Drug Interactions between cannabidiol and PhenazoForte Plus

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.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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