Drug Interactions between Addyi and fexinidazole

CONTRAINDICATED: Grapefruit juice may increase the plasma concentrations of flibanserin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In 26 healthy female subjects, administration of a single 100 mg dose of flibanserin with 240 mL grapefruit juice increased flibanserin peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.1- and 1.4-fold, respectively, compared to administration of flibanserin alone. 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.

ADJUST DOSING INTERVAL: Coadministration of flibanserin with alcohol may potentiate the risk of severe hypotension, syncope, and central nervous system depression. In a dedicated alcohol interaction study, hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenberg position) occurred in 4 (17%) of 23 subjects given flibanserin 100 mg with 0.4 g/kg alcohol (equivalent to two 12 ounce cans of beer containing 5% alcohol content, two 5 ounce glasses of wine containing 12% alcohol content, or two 1.5 ounce shots of 80-proof spirit in a 70 kg person) consumed over 10 minutes in the morning. In these four subjects, systolic blood pressure reductions ranged from 28 to 54 mmHg and diastolic blood pressure reductions ranged from 24 to 46 mmHg. In addition, 6 (25%) of 24 subjects coadministered flibanserin with 0.8 g/kg alcohol experienced orthostatic hypotension when standing from a sitting position. Systolic and diastolic blood pressure reductions in these 6 subjects ranged from 22 to 48 mmHg and 0 to 27 mmHg, respectively, with one requiring therapeutic intervention. No adverse events requiring therapeutic intervention were observed when flibanserin or alcohol was administered alone. Somnolence was reported in 67%, 74%, and 92% of subjects who received flibanserin alone, flibanserin with 0.4 g/kg ethanol, and flibanserin with 0.8 g/kg ethanol, respectively. Subsequent data from postmarketing trials showed that the risk of severe hypotension and syncope was reduced when women who consumed up to two alcoholic drinks waited at least two hours before taking flibanserin.

MANAGEMENT: Concomitant use of flibanserin with moderate or potent CYP450 3A4 inhibitors such as grapefruit juice is considered contraindicated. The patient should be advised to avoid the consumption of grapefruit and grapefruit juice during treatment, and to take flibanserin at bedtime to minimize the risk of hypotension, syncope, accidental injury, and central nervous system depression. In addition, patients should consume no more than 1 to 2 alcoholic drinks and discontinue drinking alcohol at least two hours before taking flibanserin at bedtime; otherwise, they should skip the flibanserin dose that evening. Alcohol should not be consumed until at least the morning after taking flibanserin at bedtime. A standard alcoholic drink contains 14 g of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol).

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.