Cannabidiol Approved for Severe Childhood Seizure Disorders

 

 

The United States FDA has approved​​ cannabidiol​​ (Epidiolex® by GW Pharmaceuticals), a non-psychoactive cannabinoid,​​ for the treatment of the severe childhood seizure disorders​​ Dravet Syndrome​​ and​​ Lennox-Gastaut Syndrome.​​ – June 25th, 2018​​ 

 

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~  ​​ ​​​​ Cannabidiol (Epidiolex®)  ​​ ​​​​ ~

Indications

Cannabidiol​​ (CBD, Epidiolex®) is approved for the prevention of seizures in patients aged 2 years and older with​​ Lennox-Gastaut Syndrome​​ and​​ Dravet Syndrome.

 

 

Mechanism

The precise mechanism of CBD in controlling epileptic episodes is not fully understood. It is believed to​​ modulate several endogenous neuronal systems including​​ GABA receptors, TRP-V channels, the voltage-dependent anion channel (VDAC), and the G-protein coupled receptor​​ GPR55. ​​ CBD does not appear to interact with the cannabinoid receptors CB1 and CB2 at physiologically relevant concentrations.

 

 

Administration and Dosing

Recommended starting dose is​​ 2.5 mg/kg PO BID; may titrate up to 10 mg/kg PO BID if necessary. ​​ Monitor serum ALT/AST during course of treatment.

 

 

Adverse Events

  • Transaminase Elevations, especially w/ concomitant valproate or clobazam (Label Warning. >10% in clinical trials*)

  • Anemia (>20% in clinical trials)

  • Suicidal thoughts & behavior (estimated 0.43%)

  • Weight Loss (>5% in clinical trials)

  • Somnolence (>10% in clinical trials)

  • Malaise/Fatigue/Asthenia (>10% in clinical trials)

  • Sleep Disturbance (>10% in clinical trials)

  • GI Distress (>10% in clinical trials)

  • Rash (>10% in clinical trials)

  • Infections (>10% in clinical trials)

*all doses, % increased incidence relative to placebo

 

 

Contraindications & DDI

  • Hypersensitivity to CBD

  • CYP34A/2C19 Substrate

  • UGT1A9/2B7 Inhibitor

  • CYP2C8/2C9/2C19 Inhibitor

  • Pregnancy Category C (evidence of fetal harm from animal studies, benefits may outweigh risks)

 

 

~  ​​ ​​​​ Evidence-Basis  ​​ ​​​​ ~

CBD in Dravet Syndrome

FDA approval of CBD for Dravet syndrome was based on​​ one randomized, double-blind placebo-controlled trial.

  • Trial 1:​​ 120 patients 2-19 years old 20 mg/kg CBD PO QD, primarily as add-on therapy to other antiepileptics. ​​ Median​​ decrease in seizure frequency 39%​​ in CBD group vs. 13% in placebo group.

 

 

CBD in Lennox-Gastaut

CBD effectiveness in Lennox-Gastaut was demonstrated in​​ two randomized double-blind placebo-controlled trials. ​​​​ 

  • Trial 1:​​ 171 patients, 20 mg/kg/day CBD; primarily as ​​ add-on therapy to other antiepileptic medications. ​​ Median​​ decrease in drop seizure frequency 41%​​ in CBD group vs. 14% in placebo group.

 

  • Trial 2:​​ 225 patients, 10 or 20 mg/kg PO daily CBD,​​ median​​ decrease in drop seizure​​ frequency 36-38%​​ in CBD group vs. 18% in placebo group.

 

 

~  ​​ ​​​​ What is Dravet Syndrome?  ​​ ​​​​ ~

Dravet syndrome is an​​ epileptic encephalopathy​​ characterized by febrile seizures beginning in the first year of life. ​​ It is commonly caused by loss-of-function mutations in the neuronal voltage-gated sodium channel NaV1.1, and occurs in 2-5 per 100,000 individuals. ​​ Seizures in Dravet syndrome are often​​ treatment resistant. Behavioral problems, developmental delays, and cognitive deficits are also commonly observed in patients with Dravet Syndrome.

 

 

 

~  ​​ ​​​​ What is Lennox-Gastaut Syndrome?  ​​ ​​​​ ~

Lennox-Gastaut syndrome (LGS) is an​​ epileptic encephalopathy​​ characterized by treatment-resistant epilepsy of variable type, slow spike-wave or fast paroxysmal EEG patterns, and intellectual disability. ​​ Frequent seizures begin between ages 3 and 5. ​​ LGS occurs in 1-2 per 100,000 individuals.​​ 

 

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by pharmacologyreview

 

 

 

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