Drug Interaction Report

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.

GENERALLY AVOID: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rilpivirine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. In 15 study subjects given rilpivirine (150 mg once daily) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily), mean rilpivirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were increased by 30%, 49% and 76%, respectively. In 16 study subjects given a single 500 mg dose of a less potent CYP450 3A4 inhibitor chlorzoxazone two hours after rilpivirine (150 mg once daily), mean rilpivirine Cmax, AUC, and Cmin were increased by 17%, 25%, and 18%, respectively. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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: The administration of rilpivirine in a fasting state may decrease its oral absorption. Under fasted conditions, the systemic exposure to rilpivirine was 40% lower compared to normal or high-fat caloric meals (533 to 928 Kcal). The systemic exposure was 50% lower when rilpivirine was taken with a protein-rich nutritional beverage.

MANAGEMENT: Coadministration of grapefruit or grapefruit juice with rilpivirine should preferably be avoided. For optimal absorption, it is recommended to take rilpivirine on a regular schedule with a meal.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.