Abstracts

Rationale: Cannabidiol (CBD) is being studied as a new treatment option in pediatric refractory epilepsy. This study is conducted to assess the safety and tolerability of CBD (Epidiolex, GW Pharma) as adjunctive therapy in patients aged 2 to 40 years who experience drug resistant epilepsy. During the course of this study we also evaluated the interactions between CBD and the antiepileptic drug (AED) clobazam (CLB). Methods: Twenty-five subjects, ages 6 to 19 years, were enrolled in an open-label / expanded access trial with cannabidiol as add on therapy. Of the 25, 13 were on clobazam at enrollment (range 0.18 to 2.24mg/kg/day, mean 1mg/kg/day). Patients were titrated onto CBD by 5mg/kg/day per week to a maximum dosage of 25mg/kg/day while clobazam doses either remained steady or were reduced due to perceived side effects. Baseline clobazam and norclobazam (active metabolite of clobazam) (nCLB) levels were measured at baseline, and at 4 (20mg/kg/day) and 8 weeks (25mg/kg/day) after starting CBD. Ratios of CLB:nCLB levels in patients ranged from 0.01 to 0.56 prior to starting CBD. One patient had levels drawn after being on CBD for two weeks (10mg/kg/day), as he experienced adverse events (drowsiness and ataxia) hypothesized to be related to elevated CLB levels. Increases in CLB/nCLB levels were calculated by comparing patients' baseline levels to their highest levels while on CBD treatment. Subjects/caregivers were also interviewed weekly for any side effects noted from the addition of CBD. Results: Baseline CLB (therapeutic range 30-300ng/ml) / nCLB (300-3000) levels ranged from 54/97 to 1017/2293ng/ml. CLB levels increased in 92% of patients (ranging from 17 to 268%); nCLB levels also increased in 92% of patients (ranging from 81 to 1137%). Side effects reported included: drowsiness (46%), ataxia (15%), irritability (0.15%), restless sleep (8%), urinary retention (8%), tremor (8%), and loss of appetite (8%). In some instances, drowsiness was noted during the first week of treatment with low dose CBD (5mg/kg/day). The investigators felt these side effects were common to those seen with elevated clobazam levels and thus were likely related to the interaction of CBD with CLB. Clobazam doses were decreased in 85% of patients, resulting in a resolution of symptoms. Conclusions: CBD interacts with CLB with resultant increases in the levels of clobazam, and more significantly, norclobazam, the active metabolite of clobazam. Both levels should be followed if used in combination with CBD and patients should be monitored for symptoms of drowsiness, ataxia, restless sleep, urinary retention, tremor, or loss of appetite.