June 25, 2018:
FDA approved EPIDIOLEX® (Cannabidiol) oral solution for treatment of seizures associated with:
Lennox-Gastaut syndrome and
in patients 2 yr and older.
What is EPIDIOLEX® (Cannabidiol)?
This is pharmaceutical formulation of highly-purified, plant-derived cannabidiol (CBD), a cannabinoid lacking the high associated with marijuana.
Novel Mechanism of Action in Epilepsy:
- CBD does not act through cannabinoid (CB) receptors or sodium channels.
- Prime targets are GPR55 and adenosine reuptake, TRPV1.
Positive Studies Behind this FDA Approval:
(1) Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet , Volume 391 , Issue 10125 , 1085 – 1096.
- Randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland.
- This study investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome.
- Age: 2–55 years.
- n= 171: randomized to receive cannabidiol (n=86) or placebo (n=85).
- Patients had not responded to treatment with at least two antiepileptic drugs.
- Active group received 20 mg/kg oral cannabidiol daily for 14 weeks.
- Median % reduction in monthly drop seizure frequency from baseline: 43·9% (IQR −69·6 to −1·9) in the cannibidiol group and 21·8% (IQR −45·7 to 1·7) in the placebo group.
- Adverse events: 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate.
- The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting.
(2) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376;2011-20.
- Double-blind, placebo-controlled trial.
- n= 120 (61 = received cannabidiol; 59 = placebo).
- Age = 2 to 18 years.
- Active group received 20 mg/kg oral cannabidiol daily.
- 14-week treatment period (2 weeks of dose escalation and 12 weeks of dose maintenance).
- Median frequency of convulsive seizures per month: decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo.
- The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08).
- The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08).
- Adverse events: diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests.
(3) Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome. N Engl J Med 2018;378;20:1888-97.
- Double-blind, placebo-controlled trial conducted at 30 clinical centers.
- n = 225 (76 = 20mg cannabidiol group; 73 = 10mg cannabidiol group; 76 = placebo group).
- Age = 2 to 55 years.
- Duration of treatment = 14 weeks.
- The median % reduction from baseline in drop-seizure frequency during the treatment period was: 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group).
- The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea.
- These events occurred more frequently in the higher-dose group.
- 14 patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.
COMMON ADVERSE EFFECTS:
Based on above trials results:
- GI: diarrhea, decreased appetite, and vomiting.
- Abnormal liver function test.
- Neuro: somnolence.
- Others: pyrexia, fatigue.
NOTE: These adverse events risk increases at high doses.
- FDA Approves First Cannabis Drug for Rare Forms of Epilepsy – Medscape – Jun 25, 2018.
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Dr. Harvinder Singh, M.D. (Admin)
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