The FDA has approved cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome for patients 2 years of age and older.
FDA commissioner Scott Gottlieb, MD
Scott Gottlieb, MD
The FDA has approved cannabidiol oral solution (Epidiolex) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome for patients 2 years of age and older, based on findings from 3 randomized, controlled studies.
In a phase III trial, recently reported in the New England Journal of Medicine (NEJM),1 2 doses of cannabidiol were compared with placebo for patients with LGS. There was a 41.9% reduction in drop seizures in patients prescribed a 20 mg/kg/day cannabidiol regimen, a 37.2% reduction in those on a 10 mg/kg/day cannabidiol regimen, and a 17.2% reduction in the group given placebo (P =.005 for the 20-mg cannabidiol group versus placebo group, and P = .002 for the 10-mg cannabidiol group vs. placebo group).
Cannabidiol is the first drug approved by the FDA to contain a marijuana-derived, purified drug substance. This is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome. The FDA statement highlights that cannabidiol does not cause intoxication or the euphoria that is associated with tetrahydrocannabinol, the primary psychoactive component of marijuana.
“This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies. And, the FDA is committed to this kind of careful scientific research and drug development,” said FDA commissioner Scott Gottlieb, MD.
This approval follows the unanimous support of an FDA committee which recommended the approval of cannabidiol oral solution in April 2018. “As a physician who treats LGS and Dravet syndrome, I know that patients and their families usually face significant difficulties getting seizures under control using existing therapies,” Elizabeth Thiele, MD, PhD, director of pediatric epilepsy, Massachusetts General Hospital, professor of neurology, Harvard Medical School, said in a statement at that time.
The double-blind, placebo-controlled trial was conducted at 30 clinical centers and enrolled 225 patients with LGS, between the ages of 2—55 years old, who had 2 or more drop seizures per week during a 28-day baseline period. Participants were randomly assigned to receive cannabidiol oral solution at either 20 mg per kilogram of body weight (76 patients) or 10 mg per kilogram (73 patients) or a matching placebo (76 patients). All medications were administered in 2 equally divided doses daily, for 14 weeks.
There was at least a 50% reduction in drop-seizure frequency for 39% of patients in the 20-mg group, 36% in the 10-mg arm, and for 14% with placebo. This decline represented a significant improvement with cannabidiol versus placebo for the 20-mg dose (odds ratio [OR], 3.85; P <.001) and the 10-mg dose (OR, 3.27; P = .003).
A decline in drop-seizures of at least 75% was achieved for 25% of those in the 20-mg group and for 11% and 3% in the 10-mg and placebo arms, respectively. No patients achieved a complete decline in drop-seizures, although some patients were free during a maintenance phase that began at day 15.
In a separate study for Dravet syndrome, which was also published in NEJM,2 the median frequency of convulsive seizures per month declined by -6.5 from 12.4 at baseline for patients treated with cannabidiol. In the placebo group, seizures declined by just 0.8 from baseline. There were 43% of patients achieving a 50% reduction with cannabidiol compared with 27% with placebo (OR, 2.00; P = .08).
The third study for the approval focused on LGS and was published in the Lancet.3 In this 171-patient group, drop-seizures declined by 43.9% with cannabidiol compared with 21.8% with placebo. The mean difference between the groups was -17.21%.
Across all 3 trials of cannabidiol in patients with LGS or Dravet syndrome, the most common adverse events included sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.
The drug will be dispensed with a Medication Guide that addresses the serious risks of cannabidiol, including suicidal ideation, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression, and panic attacks.
“Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes,” said Gottlieb.
CBD is currently a Schedule I substance under the Controlled Substances Act (CSA) as a chemical component of cannabis. The FDA statement emphasized the “known risks” of marijuana and their commitment to protecting people from opportunistic producers of unapproved products containing CBD.
“We’ll continue to take action when we see the illegal marketing of CBD-containing products with unproven medical claims. We’re especially concerned when these products are marketed for serious or life-threatening diseases, where the illegal promotion of an unproven compound could discourage a patient from seeking other therapies that have proven benefits,” said Gottlieb.