Drug Interaction Report

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 and/or CYP450 2C19 may decrease the plasma concentrations of cannabidiol. The proposed mechanism of action is induction of CYP450 3A4 and/or 2C19-mediated metabolism of cannabidiol. A drug interaction study evaluating coadministration of rifampin 600 mg once daily with cannabidiol showed a decrease in systemic exposure (AUC) and peak plasma concentration (Cmax) of cannabidiol by 32% and 34%, respectively. Moderate change to the active metabolite 7-OH-CBD was also observed (AUC decreased by 63%; Cmax decreased by 67%). The impact of these changes on cannabidiol efficacy is unknown.

MANAGEMENT: A dosage increase of cannabidiol up to 2-fold may be required when coadministered with potent inducers of CYP450 3A4 and/or CYP450 2C19 based on clinical response and tolerability.

GENERALLY AVOID: An isolated case report suggests that foods containing large amounts of tyramine may precipitate a hypertensive crisis in patients treated with St. John's wort. The mechanism of interaction is unknown, as St. John's wort is not thought to possess monoamine oxidase (MAO) inhibiting activity at concentrations achieved in vivo. The case patient was a 41-year-old man who had been taking St. John's wort for seven days prior to presentation at the emergency room with confusion and disorientation. The patient recalled last eating aged cheese and having a glass of red wine approximately 10 hours prior to admission. No other cause of delirium or hypertension could be identified. In addition, alcohol may potentiate some of the pharmacologic effects of St. John's wort. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Until further information is available, patients treated with St. John's wort should consider avoiding consumption of 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, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, yogurt, papaya products, meat tenderizers, fava beans, protein extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. Patients should also be advised to avoid or limit consumption of alcohol.

ADJUST DOSING INTERVAL: Food may affect the plasma concentrations of cannabidiol. In healthy volunteers, administration of cannabidiol with a high-fat/high-calorie meal increased cannabidiol peak plasma concentration (Cmax) by 5-fold and systemic exposure (AUC) by 4-fold and reduced the total variability compared with administration in the fasted state.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of cannabidiol. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of cannabidiol by certain compounds present in grapefruit. The interaction has not been studied, but the product labeling for cannabidiol recommends consideration of a dosage reduction when used with strong or moderate inhibitors of CYP450 3A4. 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.

MANAGEMENT: Cannabidiol should be taken about the same time each day consistently either with or without food. Patients should limit the consumption of grapefruit and grapefruit juice. If they are coadministered, cannabidiol levels should be monitored and the dosage adjusted as necessary.