Drug Interaction Report

MONITOR: Coadministration of cannabidiol with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Cannabidiol causes dose-related elevations of liver transaminases, both alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In controlled studies, the incidence of ALT elevations above 3 times the upper limit of normal (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 AST levels greater than 20 times the ULN. Some cases required hospitalization. In clinical trials, 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. The majority of 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 times the 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. Finally, patients with baseline transaminase levels above the ULN also had higher rates of transaminase elevations during cannabidiol treatment. In patients taking 20 mg/kg/day in controlled trials, the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 30% when ALT was above the ULN at baseline, compared to 12% when ALT was within the normal range at baseline. No patient taking cannabidiol 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline.

MANAGEMENT: 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 times the ULN accompanied by elevations in bilirubin above 2 times the 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 are taking valproate or 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 times the ULN and bilirubin levels greater than 2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the 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.

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.

GENERALLY AVOID: Food does not significantly affect the oral bioavailability of diroximel fumarate. Administration of diroximel fumarate with a high-fat, high-calorie (900 to 1000 calories; 50% from fat) meal did not affect the systemic exposure (AUC) of its active metabolite, monomethyl fumarate (MMF), but decreased its peak plasma concentration (Cmax) by 44% and prolonged the time to reach peak concentration (Tmax) from 2.5 to 7.0 hours relative to administration in the fasted state. In comparison, administration of diroximel fumarate with low-fat, low-calorie (350 to 400 calories; 10 to 15 g fat) and medium-fat, medium-calorie (650 to 700 calories; 25 to 30 g fat) meals decreased the MMF Cmax by approximately 12% and 25%, respectively, while also leaving the AUC unaffected.

GENERALLY AVOID: Coadministration of diroximel fumarate with ethanol may reduce the plasma concentrations of monomethyl fumarate (MMF). The mechanism has not been reported. Following coadministration with 240 mL of 5% v/v and 40% v/v ethanol, the mean Cmax of MMF was reduced by 9% and 21%, respectively, relative to coadministration with water. The AUC of MMF was not significantly altered, indicating that ethanol did not induce dose dumping.

MANAGEMENT: Diroximel fumarate may be taken with or without food; however, high-fat, high-calorie meals or snacks should be avoided. The manufacturer recommends meals or snacks containing no more than 700 calories and no more than 30 grams of fat. Taking diroximel fumarate with food may improve tolerability for patients experiencing flushing or gastrointestinal adverse reactions. The manufacturer also recommends avoiding concomitant use of diroximel fumarate with ethanol.