Transcript Medical Cannabis for Epilepsy: Talking to your doctor, Safety and

Lubov Romantseva, MD
Child Neurology and Epilepsy
Rush University Medical Center
Nov 12, 2016
Disclosures
 I have no financial interest in any pharmaceutical
company mentioned in this presentation
 I will discuss non-FDA approved use of medical
cannabis in epilepsy
 I am involved in clinical trials for patients with
epilepsy
Background on Cannabis
 1 Cannabis plant= 100+ bioactive phytocannabinoids
 Most understood are: CBD and THC
 CBD=Cannabidiol: likely responsible for most of anti-
seizure and anti-pain(analgesia) effects
 THC=Tetra-hydro-cannabinol: responsible for psychoactive
“high” effect, ?anti-seizure effect
 Each Strain of Cannabis has a DIFFERENT ratio of
CBD:THC
 Within one strain, each individual Cannabis plant has a
unique ratio of CBD:THC depending on climate and
growing conditions
Artisanal Cannabis preparations
are like growing Tomatoes
 Variable CBD: THC ratio from
batch to batch
 Truthful labeling?
 Quality control?
 Contaminated with pesticides?
heavy metals?
 Unregulated industry
WITHOUT a common
standard
 Vulnerable patients and
caregivers at risk for
misinformation and fraud
Evidence for Efficacy-1
 162 patients, 1-30 years old
 20% Lennox-Gastaut, 20% Dravet, 60% other epilepsies
 Open label study, safety and efficacy assessed
 Epidiolex: purified grown cannabis, high CBD: low THC
 Doses used: 2 mg/kg/day to 25-50 mg/kg/day
 Efficacy: mean 36% reduction in monthly motor seizure
count, 4% became seizure-free
 Common side effects: somnolence, diarrhea, low appetite
 Severe side effects: 1 death(SUDEP), status epilepticus 6%
 Reference: Orrin Devinsky et al. Lancet Neurology 2016;15: 270–278
Evidence for Efficacy-2
 Epidiolex study in Lennox-Gastaut patients
 Double blind, placebo controlled (gold standard)
 2-55 years old, 171 patients
 Patients: median baseline DROP seizure rate was
74/month
 Epidiolex dose 20 mg/day, added to current meds
 Response rate: median drop seizure reduction 44% in
CBD group vs 22% in placebo group, p=0.0135
 Safety profile similar to open-label study
CBD: Safety and Monitoring
 Mortality: likely low, most deaths appear due to SUDEP or
status epilepticus
 Behavior effects: variable, most are tolerable
 Interaction with standard seizure drugs**
 CBD raises CLOBAZAM(Onfi) level by 60-500%: need to
track Clobazam levels and adjust doses or risk toxicity
 CBD also likely raises Valproic acid(Depakote) level
 Bottom line: CBD interacts with several liver enzymes used in
drug metabolism(CYP3A4, CYP2C19) which may result in
unexpected effects
 Reference: A Geffrey et al. Epilepsia 2015;56:1246–1251
Safety: what is NOT known
 Longterm cognitive effects: learning, attention,
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organization, memory
Longterm psychiatric effects: impulse control, risk of
mood disturbance or psychosis, risk of future
addiction to “hard drugs” or alcohol
Longterm seizure-control rates
CBD-Drug interactions?
What seizure types/epilepsies worsen with CBD?
Future Clinical Trials
 Epidiolex(purified plant CBD) study in refractory
Infantile Spasms population (GW pharmaceuticals)
 Pilot study for Infantile Spasms to start in 2017
 Synthetic CBD: toxicity and safety studies complete
(Insys pharmaceuticals)
 Lennox-Gastaut efficacy trial: on hold
 Infantile Spasms trial out of UCLA
 Tuberous sclerosis trial
Medical Cannabis and FDA
 Epidiolex makers met with FDA in summer 2016
 Plan to submit New Drug Application(NDA) with
clinicial trial data in first half of 2017
 Epidiolex makers seek FDA approval for treatment of
 refractory Dravet syndrome
 refractory Lennox-Gastaut syndrome
 Timeline to FDA decision?
Future Clinical Trials
 Website: www.clinicaltrials.gov
 Search: “cannabidiol and epilepsy”
 31 trials registered now, in 2014 there were 4
 Conditions addressed: Lennox-Gastaut, Dravet,
Infantile Spasms, Tuberous Sclerosis, other refractory
epilepsies
 This is the BEST time to get involved in a clinical trial
and help bring CBD therapy out of the shadows
Legal status of Medical Marijuana
 Federal level
 Classified as Schedule I substance (no accepted medical
use)
 In same category as heroine and cocaine
 State level: extremely variable
 Legal for recreational and medical use
 Legal for medical use only(specific conditions)
 Not legal for any use
Medical Cannabis Law in Illinois
 IL Medical Cannabis Act of 2013
 Legal for medical use in specific medical conditions,
including refractory epilepsy in children under 18 yo
 compassionate use for patients who have FAILED standard
medical treatment, last resort option
 Specific procedures to be followed
 Patient and caregiver must register with the state, receive a
registration card, then can obtain LEGAL medical cannabis
from one of IL dispensaries
 Website: www.illinois.gov, links to
 Medical Cannabis Pilot Program webpage
Medical Cannabis in Illinois
 Physician CANNOT prescribe dose/frequency
 Not licensed by FDA, no standard dose yet
 Physician CAN certify that the patient has a
qualifying medical condition under IL law
 Certifying Physician needs to have a bona fide(pre-
existing) relationship with the patient
 If patient is a minor, 2 physicians need to certify
Medical Cannabis in Illinois
 Certification by MD is NOT a guarantee of treatment
success
 Certification states that “benefits from medical
cannabis MAY outweigh the risks” for a particular
patient
Talking to your doctor about Medical
Cannabis
 Ultimately, physicians want to do what is best for their
patients
 Safety is a huge concern: “first do no harm” is a basis of
physician practice philosophy
 Reasons for Provider hesitation:
 Lack of knowledge of longterm safety/side effects
 Inability to prescribe a specific dose
 Lack of FDA approval
 Uncertain legal status/risk of litigation, loss of license
 Lack of hospital policies regarding medical cannabis*
Talking to your doctor about
medical cannabis
 Be honest and direct
 Find out your doctor’s comfort level and knowledge
base
 Remember: most MD’s have no formal training on the
subject and are learning as we go
 Discuss all other options, share what you know
 Make a joint plan about other medications
 Change only one thing at a time
 Keep communication lines open
CBD in National Epilepsy News:
The Latest from Child Neurology Society meetingOctober 2016
 Senior Child Neurologist Dr Elizabeth Thiele from
Mass General hospital in Boston sums up the progress
made
 Video clip on Neurology Advisor website
 http://www.neurologyadvisor.com/cns-2016-
coverage/video-cannabidiol-and-our-progresstowards-a-treatment-for-refractoryepilepsy/article/569490/
Summary Points-1
 Medical cannabis has some efficacy in treating
refractory epilepsies in children and adults
 Cannabis is a complex plant and its longterm effects
on brain and body are not yet known
 Medical Cannabis has a sensitive legal status, with
Federal and State regulations at odds with each other
 Medical cannabis is NOT FDA approved at this point,
but may become so in next 2 years
Summary points-2
 Option of Medical Cannabis should be discussed
openly and directly with the treating provider
 Clobazam and Valproic acid levels need to be
monitored if CBD is added to treatment regimen
 FIRST, DO NO HARM
 Knowledge is POWER=JOIN a Clinical trial
Thank you!
Questions?