EPIDIOLEX®: CASHING IN THE CANNABIS RAIN CHECK?

Leila Petok

PGY-1 Community Pharmacy Resident

H-E-B Pharmacy/UT Austin

1

Disclosures

• No conflicts of interest to disclose

2

Objectives

At the conclusion of this presentation, the learner should be better able to:

• Describe the difference between seizures and epilepsy

• Describe clinical trials which gained Epidiolex® FDA-approval

• Comment on the side effects, drug-drug interactions, and clinical pearls of cannabidiol therapy

• Educate patients and address questions regarding differences between Epidiolex® and OTC cannabidiol products

3

5

BACKGROUND

Seizures

• Seizure - transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain

• Requires both neuronal

1. Hyperexcitability2. Hypersynchronization

• Inhibitory synaptic currents break down and the excitability spreads, locally (focal seizures) or widely (generalized seizures)

Fisher et al. Epilepsia. 2014; 55(4):475–482.

Nguyen et al. Ch. 56: Epilepsy. In: Pharmacotherapy: A Pathophysiologic Approach, 10th Ed. 2018.6

Seizures

• Seizure ≠ epilepsy

Nguyen et al. Ch. 56: Epilepsy. In: Pharmacotherapy: A Pathophysiologic Approach, 10th Ed. 2018. 7

Provoked Seizures Examples

• Drug overdose• Drug withdrawals• Acute neurologic events• Systemic illness• Fever

• Cocaine, TCA’s• Alcohol, benzodiazepines• Trauma, hemorrhage• Hypoglycemia, eclampsia• Febrile seizures

Seizures – Terminology

Kiriakopoulos & Shafer. Types of Seizures. https://www.epilepsy.com/learn/types-seizures.

• Tonic – muscles become tense or rigid

• Atonic – muscles become weak or limp

• Clonic – jerking movements

• Myoclonus – brief muscle twitches

• Nonmotor symptoms – symptoms that don’t affect movement

• Changes in sensation, emotion, thinking

• Changes in autonomic function (goosebumps, tachychardia)

• Behavioral arrest (staring spells)

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Seizures – Current Classifications

Aware | Impaired Awareness Impaired Awareness

Kiriakopoulos & Shafer. Types of Seizures. https://www.epilepsy.com/learn/types-seizures.

Nguyen et al. Ch. 56: Epilepsy. In: Pharmacotherapy: A Pathophysiologic Approach, 10th Ed. 2018.9

“NEW” CLASSIFICATION OF SEIZURE TYPESInternational League Against Epilepsy, 2017

FOCAL ONSETGENERALIZED

ONSETUNKNOWN

ONSET

MOTOR• Tonic-clonic• Epileptic spasms (Generalized)• Repeated automations (Focal)

NON-MOTOR• Absence• Autonomic function changes• Change in emotions

Epilepsy

Fisher et al. Epilepsia. 2014; 55(4):475–482. Nguyen et al. Ch. 56: Epilepsy. In: Pharmacotherapy: A Pathophysiologic Approach, 10th Ed. 2018.

A disease of the brain defined by any of the following:

1. At least two unprovoked seizures occurring >24 h apart

2. One unprovoked seizure and probability of at least 60% for further seizures occurring over the next 10 years

3. Diagnosis of an epilepsy syndrome

Resolved epilepsy – seizure-free for 10 years with no seizure medications for the last 5 years

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Classifications

Scheffer et al. 2017. Epilepsia, 58(4):512–521. 11

Epilepsy Syndromes

Scheffer et al. 2017. Epilepsia, 58(4):512–521.Types of Epilepsy. https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/epilepsy/types/index.html

• Benign Rolandic Epilepsy

• Doose Syndrome

• Juvenile Myoclonic Epilepsy

• West Syndrome

• Lennox-Gastaut Syndrome

• Dravet Syndrome

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Lennox Gastaut Syndrome (LGS)

Scheffer et al. 2017. Epilepsia, 58(4):512–521.Thiele et al. Lancet. 2018; 391: 1085–96Devinsky et al. N Engl J Med 2018;378:1888-97.

• Severe form of epileptic encephalopathy

• 2 cases out of 100,000 population

• Manifests by 8 years old, peak incidence at 3-5 years

• Multiple seizure types – tonic, atonic, atypical absence; “drop attacks” common

• Slow spike-and-wave activity on EEGs

• Typically life-long with cognitive impairment

• 20-60% of patients have delayed cognitive development at disease onset, 75-95% become cognitively impaired with increasing age

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Dravet Syndrome (DS)

Dravet Syndrome. Epilepsy Foundation website. https://www.epilepsy.com/learn/types-epilepsy-syndromes/dravet-syndrome. Nguyen et al. Ch. 56: Epilepsy. In: Pharmacotherapy: A Pathophysiologic Approach, 10th Ed. 2018.Scheffer et al. 2017. Epilepsia, 58(4):512–521.

• Genetic form of epileptic encephalopathy

• > 80% of cases due to mutations in the SCN1A gene

• 1 out of 20,000 – 40,000 population

• Seizures start within first year of life, with developmental slowing or regression at 1-2 years

• Multiple seizure types – tonic, atonic, atypical absence

• Nonspecific EEG features

• Lifelong with developmental disabilities

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Treatment Options

Lennox-Gastaut Syndrome. https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/ Dravet Syndrome. https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum/

Lennox Gaustaut Syndrome Dravet Syndrome*

• Felbamate (Felbatol®)

• Rufinamide (Banzel®)

• Clobazam (Onfi®)

• Clonazepam

• Lamotrigine

• Topiramate

• Valproate^

^Not FDA-approved for LGS, but commonly 1st line

First Line• Clobazam (Onfi®)

• Valproate

Second Line• Stiripentol (Diacomit®)Δ

• Topiramate

Third Line• Clonazepam

• Levetiracetam

• Zonisamide

• Ethosuximide

*None are FDA-approvedΔ Available in Europe only

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Treatment Options

Lagae et al. Dev Med Child Neurol. 2018. 60: 63–72. Van Rijckevorsel, K. Neuropsychiatr Dis Treat. 2008:4(6) 1001–1019.Thiele et al. Lancet. 2018; 391: 1085–96

• Treatment is aimed at controlling seizures

• Usually multiple medications are required

• Ketogenic diet or vagal nerve stimulation may be considered

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75%

25%

LGS Prognosis

Survival Mortality

80%

20%

DS Prognosis

Survival Mortality

< 10% seizure free 11% seizure free

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DRUG REVIEW

Epidiolex® (Cannabidiol)

Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018. https://www.contractpharma.com/contents/view_breaking-news/2018-06-25/fda-approves-gw-pharmas-epidiolex/9778

• The first naturally derived, FDA-approved Cannabis drug product

• Indicated for treating LGS and DS in patients 2+ years of age

• Strawberry flavored, clear to yellow color

• Gluten free, but does contain sesame oil

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Epidiolex® (Cannabidiol)

Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018.

• 100 mg/mL oral solution

• 100 mL stock bottle (NDC 70127-100-10)

• Recommended starting dose:

• 2.5 mg/kg twice daily (5 mg/kg total daily dose)

• Maximum recommended dose:

• 10 mg/kg/dose or 20 mg/kg/day

• Packaged with two 5 mL calibrated oral dosing syringes and a bottle adapter

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HOW DOES IT WORK?

Cannabis, a brief taxonomy

Hillig KW & Mahlberg PG. 2004. Am J Bot. 91(6): 966-975.https://cbdoilreview.org/cbd-cannabidiol/thc-cbd/

• 2 species of plant: Cannabis indica and Cannabis sativa

• Produce cannabinoids, terpenophenolic compounds exclusive to Cannabis

Psychoactive Non-psychoactive

• There is a greater amount of CBD found in C. sativa and a greater amount of THC found in C. indica.

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Cannabidiol MOA

Volkow, ND. National Institute of Health on Drug Abuse website. https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2015/biology-potential-therapeutic-effects-cannabidiol

• Cannabinoids interact with CB1 and CB2 receptors in the body

o CB1 – neurons and glial cells

o CB2 – immune system

• THC causes euphoria via CB1 receptors.

• CBD has little affinity for CB1 receptors, and when it does bind produces little to no effect

• Note: “hemp” is a legal and agricultural term referring to C. sativa with low THC content grown for industrial purposes

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Cannabidiol MOA

Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018. Hillig KW & Mahlberg PG. 2004. Am J Bot. 91(6): 966-975.https://hempedification.files.wordpress.com/2016/12/cbs.png

• Cannabidiol (Epidiolex®) is a cannabinoid that naturally occurs in the Cannabis Sativa L. plant.

• The precise mechanisms by which cannabidiol exerts its anticonvulsant effect in humans are unknown

• Does not appear to be via human cannabinoid receptors

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CLINICAL TRIALS

Clinical Trials

Thiele et al. Lancet. 2018; 391: 1085–96. Devinsky et al. N Engl J Med 2018;378:1888-97. Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Syndrome Study Design # of Patients Objective

I. Thiele et al. (2018)

LGS Randomized, double-blind, placebo-controlled trial at 24 clinical sites in the USA, Netherlands, Poland

N = 171• CBD = 86• PBO = 85

Assess safety and efficacy of CBD for treatment of (drop) seizures

II. Devinsky et al. (2018)

LGS Randomized, double-blind, placebo-controlled trial at 30 sites in the USA, Spain, UK, and France

N = 225• CBD 10mg = 73• CBD 20mg = 76• PBO = 76

Assess safety and efficacy of 2 doses of CBD for treatment of (drop) seizures

III. Devinsky et al. (2017)

DS Randomized, double-blind, placebo-controlled trial at 23 sites in the USA and Europe

N = 120• CBD = 61• PBO = 59

Assess safety and efficacy of CBD for treatment of (convulsive) seizures

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Study Designs

27

Baseline

4 weeks

Treatment

2 week dose escalation*

12 week maintenance

Taper

10 days

Follow-Up

4 weeks

*Initial dose of 2.5 mg/kg in all 3 studies

Thiele et al. Lancet. 2018; 391: 1085–96. Devinsky et al. N Engl J Med 2018;378:1888-97. Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Study I – Thiele et al. (2018)

Thiele et al. Lancet. 2018; 391: 1085–96.

“Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial”

Percent change in monthly frequency of drop seizures from baseline

Primary Endpoint

Proportion of patients with ≥ 50% ↓ in monthly frequency of drop seizures

Percent change in total seizure frequency from baseline

Patient or Caregiver Global Impression of Change from baseline (see Appendix B)

Secondary Endpoints

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Study I – Thiele et al. (2018)

Thiele et al. Lancet. 2018; 391: 1085–96.

Refractory = inadequately managed on ≥ 2 AEDs, inclusive of previous and current treatments

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Inclusion Criteria

• Age 2-55 years• Clinical diagnosis of LGS• Refractory• Taking 1-4 AEDs• > 1 type of generalized seizure, including drop

seizures, for ≥ 6 months

Exclusion Criteria

• History of alcohol or substance abuse• Recreational or medicinal cannabis users• (+) urine THC screen• Pregnant or lactating• Significantly impaired hepatic function• Felbamate within last year• Corticotrophins in last 6 months

Study I – Thiele et al. (2018)

Patient Characteristics

N = 171

• CBD = 86• PBO = 85

• Similar at baseline

• Mean age = 15.4

• Median of 6 previous AEDs

• Median of 3 concomitant AEDs during trial

• Median monthly frequency of drop seizures = 73.8

30Thiele et al. Lancet. 2018; 391: 1085–96.

Study I – Thiele et al. (2018)

Results

Primary EndpointCBD = 43.9% ↓ (p = 0.0135)

• 71.4 to 31.4 drop seizures

PBO = 21.8% ↓• 74.7 to 56.3 drop seizures

Secondary Endpoints≥ 50% ↓ in drop seizure frequency

CBD = 38/86 (44%, p = 0.0043)PBO = 20/85 (24%)

% Δ in total seizure frequency CBD = 41.2% ↓ (p = 0.0005)PBO = 13.7% ↓

Improvement in GIC scale CBD = 49/84 (58%, p = 0.0012)PBO = 29/85 (34%)

31Thiele et al. Lancet. 2018; 391: 1085–96.

Study II – Devinsky et al. (2018)

Devinsky et al. N Engl J Med 2018;378:1888-97.

“Effect of Cannabidiol on Drop Seizures in the Lennox–GastautSyndrome” (2 dose study)

32

Percent change in monthly frequency of drop seizures from baseline

Primary Endpoint

Proportion of patients with ≥ 50% ↓ in monthly frequency of drop seizures

Percent change in total seizure frequency from baseline

Patient or Caregiver Global Impression of Change from baseline

Secondary Endpoints

Study II – Devinsky et al. (2018)

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Inclusion Criteria

• Age 2-55 years• Clinical diagnosis of LGS• ≥ 2 type of generalized seizure, including

drop seizures, for ≥ 6 months

Exclusion Criteria

• History of alcohol or substance abuse• Recreational or medicinal cannabis users• (+) urine THC screen• Pregnant or lactating• Significantly impaired hepatic function• Corticotropins in last 6 months• Felbamate in last year

Devinsky et al. N Engl J Med 2018;378:1888-97.

Study II – Devinsky et al. (2018)

Patient characteristics

N = 225

• CBD 10 mg = 73• CBD 20 mg = 76• PBO = 76

*mg/kg/day

• Similar at baseline

• Median of 6 previous AEDs

• Median of 3 concomitant AEDs during trial

• Most common AED was clobazam

• Median number of drop seizures = 85

34Devinsky et al. N Engl J Med 2018;378:1888-97.

Study II – Devinsky et al. (2018)

Results

Primary EndpointCBD 10mg = 37.2% ↓ (p = 0.005)CBD 20mg = 41.9% ↓ (p = 0.002)PBO = 17.2% ↓

Secondary Endpoints≥ 50% ↓ in drop seizure frequency

CBD 10mg = 26/73 (36%, p < 0.001)CBD 20mg = 30/76 (39%, p = 0.003)PBO = 11/76 (14%)

% Δ in total seizure frequency CBD 10mg = 36.4% ↓ (p = 0.002)CBD 20mg = 38.4% ↓ (p = 0.009)PBO = 18.5% ↓

Improvement in GIC scale CBD 10mg = 48/73 (66%, p = 0.002)CBD 20mg = 43/75 (57%, p = 0.04)PBO = 33/75 (44%)

35Devinsky et al. N Engl J Med 2018;378:1888-97.

Study III – Devinsky et al. (2017)

Devinsky et al. N Engl J Med. 2017; 376:2011-20.

“Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome”

36

Percentage change per 28 days from the 4-week baseline period in convulsive-seizure frequency

Primary Endpoint

≥ 50% reduction in convulsive-seizure frequency per month

Reduction in total seizure frequency

Caregiver Global Impression of Change from baseline

Secondary Endpoints

Study III – Devinsky et al. (2017)

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Inclusion Criteria

• Age 2-18 years• Established diagnosis of DS• Taking 1 or more AEDs• ≥ 4 convulsive seizures during baseline

Exclusion Criteria

• History of alcohol or substance abuse• Recreational or medicinal cannabis users• (+) urine THC screen• Pregnant or lactating• Significantly impaired hepatic function

Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Study III – Devinsky et al. (2017)

Patient characteristics

N = 120

• CBD = 61• PBO = 59

• Similar at baseline

• Mean age 9.8 years

• Median of 4 previous AEDs

• Median of 3 concomitant AEDs during trial

• Median number of convulsive seizures/month = 13

38Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Study III – Devinsky et al. (2017)

Results

Primary EndpointCBD = 38.9% ↓ (p = 0.01)

• 12.4 to 5.9 seizures

PBO = 13.3% ↓• 14.9 to 14.1 seizures

Secondary Endpoints≥ 50% ↓ in convulsive seizure freq.

CBD = 43% (p = 0.08)PBO = 27%

% Δ in total seizure frequency CBD = 28.6% ↓ (p = 0.03)PBO = 9.0% ↓

Improvement in GIC scale CBD = 37/60, 62%,(p = 0.02)PBO = 20/58, 34%

39Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Treatment-Related Adverse EventsI. Thiele et al (2018) II. Devinsky et al (2017) III. Devinsky et al (2018)

CBD = 53/86 (62%)PBO = 29/85 (34%)

CBD 10 mg = 56/67 (84%)CBD 20 mg = 77/82 (94%)PBO = 55/76 (72%)

CBD = 57/61 (93%)PBO = 44/59 (75%)

Common AE • Diarrhea, vomiting• ↓ appetite• Somnolence• Pyrexia

AE leading to withdrawalCBD = 12PBO = 1

Common AE• Diarrhea, vomiting • ↓ appetite• Somnolence• URTI• Pyrexia

AE leading to withdrawalCBD 10 mg = 1CBD 20 mg = 6PBO = 1

Common AE• Diarrhea, vomiting• ↓ appetite• Fatigue, lethargy• URTI• Pyrexia

AE leading to withdrawalCBD = 8PBO = 1

• Somnolence was greater with concomitant clobazam; higher incidence of ↑ liver enzymes occurred with concomitant valproate

40

Thiele et al. Lancet. 2018; 391: 1085–96. Devinsky et al. N Engl J Med 2018;378:1888-97. Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Study EvaluationsStrengths Limitations

• Adequate power achieved

• Patient characteristics matching at baseline

• Sensitivity analyses of endpoints

• The sponsor (GW Pharmaceuticals) funded the study, supplied the drug and placebo; and assisted in data collection and writing of the studies

• Poor ethnic diversity

• CBD was used as an add-on therapy, not stand-alone

• Patients or caregivers recorded #/type of seizures

• Small sample size

• Single dose of CBD was investigated in studies I/III

Pearls and Implications

• Patients in CBD groups were more likely to experience ↑ liver transaminases, esp. if taking valproate concurrently (in Study II, 20 mg/kg > 10 mg/kg)

• CBD inhibits CYP2C19 and ↑ levels of the N-desmethyl metabolite of clobazam, which may have contributed to CBD efficacy and somnolence

41

Thiele et al. Lancet. 2018; 391: 1085–96. Devinsky et al. N Engl J Med 2018;378:1888-97. Devinsky et al. N Engl J Med. 2017; 376:2011-20.

Package Insert

Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018.

• Side effects include somnolence, ↓ appetite, diarrhea, transaminase elevations, fatigue, insomnia, infections

• Dosage adjustment recommended for hepatic impairment or concomitant valproate use

• Transaminase elevations are dose-dependent

42

Package Insert

Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018.

Concomitant Use of Employ This Strategy

Moderate/Strong Inhibitors of• CYP3A4, CYP2C19

↓ Dose of Epidiolex

Strong Inducers of• CYP3A4, CYP2C19

↑ Dose of Epidiolex

Substrates of• UGT1A9, UGT2B7• CYP2C8, CYP2C9• CYP2C19 (Clobazam)

Consider dose reduction of substrate

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• Also note: based on animal data, may cause fetal harm

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WHAT ABOUT OTC CBD?

Legal Issues – The DEA

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• September 28, 2018 – DEA placed Epidiolex® into Schedule V

o Specifically, FDA-approved drugs that contain CBD derived from cannabis and ≤ 0.1% THC

• All other cannabis/cannabis derivatives are still Schedule I

• Loop-hole: Agricultural Act of 2014, AKA “The Farm Bill”

• Very gray area, lots of confusion

Kux, L. Schedules of Controlled Substances. DEA. Federal Register: Vol. 83, No. 189; 48950-48953Lucas ED. H.R. 2642: Agricultural Act of 2014, H.R.2642 https://www.congress.gov/bill/113th-congress/house-bill/2642/text

The 2014 Farm Bill

46

• Hemp and its derivatives (CBD) are legal (?) to sell in all 50 states if grown under a licensed state pilot program

o Hemp – cannabis with < 0.3% THC

o License requires partnership with state department of agriculture or university

o Texas does not have a license to grow hemp

o DEA currently states that parts of hemp plant (not the entire plant itself) are legal to extract and sell from, but impractical due to negligible amounts of cannabinoids

• 2018 Farm Bill – hoping to clear up discrepancies

Kux, L. Schedules of Controlled Substances. DEA. Federal Register: Vol. 83, No. 189; 48950-48953

Products on the Market

47

• Most CBD products on the market are not isolates

• “Full spectrum CBD”, “Hemp extracts”

• There is no regulatory body that enforces quality assurance

• Miller et al. (2017) analyzed 87 CBD products from 31 companies available for online purchase

Bonn-Miller et al. JAMA. 2017. 318 (17): 1708-1709

Of samples had detectable THC levels

• Mean of 0.45 mg/mL21.43%

26.19% Over

42.85% Under

Comparison

48

Epidiolex® OTC Cannabidiol*

Strength 100 mg/mL 66.66 mg/mL

Cost ~ $32,500/year ~ $13,650/year

Efficacy established? Yes No

Potency/purity guaranteed? Yes, per FDA No, private testing

Need a prescription? Yes No

Patents? Yes, 5 “method of use” No

Brodwin, E. Business Insider website. 2018. https://www.businessinsider.com/cost-first-fda-approved-marijuana-medication-epidiolex-2018-8CBD Distillery website. 2018. https://www.thecbdistillery.com/product/1000mg-15ml-pure-cbd-oil-thc-free-tincture/Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018.

*Online seller, $60 for 1000 mg (15 mL) bottle. Calculated using FDA-recommended maximum dosing of Epidiolex® for a 34-kg child.

Pipeline

49

• Epidiolex® for Tuberous Sclerosis (Phase 3)

• CBDV for Epilepsy (Phase 2)

• CBDV for Autism Spectrum Disorders (Phase 2)

• IV CBD for Neonatal Hypoxic-Ischemic Encephalopathy (Phase 1)

• THC + CBD for Glioblastoma (Phase 2)

• CBD for schizophrenia (Phase 2)

• THC + CBD (Sativex®) for MS Spasticity (Phase 3 in the U.S.)

Pipeline. GW Pharmaceuticals website. 2018. https://www.gwpharm.com/products-pipeline/pipeline

Conclusions

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• Cannabidiol (Epidiolex®) is the first naturally derived, FDA-approved Cannabis product available in the U.S., indicated for severe epileptic syndromes: LGS and DS

• Pharmacists should emphasize FDA approval of Epidiolex®

• Be able to counsel on Epidiolex®

• GI upset – nausea, vomiting, diarrhea

• Increased LFT’s – with valproate

• Somnolence and sedation – especially with concomitant clobazam

• DDI’s – inducers, inhibitors, and substrates of CYP enzymes and UGTs

• Pharmacists should additionally be able to address patient questions between OTC cannabidiol products and Epidiolex®

Acknowledgements

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• Nathan D. Pope, Pharm.D., BCACP, FACA

• Collin Hovinga, PharmD, MS, FCCP

52

QUESTIONS?

EPIDIOLEX®: CASHING IN THE CANNABIS RAIN CHECK?

Leila Petok

PGY-1 Community Pharmacy Resident

H-E-B Pharmacy/UT Austin

53

References

54

1. Fisher RS, et al. A practical definition of epilepsy. Epilepsia. 2014; 55(4):475–482. 2. Nguyen VH, Baca CB, Chen JJ, Rogers SJ. Ch. 56: Epilepsy. In: Pharmacotherapy: A Pathophysiologic Approach, 10th Ed. McGraw-Hill

LLC. 2018. 1-58.3. Kiriakopoulos E, Shafer PO. Types of Seizures. Epilepsy Foundation website. https://www.epilepsy.com/learn/types-seizures. March

20, 2017. Accessed August 30, 2018.4. Scheffer IE, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminiology.

2017. Epilepsia, 58(4):512–521. doi:10.1111/epi.137095. Types of Epilepsy. Johns Hopkins Medicine website.

https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/epilepsy/types/index.html. Accessed September 19, 2018.

6. 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: 1085–96. http://dx.doi.org/10.1016/S0140-6736(18)30136-3

7. Devinsky O, et al. Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome. The New England Journal of Medicine. 2018;378:1888-97. DOI: 10.1056/NEJMoa1714631

8. Kiriakopoulos E, Shafer PO. Dravet Syndrome. Epilepsy Foundation website. https://www.epilepsy.com/learn/types-epilepsy-syndromes/dravet-syndrome. June 2017. Accessed August 30, 2018.

9. Lennox-Gastaut Syndrome. National Organization for Rare Disorders website. https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/. Accessed August 31, 2018.

10. Dravet Syndrome. National Organization for Rare Disorders website. https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum/. Accessed August 31, 2018.

11. Van Rijckevorsel, K. Treatment of Lennox-Gastaut syndrome: overview and recent findings. Neuropsychiatric Disease and Treatment2008:4(6) 1001–1019.

12. Lagae L, Brambilla I, Mingorance A, Gibson E, Battersby A. Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey. Developmental Medicine & Child Neurology. 2018. 60: 63–72. DOI: 10.1111/dmcn.13591

13. Epidiolex® [package insert]. Carlsbad, CA. Greenwich Biosciences, Inc; 2018.

References

55

14. Epidiolex® Packaging. Contract Pharma website. 2018. https://www.contractpharma.com/contents/view_breaking-news/2018-06-25/fda-approves-gw-pharmas-epidiolex/9778

15. Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cacnnabinoid variation in Cannabis (Cannabaceae). 2004. American Journal of Botany 91(6): 966-975.

16. THC and CBD molecules. CBD Oil Review website. 2018. https://cbdoilreview.org/cbd-cannabidiol/thc-cbd/. 17. Volkow, ND. The Biology and Potential Therapeutic Effects of Cannabidiol. National Insitute of Health on Drug Abuse website.

https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2015/biology-potential-therapeutic-effects-cannabidiol. Accessed September 24, 2018.

18. CB1 and CB2 Receptors. Hempedification website. https://hempedification.wordpress.com/2016/12/11/cannabinoid-receptors-and-cells/.

19. Devinsky et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. The New England Journal of Medicine. 2017; 376:2011-20. DOI: 10.1056/NEJMoa1611618

20. Kux, L. Schedules of Controlled Substances: Placement in Schedule V of Certain FDA-Approved Drugs Containing Cannabidiol; Corresponding Change to Permit Requirements. Drug Enforcement Agency. September 28, 2018. Federal Register: Vol. 83, No. 189; 48950-48953.

21. Lucas, FD. H.R.2642: An Act To provide for the reform and continuation of agricultural and other programs of the Department of Agriculture through fiscal year 2018, and for other purposes. 2014. 113th Congress of the United States at the Second Session. https://www.congress.gov/bill/113th-congress/house-bill/2642/text

22. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017. 318 (17): 1708-1709.

23. Brodwin, E. The drug maker behind the first FDA-approved medication derived from marijuana has revealed how much it'll cost. Business Insider website. 2018. https://www.businessinsider.com/cost-first-fda-approved-marijuana-medication-epidiolex-2018-8

24. 1000mg 15ml Pure CBD Oil (THC Free) Tincture. CBD Distillery website. 2018. https://www.thecbdistillery.com/product/1000mg-15ml-pure-cbd-oil-thc-free-tincture/

25. Pipeline. GW Pharmaceuticals website. 2018. https://www.gwpharm.com/products-pipeline/pipeline26. Busner J, Targum, SD. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry. 2018; 28-37.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880930/pdf/PE_4_7_28.pdf

Appendices

Appendix A: Abbreviations

Appendix B: Patient and Caregiver Global Impression of Change Scale

Appendix C: Types of Epilepsy from the International League Against Epilepsy

Appendix A: Abbreviations

OTC = over-the-counter

TCA = tricyclic antidepressant

LGS = Lennox Gastaut Syndrome

DS = Dravet Syndrome

EEG = electroencephalogram

SCN1A = sodium channel, voltage gated, type I alpha subunit (gene)

FDA = (United States) Food and Drug Administration

mg = milligram

mL = milliliter

kg = kilogram

CBD = cannabidiol

THC = tetrahydrocannabinol

CB1/2 = Cannabinoid receptor type ½

PBO = placebo

AED = antiepileptic drug

CGIC = Caregiver Global Impression of Change scale

PGIC = Patient Global Impression of Change scale

AE = adverse effects

URTI = upper respiratory tract infection

IV = intravenous

CBDV = cannabidivarin

GI = gastrointestinal

DDI = drug-drug interactions

CYP = cytochrome P450 enzymes

LFTs = liver function tests

UGT = UDP-glucuronosyltransferase

Appendix B: Patient and Caregiver Global Impression of Change Scale

CGIC:

• Since your child started treatment, please assess the status of your child’s overall condition

(comparing their condition now to their condition before treatment) using the scale below. SGIC:

• Since you started treatment, please assess the status of your overall condition (comparing

your condition now to your condition before treatment) using the scale below.

Busner J, Targum, SD. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry. 2018; 28-37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880930/pdf/PE_4_7_28.pdf

Appendix C: Types of Epilepsy from the International League Against Epilepsy