Drug Interactions between flibanserin and isoniazid / rifampin

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).

Switch to consumer interaction data

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

Switch to consumer interaction data

GENERALLY AVOID: Concurrent use of isoniazid (INH) in patients who ingest alcohol daily may result in an increased incidence of both hepatotoxicity and peripheral neuropathy. The increase in hepatotoxicity may be due to an additive risk as both alcohol and INH are individually associated with this adverse reaction. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of acetylation is genetically determined and generally classified as slow or rapid. Slow acetylators have been identified by some studies as having a higher risk of hepatotoxicity; therefore, this interaction may be more significant for patients who fall into this category. Other studies have postulated that alcohol-mediated CYP450 2E1 induction may play a role, as this isoenzyme is involved in INH metabolism and may be responsible for producing hepatotoxic metabolites. However, available literature is conflicting. The labeling for some INH products lists daily alcohol use or chronic alcoholism as a risk factor for hepatitis, but not all studies have found a significant association between alcohol use and INH-induced hepatotoxicity. Additionally, INH and alcohol are both associated with pyridoxine (B6) deficiency, which may increase the risk of peripheral neuropathy.

GENERALLY AVOID: Concomitant administration of isoniazid (INH) with foods containing tyramine and/or histamine may increase the risk of symptoms relating to tyramine- and/or histamine toxicity (e.g., headache, diaphoresis, flushing, palpitations, and hypotension). The proposed mechanism is INH-mediated inhibition of monoamine oxidase (MAO) and diamine oxidase (DAO), enzymes responsible for the metabolism of tyramine and histamine, respectively. Some authors have suggested that the reactions observed are mainly due to INH's effects on DAO instead of MAO or the amounts of histamine instead of tyramine present in the food. A Japanese case report recorded an example in 8 out of 25 patients on the tuberculosis ward who developed an accidental histamine poisoning after ingesting a fish paste (saury). Patients developed allergy-like symptoms, which started between 20 minutes and 2 hours after ingesting the food. A high-level of histamine (32 mg/100 g of fish) was confirmed in the saury paste and all 8 patients were both on INH and had reduced MAO concentrations. The 17 remaining patients were not on INH (n=5) or reported not eating the saury paste (n=12).

ADJUST DOSING INTERVAL: Administration with food significantly reduces oral isoniazid (INH) absorption, increasing the risk of therapeutic failure or resistance. The mechanism is unknown. Pharmacokinetic studies completed in both healthy volunteers (n=14) and tuberculosis patients (n=20 treatment-naive patients during days 1 to 3 of treatment) have resulted in almost doubling the time to reach INH's maximum concentration (tmax) and a reduction in isoniazid's maximum concentration (Cmax) of 42%-51% in patients who consumed high-fat or high-carbohydrate meals prior to INH treatment.

MANAGEMENT: The manufacturer of oral forms of isoniazid (INH) recommends administration on an empty stomach (i.e., 30 minutes before or 2 hours after meals). Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and INH concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with INH. Concomitant pyridoxine (B6) administration is also recommended to reduce the risk of peripheral neuropathy, with some authorities suggesting a dose of at least 10 mg/day. Patients should be advised to avoid foods containing tyramine (e.g., aged cheese, cured meats such as sausages and salami, fava beans, sauerkraut, soy sauce, beer, or red wine) or histamine (e.g., skipjack, tuna, mackerel, salmon) during treatment with isoniazid. Consultation of product labeling for combination products containing isoniazid and/or relevant guidelines may be helpful for more specific recommendations.

Switch to consumer interaction data