Drug Interactions between fexinidazole and finerenone

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of finerenone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. Pharmacokinetic modeling simulations suggest that concomitant use of finerenone with 200 mg twice daily itraconazole, a potent CYP450 3A4 inhibitor, increases finerenone peak plasma concentration (Cmax) and systemic exposure (AUC) by 137% and 531%, respectively. Clarithromycin, another potent CYP450 3A4 inhibitor, given at 500 mg twice daily is predicted to increase finerenone Cmax by 125% and AUC by 428%. Additionally, drug interaction studies showed that concomitant use of finerenone with 500 mg thrice daily erythromycin, a moderate CYP450 3A4 inhibitor, increased mean finerenone Cmax and AUC by 88% and 248%, respectively. Verapamil, another moderate CYP450 3A4 inhibitor, given as a 240 mg controlled-release tablet once daily increased mean finerenone Cmax by 120% and AUC by 170%. 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. High exposure to finerenone may potentiate the risk of hyperkalemia, and the risk may be further increased with decreasing kidney function and higher baseline potassium levels.

MONITOR CLOSELY: Dietary intake of excess potassium, especially via salt substitutes, may increase the risk of hyperkalemia in patients who are using finerenone. Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

Administration of finerenone with high-fat, high-calorie food decreased finerenone Cmax by 19%, increased AUC by 21%, and prolonged the time to reach Cmax to 2.5 hours. These changes are not considered clinically relevant.

MANAGEMENT: Patients receiving finerenone therapy should be instructed to avoid consumption of grapefruit or grapefruit juice. In addition, patients should receive dietary counseling and be advised not to use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician. If salt substitutes or supplements are used concurrently, more frequent monitoring of serum potassium levels is recommended. Patients should also be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. Finerenone may be taken with or without food.

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.