• Lennox-Gastaut syndrome and Dravet syndrome are severe forms of epilepsy that affect children and infants. Pharmacological treatment is based on combinations of antiepileptic drugs, sometimes including valproic acid and cloba­zam.These combinations frequently fail to fully prevent seizures.
   
• An oral solution of cannabidiol, a natural component of cannabis, has been granted marketing authorisation in the European Union as adjunctive treatment in these two clinical situations, in conjunction with antiepileptic therapy including at least clobazam.
   
• Clinical evaluation of cannabidiol includes two comparative double-blind randomised trials in each of these syndromes, in which cannabi­diol or placebo was added to a prior antiepileptic treatment insufficiently effective.
   
• In these four trials, after 14 weeks, the proportion of responders (patients whose seizure frequency had decreased by at least 50%) was about 20 percentage points higher in the cannabi­diol groups than in the placebo groups. According to a subgroup analysis (an approach that provides only weak evidence), this effect was mainly observed when cannabidiol was combined with clobazam, probably because mutual pharmacokinetic interactions increased the quantity of active metabolites of both drugs. It is not known whether this efficacy is maintained in the long term. These trials were not designed to evaluate any effects on the patients' psychomotor development.
   
• The main adverse effects reported with can­nabidiol in the comparative trials were elevated liver enzymes, gastrointestinal disorders (including diarrhoea and loss of appetite), and rash. Cannabidiol can also provoke neuropsychiatric disorders (including drowsiness), although the degree to which the alcohol in the oral solution contributes to these disorders, especially in children, is unknown. Cannabidiol does not have the hallucinatory and euphoric effects of tetra-hydrocannabinol (THC), another component of cannabis, and the risk of abuse and addiction is low.
   
• The potential for pharmacokinetic drug interactions with cannabidiol is high. In addition, because the risk of hepatic, neuropsychiatric and gastrointestinal disorders is increased when cannabidiol is combined with other antiepileptics, regular patient follow-up is advisable to monitor for the development of such adverse effects.
   
•  OFFERS AN ADVANTAGE  For patients with Lennox-Gastaut syndrome or Dravet syndrome in whom antiepileptic therapy has proved insufficiently effective, four placebo-controlled clinical trials have shown that adding cannabidiol for 14 weeks leads to a reduction in seizure frequency. There is weak evidence that cannabidiol is more effective when combined with cloba­zam, possibly due to mutual pharmacokinetic interactions between these two drugs. It is not known whether the addition of canna­bidiol improves children's psychomotor development. Cannabidiol can provoke hepatic, gastrointestinal and cutaneous disorders. It can also cause neuropsychiatric disorders, although the extent to which the alcohol in the oral solution contributes to these effects is unknown. In practice, for patients with these syndromes, in whom antiepileptic drugs are often poorly effective, adding cannabi­diol to antiepileptic therapy is an option to discuss with patients or their carers, informing them of the uncertainties over its long-term effects.
  

©Prescrire 1 September 2020

Source: "Cannabidiol (Epidyolex°) in certain severe forms of childhood epilepsy: an option to consider, but liver function must be monitored" Prescrire International 2020; 29 (218): 205-207. Subscribers only.

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