Drug Interactions between flibanserin and isocarboxazid

CONTRAINDICATED: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with monoamine oxidase inhibitors (MAOIs). The mechanism is inhibition of MAO-A, the enzyme responsible for metabolizing exogenous amines such as tyramine in the gut and preventing them from being absorbed intact. Once absorbed, tyramine is metabolized to octopamine, a substance that is believed to displace norepinephrine from storage granules.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of MAOIs. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: In general, patients treated with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, linezolid, procarbazine) should avoid consumption of products that contain large amounts of amines and protein foods in which aging or breakdown of protein is used to increase flavor. These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, salamis, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, sauerkraut, yogurt, papaya products, meat tenderizers, fava bean pods, protein extracts, yeast extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. At least 14 days should elapse following discontinuation of MAOI therapy before these foods may be consumed. Specially designed reference materials and dietary consultation are recommended so that an appropriate and safe diet can be planned. Patients should be advised to promptly seek medical attention if they experience potential signs and symptoms of a hypertensive crisis such as severe headache, visual disturbances, difficulty thinking, stupor or coma, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms. Patients should also be counseled not to use MAOIs with alcohol, and to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them.

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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).

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