Drug Interaction Report

MONITOR: Coadministration of cannabidiol with cyclosporine may potentiate the risk of liver injury as cannabidiol causes dose-related transaminase elevations and cyclosporine can cause hepatotoxicity. Additionally, there have been literature reports suggesting concomitant use of cannabidiol with calcineurin inhibitors may result in increased calcineurin inhibitor (e.g. cyclosporine) serum levels which may increase the risk of adverse effects. The mechanism for increased calcineurin inhibitor levels is not clearly understood, but has been reported with sirolimus, everolimus, or tacrolimus. Transaminase elevations have been reported in controlled studies with cannabidiol. The incidence of alanine aminotransferase (ALT) elevations above 3 times the upper limit of normal (3 x ULN) was 13% with cannabidiol versus 1% with placebo, and 17% in patients taking cannabidiol 20 mg/kg/day compared to 1% taking 10 mg/kg/day. Less than 1% of cannabidiol-treated patients had ALT or aspartate aminotransferase (AST) levels greater than 20 x ULN. Some cases required hospitalization. Serum transaminase elevations typically occurred within the first two months of treatment initiation, but up to 18 months were reported in some cases, particularly in patients taking concomitant valproate. Resolution occurred with discontinuation or dosage reduction of cannabidiol and/or concomitant valproate in about two-thirds of the cases. In about one-third of the cases, transaminase elevations resolved during continued cannabidiol treatment, without dose reduction. Most ALT elevations occurred in patients taking concomitant valproate. Concomitant use of clobazam also increased the incidence of transaminase elevations, but to a lesser extent. In cannabidiol-treated patients, the incidence of ALT elevations greater than 3 x ULN was 30% in patients taking both concomitant valproate and clobazam, 21% in patients taking concomitant valproate (without clobazam), 4% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither drug. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs.

MANAGEMENT (Hepatotoxicity): Caution is advised if cannabidiol is used in patients who are currently receiving or have recently received treatment with other hepatotoxic agents, and vice versa. Serum transaminases and total bilirubin levels should be obtained prior to initiating cannabidiol, and patients with elevated baseline transaminase levels above 3 x ULN accompanied by elevations in bilirubin above 2 x ULN should be evaluated. Repeat levels should be obtained at 1 month, 3 months, and 6 months after initiation of cannabidiol treatment, and periodically thereafter or as clinically indicated (e.g., within 1 month following changes in cannabidiol dosage or addition of/changes in medications that are known to impact the liver). Consider more frequent monitoring of serum transaminases and bilirubin in patients who have elevated liver enzymes at baseline. Patients who develop clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, jaundice, dark urine) should have serum transaminases and total bilirubin measured promptly, and cannabidiol treatment interrupted or discontinued as appropriate. Cannabidiol should be discontinued in patients with elevations of transaminase levels greater than 3 x ULN and bilirubin levels greater than 2 x ULN. Patients with sustained transaminase elevations of greater than 5 x ULN should also have treatment discontinued. Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes. Also consider dosage adjustment or discontinuation of any coadministered medication that is known to affect the liver.

MANAGEMENT (Elevated cyclosporine levels): Although concomitant use of cyclosporine and calcineurin inhibitors has not been studied, caution is advised if cannabidiol is coadministered with cyclosporine. Clinical and laboratory monitoring should be considered whenever cannabidiol is added to or withdrawn from cyclosporine therapy. Patients should be advised to notify their doctor if they experience possible signs of cyclosporine toxicity such as nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, headache, tremors, and convulsions.

GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

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.