1. Epidiolex: Clinical Pearls
Emma Carter, MD
Assistant Professor of Pediatric Neurology
MUSC Children’s Health
Medical University of South Carolina

2. Disclosures
I have no financial relationships with industry or commercial supporters to disclose.
I do not intend to discuss an unlabeled, unapproved, or investigate use of a commercial product or device.

3. History
GW Pharmaceuticals was co-founded in 1998 by Drs. Geoffrey Guy and Brian Whittle
Clinical trials began in 1999 in the UK
First marketed product approved in 2010 in the UK – Nabiximols (Savitex)
Second marketed product FDA approved in US in June 2018 – Cannabidiol (Epidiolex)
Savitex is a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other MS sxs. It’s a combo of THC and CBD
Not approved in the US
Has approval in Spain, Czech Republic, Germany, Denmark, Sweden, Canada (28 countries)
Epidiolex = Purified oil formulation of CBD

4. History
Epidiolex FDA approval specifically for seizure treatment in patients ≥ 2 yo with Dravet syndrome or LGS
DEA reclassified pharmaceutical-grade CBD (< 0.1% THC) as schedule V agent in September 2018
SC Board of Health and Environmental Control adopted this reclassification in October 2018

5. Epidiolex Basics Purified CBD oil with concentration of 100 mg/mL
Delivered in glass bottles of 100 mL
Inactive ingredients include dehydrated alcohol, sesame seed oil, strawberry flavor, and sucralose (no gluten)
Comes with two 5 mL syringes to dose (can get 1 mL syringes)
Stored at room temperature
Open bottle should be disposed of after 12 weeks

6. Epidiolex Basics Dosing
Week 1 Patient takes 5 mg/kg/day div BID (2.5 mg/kg BID)
Week 2 Patient takes 10 mg/kg/day div BID (5 mg/kg BID) –
Pending tolerability and effectiveness, can titrate to 15 mg/kg/day div BID for 1 week and then to 20 mg/kg/day div BID (max dose)
Prescriptions and Epidiolex Engage Enrollment Form
Can fax to authorized specialty pharmacy for patient’s insurance plan OR
Send to the hub (Epidiolex Engage)
Forms found at form.pdf (English and Spanish forms available)
Often times prior authorization is required

7. Epidiolex Basics MUSC Specialty Pharmacy in RT What about insurance?
Most prescriptions sent here and either filled in-house or sent to insurance preferred specialty pharmacy
Mailed directly to the patient monthly
What about insurance?
Most insurances cover if prescribing for indication of LGS or Dravet syndrome
Off label use in refractory epilepsy patients
Assistance programs available (Epidiolex Copay Savings Program, Patient Assistance Program, Hospital to Home Program)

8. Safety
Dosing should be adjusted in patients with moderate and severe hepatic impairment

9. Safety Most common side effects (≥ 10%): Hepatocellular Injury
somnolence, anorexia, diarrhea, transaminase elevations, fatigue, malaise, rash, insomnia, sleep disorder, poor quality sleep, infections
Hepatocellular Injury
Dose-related elevations of ALT and AST
Number of treated patients with ALT elevation 3x above ULN:
30% if taking Valproate and Clobazam
21% if taking Valproate (without Clobazam)
4% if taking Clobazam (without Valproate)
3% if taking neither drug
Most commonly seen in first 2 months of treatment AND with concomitant Valproate use
Improved with discontinuation or reduction of Epidiolex (66%) OR resolved with no changes (33%)
Dose related – mostly seen at 20 mg/kg/day dosing

10. Safety Somnolence Dose-related
32% Epidiolex-treated patients vs. patients on placebo
34% of patients on Epidiolex 20 mg/kg/day vs 27% of patients on Epidiolex 10 mg/kg/day
More commonly seen with concomitant use with Clobazam
Epidiolex increases Clobazam active metabolite by 3-fold (N-desmethylclobazam)
Some prescribing physicians preemptively decrease Clobazam dose or decrease if somnolence becomes apparent (no specific guidelines)
Seen at onset of taking Epidiolex (effects may diminish with time)
Use appropriate counseling in adolescent/adult patients
Avoid driving or use of heavy machinery when starting Epidiolex and until able to gauge degree of somnolence/sedation

11. Safety Suicidal Ideation
With all AEDs including Epidiolex, monitor for worsening depression, suicidal thoughts or behavior, or changes in mood
Pooled analyses of 199 placebo-controlled trials of 11 different AEDs showed:
2x risk of SI or suicidal behavior in patients randomized to AED compared to placebo (adjusted RR 1.8)
4 suicides in AED treated patients vs 0 suicides in placebo treated patients
Most studies 24 weeks or less so unclear about emergence beyond this duration
Data consistent among the drugs analyzed and did not significantly vary by age
If symptoms emerge, should think about symptoms being medication-induced vs. symptoms being related to the illness itself
Epilepsy and many other illnesses for which AEDs are prescribed are associated with M&M and an increased risk of SI/suicidal thoughts

12. Safety Diarrhea Also seems to be dose-related
In controlled Epidiolex trials seen in:
9% of patients taking 10 mg/kg/day vs. 20% of patients taking 20 mg/kg/day vs. 5% of patients on placebo
No specific guidelines in avoiding/treating diarrhea
Review list of prescribed medications and adjust patient’s bowel regimen if taking
See if effects improve when Epidiolex taken with food
Consider adjusting dose frequency (take TID instead of BID)
Beal et al. AES abstract 2017 (2.305), Adverse Events with CBD in Treatment Resistant Epilepsy in a Pediatric Population and Proposed Interventions
Abstract – 4 of 18 patients with diarrhea; changed dose to TID (total dose not changed) which resolved diarrhea in 2/4 of the patients, diarrhea resolved after D/Cing Epidiolex in ¼ of patients, and diarrhea resolved in ¼ of patients with no change to dose
Proposed theory that not the oil itself as placebo also made of oil; more of direct gut effect
Take food with medication to improve absorption

13. Safety Monitoring recommendations:
Obtain baseline transaminase levels and total bilirubin
Follow-up these levels at 1 month, 3 months, and 6 months
Check 1 month after dose changes
Discontinue if transaminase elevation > 3x ULN AND if bilirubin level > 2x ULN OR
Sustained transaminase elevation > 5x ULN

14. Safety Drug-drug interactions
Epidiolex metabolized by CYP3A4 and CYP2C19
Medications inhibiting these enzymes will increase plasma levels and medications inducing these enzymes will decrease the plasma levels
In vivo studies showed:
Co-administration of Epidiolex and CYP2C19 drugs (diazepam) may increase plasma levels of these medications – consider reduction in dosage
In vitro studies predicted:
Enzyme inhibition with UGT1A9 (propofol, diflunisal, fenofibrate), UGT2B7 (gemfibrozil, lamotrigine, morphine, lorazepam), CYP2C8 and CYP2C9 (phenytoin) – consider reducing medication doses if side effects noted
Enzyme inhibition and/or induction with CYP1A2 (theophylline, caffeine) and CYP2B6 (bupropion, efavirenz) – consider adjusting medications doses

15. Patient Resources Use with G-tubes Travel Kit Traveling tips
Encourage families to obtain information through company and from physicians -
Dosing instructions with feeds, do not mix with formula, PVC g-tubes not recommended due to potential to harden
Travel Kit
Traveling tips
TSA allows larger amounts of medically necessary liquids, but must be declared at inspection checkpoint
Encourage families to say Epidiolex and not CBD oil
On website under FAQs section, one question says “Can Epidiolex be taken with a gastrostomy tube?” – there is a number listed to contact the company
Tubes made with PVC are not recommended as they may harden with continued use. In the cases where it cannot be avoided, tubes with PVC elements should be replaced as soon as they show any signs of hardening.
Tubes made with silicone and polyurethane do not show signs of physical incompatibility so can be used until there are any signs of physical incompatibility.
Low dose volumes (< 0.5 mL) may have low accuracy when administered via NG-tubes with longer lengths. Advice from clinicians should be sought in such cases.
If other medications are administered at the same time as Epidiolex, it is recommended that these medications be administered first. Ensure tubing is completely flushed with warm water after administration of the other medication and before Epidiolex is administered.
Epidiolex should not be mixed with formula.

16. Resources and Special Thanks
EPIDIOLEX (Cannabidiol) Oral Solution - Accessdata.fda.gov.
“Healthcare Professionals.” GW Pharmaceuticals, Plc,
Samanta, Debopam. “Cannabidiol: A Review of Clinical Efficacy and Safety in Epilepsy.” Pediatric Neurology, vol. 96, 2019, pp. 24–29., doi: /j.pediatrneurol
Franco, Valentina, and Emilio Perucca. “Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.” Drugs, 2019, doi: /s
Vandolah, Harrison J., Brent A. Bauer, and Karen F. Mauck. "Clinicians’ Guide to Cannabidiol and Hemp Oils." Mayo Clinic Proceedings (2019): n. pag.
Special Thanks to Allison Little, PharmD and Medical Science Liaison for Greenwich Biosciences