Introduction
Epidiolex (cannabidiol) is the first FDA-approved prescription pharmaceutical formulation of highly purified cannabidiol (CBD), a naturally occurring cannabinoid derived from Cannabis sativa. It represents a significant advancement in the treatment of certain severe seizure disorders and is classified as an antiepileptic drug (AED). Unlike medical marijuana products, Epidiolex undergoes rigorous pharmaceutical manufacturing processes to ensure consistent dosing, purity, and quality control.
Mechanism of Action
The exact mechanism by which cannabidiol exerts its antiseizure effects is not fully understood. Unlike tetrahydrocannabinol (THC), cannabidiol does not produce psychoactive effects through CB1 receptor activation. Proposed mechanisms include:
- Modulation of GABAergic neurotransmission
- Interaction with G-protein-coupled receptor 55 (GPR55)
- Effects on adenosine signaling
- Modulation of intracellular calcium levels
- Potential effects on transient receptor potential vanilloid (TRPV) channels
The drug's anticonvulsant effects appear to be multifactorial and distinct from other antiepileptic medications.
Indications
Epidiolex is FDA-approved for the treatment of seizures associated with: 1. Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older 2. Dravet syndrome (DS) in patients 2 years of age and older 3. Tuberous sclerosis complex (TSC) in patients 1 year of age and older
Dosage and Administration
Initial Titration:- Start at 2.5 mg/kg twice daily (5 mg/kg/day)
- Increase after one week to 5 mg/kg twice daily (10 mg/kg/day)
- May further increase based on efficacy and tolerability to maximum recommended maintenance dose of 10 mg/kg twice daily (20 mg/kg/day)
- Oral administration only
- Should be taken consistently with regard to meals
- Use the provided syringe for accurate dosing
- Shake bottle well before each use
- May be administered orally or via gastrostomy tube
- Hepatic impairment: Requires dosage adjustment (see full prescribing information)
- Renal impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe impairment
- Elderly: Use with caution due to increased likelihood of hepatic, renal, or cardiac dysfunction
Pharmacokinetics
Absorption:- Time to peak plasma concentration (Tmax): 2.5-5 hours
- High-fat meal increases exposure (Cmax increased by 5-fold, AUC increased by 4-fold)
- Apparent volume of distribution: 20,963-42,849 L
- Plasma protein binding: >94%
- Extensive hepatic metabolism primarily via CYP3A4 and CYP2C19
- Significant first-pass metabolism
- Active metabolites: 7-OH-CBD and 7-COOH-CBD
- Half-life: 56-61 hours
- Primarily fecal excretion (≈85%)
- Renal excretion: <3%
Contraindications
1. History of hypersensitivity to cannabidiol or any component of the formulation 2. Patients with severe hepatic impairment (Child-Pugh Class C)
Warnings and Precautions
Hepatotoxicity:- Can cause dose-related transaminase elevations
- Monitor liver enzymes before treatment and periodically thereafter
- More common when used with valproate or clobazam
- May cause sedation and somnolence
- Patients should avoid operating hazardous machinery until effects are known
- Warn patients about CNS depression effects
- Antiepileptic drugs increase risk of suicidal thoughts and behavior
- Monitor for emergence or worsening of depression, suicidal thoughts, or behavior
- Gradually withdraw to minimize risk of increased seizure frequency
- Monitor for rash and other hypersensitivity reactions
Drug Interactions
Strong CYP3A4 Inhibitors (ketoconazole, clarithromycin):- Increase cannabidiol exposure
- Consider reducing Epidiolex dose
- Decrease cannabidiol exposure
- May require dose adjustment
- Increases incidence of transaminase elevations
- Requires enhanced liver monitoring
- Increases levels of active metabolite norclobazam
- May require clobazam dose reduction
- Additive CNS depression effects
Adverse Effects
Most Common (≥10%):- Somnolence
- Decreased appetite
- Diarrhea
- Fatigue
- Pyrexia
- Vomiting
- Lethargy
- Rash
- Insomnia
- Infections
- Hepatotoxicity (elevated liver enzymes)
- Suicidal behavior and ideation
- Hypersensitivity reactions
- Withdrawal seizures
Monitoring Parameters
1. Liver function tests: Baseline, at 1, 3, and 6 months after initiation, and periodically thereafter 2. Seizure frequency and type: Regular documentation 3. Therapeutic response: Assessment of seizure control 4. Adverse effects: Particularly sedation, somnolence, and gastrointestinal effects 5. Mental status: Monitoring for depression and suicidal ideation 6. Drug interactions: Especially with concomitant AEDs 7. Growth parameters: In pediatric patients
Patient Education
1. Take medication exactly as prescribed; do not adjust dose without medical supervision 2. Use provided dosing syringe for accurate measurement 3. Report any signs of liver problems (nausea, vomiting, abdominal pain, fatigue, jaundice) 4. Be aware of potential sedation and avoid driving or operating machinery until effects are known 5. Do not stop medication abruptly due to risk of increased seizures 6. Inform all healthcare providers about Epidiolex use 7. Report any mood changes, depression, or suicidal thoughts immediately 8. Keep medication out of reach of children 9. Store at room temperature (68-77°F) 10. Report any rash or allergic reactions
References
1. FDA. Epidiolex (cannabidiol) prescribing information. 2018, revised 2023. 2. Devinsky O, et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018;378(20):1888-1897. 3. 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(10125):1085-1096. 4. Devinsky O, et al. Cannabidiol in Dravet Syndrome Study Group. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011-2020. 5. Hess EJ, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617-1624. 6. Morrison G, et al. Cannabidiol (Epidiolex®) for the Treatment of Seizures in Tuberous Sclerosis Complex. J Pediatr Pharmacol Ther. 2021;26(5):477-486.