Cannabidiol Oral Solution (Epidiolex)
August 30, 2018
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a purified drug substance derived from marijuana for the treatment of two rare but severe forms of epilepsy in children. Cannabidiol (CBD) is a cannabinoid that does not share the psychoactive properties of tetrahydrocannabinol (THC). The product was granted priority review and received fast-track and orphan designations. It is marketed as an oral solution called Epidiolex.
INDICATIONS
Epidiolex is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients ≥ 2 years of age.1
DOSAGE
The recommended starting dose is 2.5 mg/kg taken orally twice daily.1 After one week, the dose can increase to 5 mg/kg twice daily. Based on response and tolerability, the dose may rise to a maximum of 10 mg/kg twice daily. Serum transaminases (ALT and AST) and total bilirubin levels should be determined prior to treatment initiation. Dosage adjustment is recommended in patients with moderate or severe hepatic impairment. A dose reduction should be considered with concomitant administration of a moderate or strong CYP3A4 or CYP2C19 inhibitor. A dose increase may be required with strong inducers of these isoenzymes. Epidiolex is available as an oral solution 100 mg/mL.
POTENTIAL ADVANTAGES
The addition of CBD to conventional antiepileptics results in a significant reduction in the number of seizures in treatment-resistant patients with Lennox-Gastaut syndrome or Dravet syndrome.1-4
POTENTIAL DISADVANTAGES
CBD is associated with dose-related elevation of serum transaminases (three times the upper limit of normal), somnolence/sedation, and weight loss (≥ 5%).1 Other adverse reactions include decreased appetite, diarrhea, fatigue/malaise/asthenia, rash, and anemia. As with other antiepileptics, CBD may increase the risk of suicidal behavior and ideation.
COMMENTS
The safety and efficacy of CBD were evaluated in three randomized, double-blind, placebo-controlled studies. Two included subjects with Lennox-Gastaut syndrome and one included subjects with Dravet syndrome.1-4
In the two studies that included Lennox-Gastaut subjects (n = 171 and n = 225), subjects were 2-55 years of age, previously inadequately controlled on a median of six antiepileptics, and on three concomitant antiepileptics at time of study entry, with or without vagal nerve stimulations and/or ketogenic diet.1-3 Ninety-four percent of subjects in both studies were taking at least two antiepileptic drugs. The most common antiepileptics (> 30%) were clobazam, valproate, and levetiracetam. The primary efficacy outcome was the percent change from baseline in the frequency of drop seizures per 28 days over the 14-week treatment period. Secondary outcomes included the percent with a 50% reduction from baseline in drop-seizure frequency and Patient or Caregiver Global Impression of Change (S/CGIC) from baseline. Drop seizure was defined as an epileptic seizure involving the entire body, trunk, or head that leads to or could lead to a fall, injury, or slumping in a chair.2 Median baseline frequency of drop seizures ranged from 71-87 per 28 days. These study authors used a two-week titration period followed by a 12-week maintenance period.
In study 1, subjects were randomized to CBD 20 mg/kg/day or placebo. In study 2, subjects were randomized to 10 mg/kg/day, 20 mg/kg/day, or placebo. In study 1, there was a median change at the 20 mg/kg/day dose of -44% (from a median baseline of 73.8 seizures/28 days) compared to -22% (median baseline of 71 seizures/28 days) for placebo. Forty-four percent demonstrated a ≥ 50% reduction in drop seizures compared to 24% for placebo. In study 2, median changes were -42%, -37%, and -17% for 20 mg/kg/day, 10 mg/kg/day, and placebo from baseline seizure frequencies of 86, 87, and 80, respectively. The percentage of subjects with ≥ 50% reduction in seizures were 39%, 36%, and 14%, respectively. In both studies, S/CGIC showed “slightly improved” compared to “no change” for placebo.
In the study of Dravet syndrome subjects with drug-resistant seizures (2-18 years of age), CBD 20 mg/kg/day reduced the median percentage of total convulsive seizures by 39% from a baseline of 12 convulsive seizures per 28 days. This was compared to 13% for placebo (baseline 15 seizures/28 days). The discontinuation rate was 11.8% for the 20 mg/kg dose, 2.7% for the 10 mg/kg dose, and 1.3% for placebo.1 The most common reason for discontinuation was elevation of serum transaminases. CBD does not appear to lead to abuse-related adverse events or cause physical dependence.1
CLINICAL IMPLICATIONS
Lennox-Gastaut syndrome is a rare but severe form of epileptic encephalopathy with early childhood onset.5,6 It is characterized by several seizure types and severe cognitive impairment. FDA-approved drugs to treat this syndrome include felbamate, topiramate, and clobazam. There are other drugs used off-label with limited success.7 Dravet syndrome is a rare genetic form of epileptic encephalopathy associated with drug-resistant intractable seizures and high mortality. There are no FDA-approved drugs available to treat this syndrome.6,8 Treatment commonly is initiated with valproate and benzodiazepines (e.g., clobazam) off label. CBD offers a significant option for these two severe forms of seizures that are generally multidrug-resistant. CBD is pending DEA rescheduling. The cost was not available at the time of this review.
REFERENCES
- Epidiolex Prescribing Information. Greenwich Biosciences, Inc., June 2018. Available online at: https://bit.ly/2ve7Bl6. Accessed Aug. 3, 2018.
- Devinsky O, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 2018;378:1888-1897.
- Thiele EA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018;391:1085-1096.
- Devinsky O, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011-2020.
- Child Neurology Foundation. Disorder Directory: LGS (Lennox-Gastaut syndrome). Available online at: https://bit.ly/2O8sQLZ. Accessed Aug. 3, 2018.
- U.S. Food & Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. June 25, 2018. Available online at: https://bit.ly/2AqKHMq. Accessed Aug. 3, 2018.
- Kanner AM, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2018;91:82-90.
- Wirrell EC, et al. Optimizing the diagnosis and management of Dravet syndrome: Recommendations from a North American consensus panel. Pediatr Neurol 2017;68:18-34.e3.
Epidiolex is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients ≥ 2 years of age.
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