-gp such as diltiazem, erythromycin and verapamil, all of which are also substrates of CYP450 3A4 and P-gp. When 10 mg of sirolimus oral solution was administered with 120 mg of diltiazem in 18 healthy volunteers, sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.4- and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites, desacetyldiltiazem and desmethyldiltiazem. When sirolimus oral solution 2 mg once a day was coadministered with erythromycin ethylsuccinate 800 mg every 8 hours to steady state in 24 healthy volunteers, sirolimus Cmax and AUC increased by 4.4- and 4.2-fold, respectively, while erythromycin Cmax and AUC increased by 1.6- and 1.7-fold, respectively. Likewise, when sirolimus oral solution 2 mg once a day was coadministered with verapamil 180 mg every 12 hours to steady state in 25 healthy volunteers, sirolimus Cmax and AUC increased by 2.3- and 2.2-fold, respectively, while Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil both increased by 1.5-fold. Increased exposures to sirolimus may increase the risk of adverse effects such stomatitis, nausea, diarrhea, vomiting, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, edema, rash, alopecia, and hemorrhage.

MANAGEMENT: When administered concomitantly with moderate or weak CYP450 3A4 inhibitors, the manufacturer recommends reducing the dosage of protein-bound sirolimus intravenous suspension to 56 mg/m2. Clinical response and toxicities should be closely monitored, and the dosage of protein-bound sirolimus further adjusted as necessary. In addition, patients may also require monitoring for potentially increased effects of concomitant CYP450 3A4 inhibitors, as many are also substrates of CYP450 3A4 and/or P-gp and may be impacted by sirolimus. The prescribing information for concomitant medications should be consulted.

GENERALLY AVOID: Use of alcohol or products containing alcohol during nitroimidazole therapy may result in a disulfiram-like reaction in some patients. There have been a few case reports involving metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have questioned the disulfiram-like properties of metronidazole. One study found neither elevations in blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects who received placebo.

GENERALLY AVOID: The potential exists for pharmacodynamic interactions and/or toxicities between fexinidazole and herbal medicines and supplements. In addition, grapefruit and grapefruit juice may, theoretically, increase the plasma concentrations of fexinidazole and the risk of adverse effects. The mechanism is decreased clearance of fexinidazole due to 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.

ADJUST DOSING INTERVAL: Food significantly increases the oral absorption and bioavailability of fexinidazole. Compared with the fasted state, the systemic exposure (AUC) of fexinidazole and its metabolites (fexinidazole sulfoxide [M1], fexinidazole sulfone [M2]) were 4- to 5-fold higher following administration with food.

MANAGEMENT: To ensure maximal oral absorption, fexinidazole should be administered with food each day at about the same time of day (e.g., during or immediately after the main meal of the day). Coadministration of fexinidazole with grapefruit, grapefruit juice, or herbal medicines or supplements should be avoided. Because clear evidence is lacking concerning the safety of ethanol use during nitroimidazole therapy, patients should be apprised of the potential for interaction and instructed to avoid alcoholic beverages and products containing alcohol or propylene glycol while using oral, intravenous, or vaginal preparations of a nitroimidazole. Alcoholic beverages should not be consumed for at least 48 hours after completion of fexinidazole therapy.

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with grapefruit juice may increase the systemic exposure to sirolimus. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of sirolimus by certain compounds present in grapefruit. However, grapefruit juice primarily inhibits CYP450 3A4-mediated first-pass metabolism in the gut wall and may have limited effects on medications that are not administered orally. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. 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.

MANAGEMENT: The manufacturer recommends avoiding grapefruit and grapefruit juice during treatment with protein-bound sirolimus.