Cannabidiol effective in long term for treatment-resistant Dravet syndrome: Australian study


By Natasha Doyle

25 Aug 2021

“Reassuring” new data suggests cannabidiol (CBD) is safe and effective long-term treatment in Dravet syndrome, according to an Australian-led study.

An extension of the GWPCARE trials showed that patients treated with oral liquid cannabidiol (Epidyolex) had sustained reductions in convulsive and total seizures, improved overall condition and no new adverse events at three-year follow-up.

In a trial led by Professor Ingrid Scheffer, Austin Health Chair of Paediatric Neurology Research, participants received a mean CBD dose of 22 mg/kg/day for median 444 days, with median three concomitant anti-seizure medications.

Adverse events occurred in 97% of the 315 patients, with most experiencing diarrhoea, pyrexia, decreased appetite and excess drowsiness.

Sixty-nine patients had liver transaminase elevations >3x the upper limit of normal, 84% of whom were on valproic acid. However, only 28 patients discontinued treatment due to side effects, according to results published in Epilepsia.

Meanwhile convulsive seizure frequency dropped 45–74% in the 12-week follow-up periods to Week 156, and total seizures reduced by 49–84%.

“The proportion of patients/caregivers reporting improvement was ≥83% at all time points assessed, suggesting that the reduced seizure frequencies were clinically meaningful for most patients/caregivers,” the authors wrote.

Further, 85% of patients/caregivers reported improvements in overall condition.

CBD in practice

“Our long-term open-label extension data extend previous findings, demonstrating that add-on CBD treatment in patients with Dravet syndrome led to sustained reductions in seizure frequency in the majority of patients with an acceptable safety profile,” they wrote.

When treating with CBD, neurologists should pay close attention to diarrhoea and excessive tiredness complaints, Professor Scheffer told the limbic.

“Diarrhoea is very unusual among our anti-seizure drugs — none of the others cause diarrhoea — I suspect it may relate to the oil,” she said.

Patients can “become quite sedated on clobazam, so you have to watch that carefully”.

“If they’re on a high dose, I might bring that down just when I introduce the CBD, or if they’re on a lower dose, I might leave it. But as soon as they become tired, give them a plan to reduce the clobazam a little bit,” she suggested.

Regarding CBD and valproic acid, the authors suggested discontinuation or dose reduction of either or both drugs should be considered to reduce liver enzyme elevation risk.

Previous GWPCARE studies and a CBD expanded-access program have reported an interaction between the drugs which increased the risk of liver enzyme elevation, they noted.

Managing patient doses based on individual responses was also key to improving outcomes, their paper suggested.

Although CBD had better safety and tolerability profiles and similar efficacy at 10 versus 20 mg/kg/day in one of the original GWPCARE trials (GWPCARE 2), patients taking ≤20 mg/kg/day were more likely to discontinue treatment due to adverse effects in the extension study.

“Only three of 137 (2%) patients taking CBD at modal doses of >20 mg/kg/day experienced AEs leading to discontinuation, compared with 25 of 178 (14%) patients taking ≤20 mg/kg/day, indicating that some patients are capable of tolerating CBD at higher doses than those evaluated in the randomised controlled trials,” the authors wrote.

Patients in the trial could titrate up to 30 mg/kg/day where necessary.

In practice, Professor Scheffer recommends starting with the lowest dose.

“If I’m starting a patient on CBD, I take them up to 10 mg/kg/day in a child, and I think it’s 500 BD in an adult, and then I don’t go up to the 20 mg/kg/day unless there’s a response, because the 10 mg/kg/day is almost as good as 20 mg/kg/day and it’s an expensive drug,” she said.

This study “demonstrates the sustained long-term benefits of Epidyolex, the regulated and highly purified formulation of plant-based CBD, for patients with Dravet syndrome, a critical issue for CBD in joining our anti-seizure medication armamentarium,” the authors concluded.

And long-term, add-on CBD treatment had a reassuringly similar safety profile to that observed in the original randomised controlled trials, they added.

Currently, Epidyolex is approved for use in Australia as an adjunctive therapy for patients ≥2 years old with seizures associated with Dravet or Lennox-Gastaut syndromes and PBS listed for use with at least two other anti-epileptic drugs as a third line treatment for Dravet syndrome.

Already a member?

Login to keep reading.

Email me a login link