UTAH MEDICAID DUR REPORT MARCH 2019

CANNABIDIOL AND STIRIPENTOL FOR THE TREATMENT OF SEIZURES ASSOCIATED WITH LENNOX-GASTAUT AND DRAVET SYNDROMES

Cannabidiol Oral Solution (Epidiolex) Stiripentol Oral Capsule and Powder for Oral Suspension (Diacomit)

Report finalized: February 2019

Drug Regimen Review Center

Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Jacob Crook, MStat, Data and Statistical Analyst Joanne LaFleur, PharmD, MSPH, Associate Professor

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2019 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

Contents

Introduction ...... 1 Methods ...... 2 Disease Overview ...... 2 Table 1. ILAE Multilevel Classification of Epilepsies ...... 3 Table 2. Diagnosis of Lennox-Gastaut Syndrome ...... 6 Table 3. Diagnosis of ...... 7 Treatment Strategies and Guideline Recommendations ...... 8 Table 4. Clinical Guideline Recommendations for the Management of LGS in Adults and Pediatrics ...... 9 Table 5. Treatment Algorithm for the Management of LGS (as suggested by Cross et al) .. 10 Table 6. Recommendations from the Task Force of the ILAE Pediatric Commission Concerning Treatment of DS...... 10 Table 7. North American Consensus Panel Recommendations (2017) for the Management of DS with AEDs ...... 11 Cannabidiol and Stiripentol Information ...... 12 Table 8. Prescribing Information for Cannabidiol and Stiripentol ...... 12 Table 9. Warnings, Contraindications, and Adverse Reactions for Cannabidiol and Stiripentol ...... 15 and Systematic Review Evidence ...... 16 Utah Medicaid Utilization Data ...... 18 Discussion Topics and Potential Prior Authorization Criteria ...... 19 Summary ...... 21 References ...... 23 Appendix A: FDA-Approved Antiepileptic Drugs as of January 2019 ...... 27 Appendix B: Literature Search Strategies ...... 29 Appendix C: FDA-Approved Cannabinoid-Containing Products ...... 30 Appendix D: Drug Interactions with Cannabidiol and Stiripentol ...... 31 Appendix E: Key Findings in Published Clinical Trials ...... 32

Introduction

Cannabidiol (Epidiolex) and Stiripentol (Diacomit) are two antiepileptic orphan drugs approved in 2018 by the U.S. Food and Drug Administration (FDA) for the treatment of seizures associated with 2 rare epilepsy syndromes: Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS).1-3 Both cannabidiol and stiripentol are new molecular entities in the antiepileptic drug (AED) class.4,5

• Cannabidiol, a natural compound from the Cannabis sativa plant, is approved as an add-on medication for the “treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.”1,4 • Stiripentol, a synthetic aromatic allylic , is approved as an add-on medication for the “treatment of seizures associated with Dravet syndrome in patients 2 years of age and older taking .”2,5 Stiripentol is additionally approved in Europe, Japan, and Canada for DS in combination with clobazam and .4,6

As evaluated in clinical trials, these agents are used as adjunctive treatments to conventional AEDs (mainly valproic acid and clobazam).4,5 Cannabidiol- and stiripentol-containing products are available as oral formulations whose recommended dosage is adjusted based on the patient’s body weight.1,2

The mechanisms of action of cannabidiol and stiripentol as are not clearly understood;1,2 however, studies suggest each agent acts on a different target that is key in the reduction of seizures.4,7 Cannabidiol has a lower affinity for cannabinoid receptors preventing the occurrence of psychoactive and abuse-related adverse effects.1,8

Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare, severe, treatment-resistant forms of epilepsy presenting in early childhood.9-11 Both disorders are typically characterized by multiple seizure types (focal and generalized onset seizures) that are recurrent and refractory to antiepileptic drugs (AEDs) and medical interventions (eg, ketogenic diet and surgery).9,10,12 Developmental retardation, learning disability, and behavior impairment are usually observed in these patients.9-11 Patients with these complex epileptic syndromes are unlikely to achieve seizure freedom even with AED therapy and disease prognosis is very unfavorable.4,5,10,13 Quality of life is profoundly affected and mortality risk is increased due to the severity and recurrence of seizures.14

Treatment strategies focus on reducing the frequency of seizures, optimizing cognitive ability and behavior, and improving quality of life.10 Current therapeutic options with FDA approval for the treatment of seizures in patients with LGS include clobazam, , , , , , and the recently approved agent, cannabidiol.1,10,15,16 In addition, some broad- spectrum AEDs such as valproic acid and may be used, off-label, for this condition.10

Cannabidiol and stiripentol are the first FDA approved agents for the reduction of seizures in patients with Dravet syndrome.1,2 Clobazam and valproic acid, although not approved for the treatment of seizures in patients with DS, are the most frequently used AEDs in this population.4,7,14

Currently, there are approximately 29 AEDs available in the United States.15,16 Table 1 of Appendix A includes a list of FDA-approved AEDs as of January 2019 with their labeled indications and suggested mechanisms of action.

1

Cannabidiol (Epidiolex) has Utah Medicaid prior authorization criteria in place since February 2019. The purpose of this review is to provide evidence that can assist the Medicaid Drug Utilization Review (DUR) Board in assuring appropriate use of cannabidiol and stiripentol.

Methods

A literature search for systematic reviews and meta-analyses addressing the efficacy and safety of cannabidiol and stiripentol was conducted in the Cochrane Library and Ovid Medline. Reference lists of relevant systematic reviews were additionally screened. Search strategies are provided in Appendix B.

Information concerning product labeling and FDA clinical review documents was obtained from the FDA website. Additional information was found in Micromedex and Lexicomp. Treatment guidelines for the management of LGS and Dravet syndrome were searched for in the American Academy of Neurology and the American Epilepsy Society websites.

Disease Overview

A. Definition and Classification of Epilepsy Epilepsy is a neurological disorder characterized by repetitive seizures.17 In 2015, the Centers for Disease Control and Prevention (CDC) estimated a prevalence of active epilepsy in the United States of 1.2%.17 This percentage represents approximately 3 million adults and 470,000 children.17 In Utah, the number of patients with active epilepsy in 2015 was approximately 29,300 (24,000 patients 18 years and older and 5,300 patients younger than 18 years).17

An epileptic seizure is defined by the International League Against Epilepsy (ILAE) as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.”18,19 Significant signs and symptoms may include automatic behaviors, emotions, extension or flexion of postures, jerking arrhythmically (ie, myoclonus), jerking rhythmically (ie, clonus), and thinking problems.

In 2014, the ILAE clinically defined epilepsy as a disease of the brain characterized by any of the following conditions18:

(1) “At least two unprovoked (or reflex) seizures occurring > 24 h apart

(2) One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years

(3) Diagnosis of an epilepsy syndrome”18

The ILAE considers epilepsy to be resolved if (1) patients with an age-dependent epilepsy syndrome have passed the applicable age or (2) patients who have not experienced a seizure for the last 10 years and have not been taking antiepileptic drugs for the last 5 years.18

In 2017, the ILAE published a new multilevel classification of epilepsies that consists of 3 different levels (seizure type, epilepsy type, and epilepsy syndrome).12 The main objective of this practical classification is for the diagnosis of patients; however, it is additionally useful in research and development of future

2

antiepileptic drugs.12 For a diagnosis of epilepsy, clinicians may classify patients in one or more classification levels depending on the information available.12 For instance, if there is no access to electroencephalogram (EEG) tests, video recording, and imaging tests, diagnosis is made based only on the first classification level (seizure type).12 In addition, epilepsy type (second classification level) may be the final level of classification if the clinician is not able to classify the patient under a known epilepsy syndrome (third classification level).12

Each seizure type is classified based on seizure onset, awareness, predominant sign or symptoms, and motor/non-motor characteristics.12 In addition, seizure type can be specifically defined using several descriptive words (eg, focal sensory seizure or focal automatism seizure) or broadly defined according to the main epilepsy type category (eg, focal onset seizure or generalized onset seizure).20

Table 1 displays the 2017 multilevel classification of epilepsy proposed by the ILAE.

Table 1. ILAE Multilevel Classification of Epilepsies12,20 Classification Levels Category Subcategories Definition or main features

First Level: • Focal aware seizurea (without loss of Seizures “originating consciousness) within networks limited to SEIZURE TYPE • Focal impaired awareness seizureb one hemisphere”21 (This level assumes (loss of consciousness) that the clinician • Motor onset (eg, automatisms, has confirmed the atonic, clonic, epileptic spasms, Focal onset diagnosis of an hyperkinetic, myoclonic, and tonic epileptic seizure, seizures) according to the • Nonmotor onset (eg, autonomic, 18,19 ILAE definition ) behavior arrest, cognitive, emotional, and sensory) • Focal to bilateral tonic-clonicc • Motor seizures (eg, tonic-clonic, Seizures originating “at clonic, tonic, myoclonic, myoclonic- some point within, and tonic-clonic, myoclonic-atonic, atonic, rapidly engaging, Generalized epileptic spasms) bilaterally distributed onset • Nonmotor (absence) seizures (eg, networks”21 typical, atypical, myoclonic, eyelid myoclonia)

• Motor (eg, tonic-clonic, epileptic Seizures for which “the spasms) nature of the underlying Unknown onset • Nonmotor (eg, behavior arrest) cause is as yet unknown”21 • Unclassifiedd Second Level: Focal epilepsy Individuals with focal epilepsy may have Unifocal and multifocal the seizure types with focal onset (see disorders, and seizures EPILEPSY TYPE seizure type) occurring in one (This level assumes hemisphere. Focal that the patient is epileptiform discharges diagnosed with are usually seen on EEG

3

Table 1. ILAE Multilevel Classification of Epilepsies12,20 Classification Levels Category Subcategories Definition or main features epilepsy, according Combined Eg, LGS and DS Both generalized and focal to the 2014 ILAE generalized and seizures occur definition18) focal epilepsy Generalized Individuals with generalized epilepsy may Patients usually show epilepsy have the seizure types with generalized generalized seizure types onset (see seizure type) and “generalized spike- wave activity on EEG”12 Unknown Individuals with unknown seizure type Patient with epilepsy but there is limited information available to confirm the epilepsy type Third Level: Epilepsy Examples of epilepsy syndromes: Diagnosis for epilepsy syndromes syndromes is established EPILEPSY • Infancy syndromes (DS, West based on seizure type, SYNDROMES syndrome, myoclonic epilepsy in EEG, and imaging features. infancy, etc)19 Epilepsy syndromes are • Childhood syndromes(eg, LGS, early usually age-related and are onset benign childhood occipital often associated with epilepsy childhood absence epilepsy, intellectual and psychiatric etc)19 impairment • Others (eg, neonatal syndromes, adolescence syndromes) Abbreviations: DS, Dravet syndrome; EEG, electroencephalography; ILAE, International League Against Epilepsy; LGS, Lennox-Gastaut syndrome a Previously known as “simple partial seizure” b Previously known as “complex partial seizure” c Previously known as “partial onset with secondary generalization” d Seizures should be classified as “unclassified” when there is insufficient information or due to the rare nature of the seizure

4

B. Treatment-Resistant Epilepsies Treatment-resistant epilepsy, also known as drug-refractory or intractable epilepsy, is defined by the ILAE as “failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom.”22 Patients with treatment-resistant epilepsy are at higher risk for sudden unexpected death in epilepsy (SUDEP), other epilepsy-related deaths, and developmental impairment.23 Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are 2 examples of treatment-refractory epilepsies characterized by the presence of recurrent generalized and focal onset seizures in early childhood.12

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a rare and severe epileptic disorder occurring in early life (between 3 to 5 years) and persisting into adulthood.9,10 It is also known as a “childhood epileptic encephalopathy with diffuse slow spikes and waves.”9 LGS affects 1 to 2 million people worldwide.9 Among all patients with childhood epilepsy, less than 5% are diagnosed with LGS.9 Characteristics of LGS Patients with LGS experience 3 electroclinical manifestations: (1) Numerous seizure types that are recurrent and treatment-resistant (2) Irregular EEG, including an interictal EEG pattern of “diffuse, slow spike-and-wave” (SSW) discharges (3) Developmental retardation9-11 The most common type of seizures are tonic seizures (ie, constant muscle contractions for a few seconds or minutes), which are primarily seen during sleep.9-11 The second most frequent type of seizures are atypical absence seizures characterized by partial or complete loss of awareness.9,11 In addition, sudden falls known as drop attacks typically occur in LGS patients.9-11 These episodes are caused by loss of muscle strength (atonic seizure) or uncontrolled muscle contraction (tonic seizure) and may lead to serious and potentially fatal injuries.9 Other seizure types occurring at a lower frequency such as tonic-clonic generalized seizures may be present in patients with LGS.9,11 Mortality risk is higher in patients with LGS compared to people of the same age mainly due to uncontrolled seizures and serious injuries from drop attacks.9 Seizures in LGS are generally brief.9 However, more than two thirds of patients with LGS experience cluster seizures (repetitive seizures occurring in groups) or status epilepticus (a condition characterized by prolonged seizures [usually more than 5 to 15 minutes depending on the seizure type] that requires emergency medical care).24 Regarding EEG recording features, a slow spike-wave pattern is the classic feature occurring when the patient is awake.11 In addition, the patient presents rapid rhythms on EEG during sleep, also known as “generalized paroxysmal fast activity.”11,25 The majority of children with LGS exhibit learning difficulties or intellectual abnormalities even prior to seizure initiation.9,11 Worsening of these problems may occur if the patient experiences recurrent and severe seizures.9 Additionally, neurological, behavioral, and motor dysfunction can appear. Severe

5

behavioral impairments (eg, attention-deficit hyperactivity disorder, aggressiveness, psychosis, and depression) are frequently present.11 Due to these impairments, most LGS patients need assistance with activities of daily living.9 Etiology of LGS Patients may develop LGS due to several factors, although 10% of LGS cases have unidentified causes.9 Known causes of LGS include neurological abnormalities due to brain injuries, perinatal complications, infections, or malformations, history of epilepsy (eg, infantile spasms or West syndrome), gene mutations, or genetic disorders (eg, tuberous sclerosis complex).9,11,25 Diagnosis of LGS The diagnosis of LGS is based on clinical findings (especially tonic seizures) and EEG abnormalities.11 However, diagnosis is challenging because the typical EEG abnormalities may evolve and even disappear with time, typical seizure types associated with LGS (eg, tonic seizures) and EEG features are not specific to LGS only, and additional seizure types can occur (eg, epileptic spasms, myoclonic seizures, focal seizures, and generalized tonic-clonic seizures).10,11 Intellectual abnormalities and behavioral impairment are typical in patients with LGS; however they are not usually considered in making the diagnosis because some patients do not experience these problems.10 Sleep EEG recordings to assess electrical activity in the brain during sleep may be required for LGS diagnosis.10,11 Magnetic resonance imaging (MRI) to evaluate if structural abnormalities exist is helpful for LGS diagnosis.10 Genetic investigations may support the diagnosis, however, the genetic profile of LGS is very heterogeneous.10 Table 2 outlines the main features of LGS supporting its diagnosis.

Table 2. Diagnosis of Lennox-Gastaut Syndrome9-11,25 Electroclinical Features of LGS • Tonic seizures (the most common seizures, especially at night) • Atypical absences • Drop attacks Clinical Features • Non-convulsive status epilepticus • Other seizure types: myoclonic seizures, focal seizures with or without secondary generalization, tonic-clonic generalized seizures, and unilateral clonic seizures • Slow spike-wave pattern (during wakefulness) EEG Recording Features • Rapid rhythms (during sleep) Abbreviations: EEG, electroencephalogram; LGS, Lennox-Gastaut Syndrome

Dravet Syndrome Dravet syndrome (DS), also called severe myoclonic epilepsy of infancy (SMEI), is a rare and severe epileptic encephalopathy characterized by a variety of treatment-refractory seizures, early onset (before the first year of life), and developmental delay.21,26-29 Patient’s and family’s quality of life is severely affected.26 The incidence of DS in the United States is unknown. A population-based cohort study in California infants estimated an incidence for DS of 1 per 15,700 births.30 The average life expectancy is 8 years

6

(ranging from infancy to 18 years old) and the most frequent mortality cause in DS is sudden unexpected death in epilepsy (SUDEP).26,31 Risk factor for SUDEP include uncontrolled or recurrent seizures and generalized onset seizures.32 Symptoms of DS As defined by the ILAE in 1989, Dravet syndrome or SMEI begins in the first year of life with a unique clinical presentation: (1) frequent convulsive seizures that are usually prolonged and caused by fever (eg, generalized onset seizures or unilateral febrile clonic seizures) and (2) normal psychomotor development at onset.14,26-29 Later, other seizure types such as myoclonic seizures, partial seizures, atypical absence, and status epilepticus occur, even with AED therapy.26,28,29,33 Due to the presence of recurrent and prolonged seizures, developmental delay including cognitive deficit, motor dysfunction, language problems, hyperactivity, and behavioral impairment begin to be apparent at age 2.26,28,29 DS is often not associated with EEG changes at onset;14,33 later, the EEG shows nonspecific anomalies (ie, “generalized spike- waves and polyspike-waves, early photosensitivity, and focal abnormalities”29).14,26 Etiology of DS Approximately 80% to 85% of patients with DS exhibit a mutation in the gene encoding for the sodium voltage-gated channel alpha subunit 1 (SCN1A), which plays an important role in the adequate function of brain cells.26,28,30 Diagnosis of DS Diagnosis of DS is based on family history of epilepsy or febrile seizures (15 to 25% of cases), clinical findings (especially the occurrence of febrile convulsive seizures during the first year of life), developmental features, disease onset, and EEG features.14 Experts in the field consider that genetic testing should be performed in all patients with clinical findings suggestive of DS.14 Appropriate diagnosis is key in this syndrome in order to avoid the use of ineffective therapies that may worsen seizures.14,33 Table 3 outlines the main clinical presentation of DS, according to the 2017 North American Consensus Panel regarding diagnosis and management of DS.

Table 3. Diagnosis of Dravet Syndrome14 Main Clinical Features of DS Older Children and Adults Previously Young Children Undiagnosed • Onset of seizures: 1 year to 18 months • Recurrent seizures (eg, focal • Recurrent generalized tonic-clonic or seizures, generalized seizures, hemiconvulsive seizures that are usually myoclonic, atypical absences, and prolonged (mandatory for diagnosis) tonic seizures) Clinical Features • Myoclonus seizures observed by age 2 • Seizure trigger: hyperthermia • Atypical absences and focal seizures • “Seizure exacerbation with the use observed after age 2 of sodium channel agents”14 • Hyperthermia triggers seizures in the majority of patients Developmental • “Normal developmental and neurological • Intellectual impairment by age 18- Features examination at onset” 60 months

7

Table 3. Diagnosis of Dravet Syndrome14 Main Clinical Features of DS Older Children and Adults Previously Young Children Undiagnosed • Abnormal neurological examination by age 3-4 years • Nonspecific EEG features at onset: • Abnormal EEG: “diffuse background - ≤ 2 years: EEG may be diffusely slow or slowing, often with multifocal normal and/or generalized interictal EEG Features/ - > 2 years: EEG is typically diffusely slow discharges. A photoparoxysmal Neuroimaging • Normal MRI response may be seen”14 • MRI usually normal but may show some abnormalities Abbreviations: AED, antiepileptic drug; DS, Dravet syndrome; EEG, electroencephalogram; MRI, magnetic resonance imaging; SCN1A, sodium voltage-gated channel alpha subunit 1

Treatment Strategies and Guideline Recommendations In epilepsy, the selection of an AED depends on seizure or syndrome type, age, concurrent medications, comorbid conditions, efficacy and safety of AEDs, and patient’s tolerability to AEDs.34 Patients with LGS or DS are unlikely to become seizure free even with AED therapy and cognitive function usually deteriorates over time.10,11,13,35 Thus, the management of LGS and DS focuses on reducing the frequency of the most severe seizures (drop attacks in LGS and generalized tonic-clonic seizures in DS), optimizing cognitive ability and behavior, reducing treatment adverse reactions, and improving quality of life.10,14 The majority of patients with LGS or DS are refractory to the standard AEDs and usually require more than 2 AEDs.25,35 Lennox-Gastaut Syndrome Non-pharmacological treatment of LGS may include ketogenic diet (ie, high-fat diet), resective surgery in specific cases with structural lesions, vagus nerve stimulation, and corpus callosotomy (for atonic seizures and drop attacks).10,11,13,36 Pharmacological treatment currently approved by the FDA to reduce seizure frequenc y in LGS includes cannabidiol, clobazam, clonazepam, felbamate, lamotrigine, rufinamide, and topiramate.1,10,16 Although felbamate is effective in LGS, its use is limited mainly due to safety concerns (aplastic anemia and liver failure).10,13 A 2013 Cochrane review of randomized controlled trials showed that lamotrigine, topiramate, felbamate, and rufinamide may be helpful as adjunctive treatment and clobazam may be useful for drop attacks in patients with LGS.37 Overall, the authors concluded that these drugs are not highly efficacious for LGS based on the available studies.37 Based on results from uncontrolled and open label studies, broad-spectrum AEDs including valproic acid and levetiracetam may be used off-label for the treatment of patients with LGS.10,11 Guidelines Recommendations Treatment-resistant epilepsy guidelines from the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) have been published in 1999, 2004, and 2018.34,38,39 These guidelines recommend clobazam, felbamate, lamotrigine, rufinamide, and topiramate as effective for the reduction

8

of seizures in patients with LGS based on moderate to strong quality evidence.34,38,39 Cannabidiol was FDA-approved after the date of the last literature search performed in the 2018 AAN/AES guideline (November 2015) and no recommendation is available for cannabidiol in this guideline.34 Table 4 describes guideline recommendations for the management of LGS.

Table 4. Clinical Guideline Recommendations for the Management of LGS in Adults and Pediatrics Guideline; Sponsoring Strength of Recommendation Organization, Year Recommendation a Practice guideline update Agents established as effective (as add-on therapy) to

summary: Efficacy and decrease seizure frequency in LGS: Level A tolerability of the new • Rufinamide (2 Class I studies)b antiepileptic drugs II: Agents that are probably effective as add-on therapy to Treatment-resistant epilepsy; reduce seizure frequency in LGS: Level B AAN and AES, 201834 • Clobazam (2 Class II studies)b The following agents are effective in LGS to reduce drop Efficacy and tolerability of attacks in LGS: the new antiepileptic drugs • Lamotrigine (1 class I study and 1 class III study)b Level A II: Treatment of refractory • Topiramate, as adjunctive therapy (1 class I study and 1 epilepsy; AAN and AES, class IV study) 200439 There are no class I or II studies for levetiracetam, N/A , , or Practice advisory: The use of felbamate in the treatment • Felbamate as adjunctive therapy is effective in patients of patients with intractable with LGS older than 4 years and unresponsive to primary Level A epilepsy; AAN and AES, AEDs (one class I study)b 199938 Abbreviations: AAN, America Academy of Neurology; AED, antiepileptic drugs; AES, American Epilepsy Society; LGS, Lennox-Gastaut syndrome; N/A, not available a Levels of recommendation according to the 2017 AAN’s Clinical Practice Guideline Process Manual40: • Level A (Strong recommendation): The agent is established as effective based on at least 2 consistent class I studies (strong evidence) and MUST be recommended • Level B (Moderately strong recommendation): The agent is probably effective based on at least 1 class I study or 2 consistent class II studies (moderate evidence) and SHOULD be recommended • Level C (Weak recommendation): The agent is possibly effective based on at least 1 class II study and 2 consistent class III studies (weak evidence) and MAY be recommended b Study Classification according to the 2017 AAN’s Clinical Practice Guideline Process Manual (Criteria for rating therapeutic studies)40: • Class I: RCT in a representative population, triple-masked studies, and other additional Class I criteria • Class II: eg, RCT that lacks one or two Class I criteria • Class III: eg, controlled studies, crossover trial missing specific criteria, etc. • Class IV: Studies not meeting Class I, II, or III criteria

Expert Opinion Recommendations Treatment guidance for LGS is very limited and selection of AEDs is primarily based on clinical judgement.11 According to a 2005 survey involving US specialists in pediatric epilepsy and a 2007 survey involving European specialists, valproate, lamotrigine, and topiramate were suggested as first-line

9

agents for the treatment of seizures in LGS.35 Additionally, the Epidiolex FDA-review highlights that “valproic acid, although not approved for use in patients with LGS, is considered a first-line treatment along with lamotrigine and topiramate.”4 Cross et al (2017) suggest the following treatment algorithm for newly diagnosed patients with LGS, based on available evidence and expert opinion (see Table 5)10:

Table 5. Treatment Algorithm for the Management of LGS (as suggested by Cross et al)10 1. First-line: valproic acid 2. If no seizure control, add lamotrigine 3. If no seizure control, add rufinamide and try to discontinue one of the 2 previous AEDs (valproic acid or lamotrigine) 4. If no seizure control, add topiramate, clobazam, or felbamate. The selection of one of those AEDs depends on patients’ characteristics and preferences. 5. At the time of the publication of this article, limited evidence was available for cannabidiol and stiripentol10 Abbreviations: AED, antiepileptic drug Note: In general, when an additional AED is incorporated to a two-drug regimen, discontinuation of one of the 2 previous AEDs should be considered as there is no evidence regarding the efficacy of using more than 2 AEDs in combination and the risk for adverse events and drug-drug interactions increases

Dravet Syndrome Cannabidiol and stiripentol are the first products approved by the FDA for the treatment of seizures in patients with Dravet syndrome.1,2 Guidelines Recommendations The 2018 AAN/AES guideline on AEDs for treatment-resistant epilepsies does not include recommendations for the management of Dravet syndrome.34 Literature search strategies developed for this guideline predated the approval of cannabidiol and stiripentol. Evidence supporting the efficacy of available off-label agents for DS is very limited. A Task Force of the ILAE Pediatric Commission developed recommendations in 2015 for the management of DS, based on systematic reviews and the American Academy of Neurology Classification of Evidence (see Table 6).41

Table 6. Recommendations from the Task Force of the ILAE Pediatric Commission Concerning Treatment of DS AAN Level of Reference Antiepileptic Drug Recommendations Evidencea Established as A Stiripentol (with clobazam and valproate) effective Summary of Topiramate Possibly effective C recommendations for the Zonisamide Possibly effective C management of Valproate Possibly effective C infantile seizures: Task Force Possibly effective C Report for the ILAE Commission of Pediatrics; Ketogenic diet Possibly effective C 201541 Lamotrigine Avoid A Avoid A Avoid A a See American Academy of Neurology (AAN) levels of evidence described in Table 4

10

Expert Opinion Recommendations

A North American Consensus Panel defining standards for the diagnosis and management of DS was published in 2017.14 A literature review was performed and a North American Expert Panel of 13 epileptologists with expertise in DS and 5 parents/caregivers was created.14 Based on their consensus, clobazam or valproic acid are considered first-line agents.14 Combination of clobazam with valproic acid is recommended if seizures are uncontrolled with one of these agents. Stiripentol is considered a second-line agent for use in combination with clobazam and valproic acid.14 A summary of consensus of expert panel recommendations regarding treatment of DS is shown in Table 7.

Table 7. North American Consensus Panel Recommendations (2017) for the Management of DS with AEDs14 Strength of AAN Class of Reference Recommendations Agreement Evidence First-line agents for DS: • Clobazam OR valproic acid. The agents should be Strong III combined if seizures are uncontrolled with clobazam or valproic acid Second-line agents for DS: • Stiripentol OR topiramate (one of these agents I (Stiripentol with should be used if the combination regimen of clobazam and clobazam and valproic acid does not control Strong valproaic acid) seizures) Optimizing the Stiripentol should be used in combination with III (topiramate) Diagnosis and clobazam AND valproate Management of Third-line agents: III (levetiracetam) Dravet Syndrome: • Clonazepam, levetiracetam, or zonisamide Strong Recommendations (Moderately effective agents) IV ( and From a North • (for atypical absences) and Moderate rufinamide) American (possibly effective agents) Consensus Panel; • Rufinamide, , or bromides (no No consensus Not available for 2017 consensus regarding efficacy) other AEDs Agents not recommended for DS: Carbamazepine, oxcarbazepine, lamotrigine, Strong II phenytoin, and usually worsen seizures and should be avoided Use of alternative therapies (Medical marijuana): • Medical marijuana is moderately effective for DS Strong III • No consensus on the specific type of medical No consensus marijuana recommended Abbreviations: AED, antiepileptic drugs; DS, Dravet syndrome

11

Cannabidiol and Stiripentol Information

Information from the FDA-approved cannabidiol and stiripentol labels is summarized in Table 8.

Table 8. Prescribing Information for Cannabidiol and Stiripentol Generic Name Brand name Formulations Labeled Indications Labeled Dosage (Approval Date) • Initial dosage: 2.5 mg/kg twice daily Cannabidiol • Maintenance dosage after 1 week: Treatment of seizures 5 mg/kg twice daily associated with Lennox- Oral solution: • Maximum recommended Gastaut syndrome or Dravet 100 mg/mL maintenance dosage: syndrome in patients 2 years 10 mg/kg twice daily Epidiolex1 of age and older • (June 2018) Dose adjustments in hepatic impairment Stiripentol Oral capsule: Treatment of seizures 250 mg and associated with Dravet 500 mg syndrome in patients 2 years • 50 mg/kg/day in 2 or 3 divided of age and older taking doses Powder for Oral clobazam. There are no clinical • Maximum recommended dosage: suspension: data to support the use of 3,000 mg/day Diacomit2 250 mg and Diacomit as monotherapy in (August 2018) 500 mg Dravet syndrome

A. Cannabidiol Information Approximately 100 natural cannabinoids have been identified in the cannabis plant, including cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC).23,42

Delta-9-THC is the primary psychoactive compound of the cannabis plant.42 Its interaction with cannabinoid receptors (CBR), especially CBR1 located in the brain, produces psychoactive adverse effects (euphoria effects or “high”, reduced working memory, sedation, tachycardia, and paranoia).23

CBD, in contrast, exhibits low affinity for cannabinoid receptors, which explains its negligible psychoactive effects, abuse potential, and physical dependence potential.1,8,23,42 The mechanism of action of CBD as an is not clearly understood.1,2,42 Cannabidiol is thought to produce its antiseizure effect by acting on key targets associated with a reduction in seizure frequency (eg, “blockade of G-protein coupled receptor 55 [GPR55] and T-type voltage-gated calcium channels and 8 stimulation of 5-HT1a and 5-HT2a receptors”). Epidiolex is the first plant-derived cannabinoid product available in the U.S. that has demonstrated efficacy in reducing the frequency of seizures in patients 2 years of age and older with LGS and DS.8

Marijuana (cannabis) is classified as Schedule I controlled substance (ie, a drug with a high abuse potential and no accepted medical use) by the United States Drug Enforcement Administration (DEA).8,43,44 However, as robust clinical evidence is now available for CBD in LGS and DS patients, the DEA rescheduled CBD as a Schedule V controlled substance (ie, drugs with the least abuse potential and

12

established medical use) in September 2018.45,46 Appendix C provides additional information regarding other FDA-approved cannabinoid-containing products. Dosage and Administration

CBD is available as an oral solution provided with oral dosing syringes. Due to its composition, it is compatible with ketogenic diets.8 The recommended initial dose is 2.5 mg/kg twice daily, which can be uptitrated to 5 mg/kg twice daily after the first week.1 If this dosage is tolerated and further seizure control is required, uptitration to a maximum dose of 10 mg/kg twice daily is recommended. Dosage adjustments in patients with moderate to severe hepatic impairment are required.1 Product Distribution

Cannabidiol (Epidiolex) is provided through a specialty pharmacy program.47 In addition, the Epidiolex Engage program supports patient’s access to this medication.48 Safety Concerns

The most frequent adverse events associated with the use of CBD include somnolence, gastrointestinal events (decreased appetite and diarrhea), elevated transaminases, fatigue, rash, insomnia, sleep disorder, and infections.1

Important warning considerations related to CBD therapy are listed below1:

• Hepatocellular injury: Elevation of hepatic transaminases is dose-related and is more likely to appear when CBD is co-administered with other AEDs, especially with valproate and clobazam. Hepatic transaminase and total bilirubin levels should be monitored at baseline and regularly during treatment. Dose reduction or discontinuation of CBD, or concomitant AED should be considered if liver enzyme elevation occurs.

• Somnolence and sedation: These adverse reactions are dose-related and are more common at the beginning of treatment. In clinical trials, somnolence and sedation occurred with a higher incidence in the CBD group (32%) compared to placebo group (11%). The incidence was greater in patients taking CBD with clobazam. The ability to drive or operate hazardous machinery may be impaired.

• Hypersensitivity reactions: one patient experienced pruritus, erythema, and angioedema during clinical trials. CBD should be discontinued if hypersensitivity reactions occur.

Drug class warnings associated with the use of any AED are described below1:

• Suicidal behavior and ideation: AEDs may increase the risk for suicidal ideation and behavior. Patients should be monitored for the development of these symptoms during treatment. Pooled analyses including studies of 11 AEDs versus placebo for any indication showed that patients receiving an AED had twice the risk of suicidal ideation or behavior than patients taking placebo. Of note, no cases of completed suicides or suicidal ideation were reported in the CBD pivotal trials.8

• Withdrawal of AEDs: If withdrawal of an AED (eg, CBD) is necessary, the dose should be gradually reduced in order to decrease the risk for increased seizure frequency and status epilepticus.

13

Risk of Abuse and Physical Dependence

Animal and human studies demonstrated no rewarding effects or abuse-related adverse events associated with the use of CBD.1 In addition, no withdrawal symptoms after CBD discontinuation were reported in a physical dependence study in humans.1 Drug-Drug Interactions

CBD is metabolized by (CYP)2C19 and CYP3A4 enzymes.1 The CBD dose should be reduced or increased if co-administered with strong inhibitors or strong inducers of CYP2C19 and CYP3A4 enzymes, respectively. In addition, CBD is metabolized by uridine 5' diphospho-glucuronosyl transferase 1A9 (UGT1A9) and UGT2B7 isoforms; dose reduction of substrates of UGT1A9 or UGT2B7 should be considered.1 Appendix D outlines drug interactions with CBD. Pregnancy

Animal data show that CBD may cause fetal damage.1

B. Stiripentol Information The mechanism of action of stiripentol as an anticonvulsant is unknown.1,2 Stiripentol is thought to produce its antiseizure effect by enhancing the gamma-aminobutyric acid-ergic (GABAergic) inhibitory action.5,49 In addition, stiripentol increases the plasma levels of adjunctive AEDs (eg, clobazam) by inhibiting cytochrome P450.50 Dosage and Administration

Stiripentol is available as capsules or powder for oral suspension. A dose of 50 mg/kg/day is usually recommended in 2 or 3 divided doses.2 Safety Concerns

The most frequent adverse events associated with stiripentol therapy include somnolence, decreased appetite, agitation, , weight decreased, hypotonia, nausea, tremor, dysarthria, and insomnia.2

Important warning considerations related to stiripentol therapy are listed below2:

• Somnolence: In clinical trials of DS, somnolence occurred with a higher incidence in the stiripentol group (67%) compared to placebo group (23%). All patients were additionally receiving clobazam, which has sedative effects. In the presence of somnolence, a dose reduction of clobazam or other AEDs causing somnolence should be considered. The ability to drive or operate hazardous machinery may be impaired.

• Decreased appetite and decreased weight: In clinical trials of DS, decreased appetite and decreased weight were reported with a higher incidence in the stiripentol group (46% and 27%, respectively) compared to the placebo group (10% and 6%, respectively). Pediatric patients should be carefully monitored to assure appropriate weight gain and development. A reduction in the dose of concomitant valproate may reduce these adverse effects.

14

• and Thrombocytopenia: A decrease in neutrophil and platelet count has been observed in clinical trials for patients with DS. Hematologic testing should be performed before treatment and every 6 months afterwards.

• Risks in Patients with Phenylketonuria (PKU): Diacomit oral solution contains phenylalanine, which may worsen PKU.

Drug class warnings associated with the use of any AED include the risk of suicidal behavior and ideation as well as an increased risk of frequent seizures and status epilepticus with abrupt discontinuation of AED therapy (see CBD information).2 Drug-Drug Interactions

There are many possible drug interactions with stiripentol as it is metabolized by the CYP1A2, CYP2C19, and CYP3A4 enzymes, along with UGT1A7, UGT1A9, and UGT2B7 isoforms.2 Stripentol may increase the concentration of concomitant drugs metabolized by UGT1A9, UGT2B7, CYP2C8, and CYP2C9.2 Stripentol may induce or inhibit CYP1A2 and CYP2B6. In addition, higher plasma concentrations of AEDs (eg, clobazam) can occur when co-administered with stiripentol.2 If adverse reactions occur, a clobazam dosage reduction may be considered.2 Appendix D outlines drug interactions with stiripentol. Pregnancy

Animal data show that stiripentol may cause fetal damage.2

Table 9 summarizes warnings and precautions, contraindications, and common adverse events.

Table 9. Warnings, Contraindications, and Adverse Reactions for Cannabidiol and Stiripentol Agent Warnings and Precautions Contraindications Common Adverse Reactions • Withdrawal of AEDs: discontinue Epidiolex Hypersensitivity Frequency ≥ 10% (and greater treatment gradually to decrease the risk of to cannabidiol or than placebo): more frequent seizures and status any of the • Somnolence, decreased epilepticus ingredients in appetite, diarrhea, • Suicidal behavior and ideation Epidiolex transaminase elevations, Cannabidiol1 • Hepatocellular Injury: transaminase fatigue, malaise, and elevations may occur, especially in asthenia, rash, insomnia, combination with valproate and clobazam sleep disorder/poor- • Somnolence and sedation quality sleep, infections • Hypersensitivity reactions • Withdrawal of AEDs: discontinue Diacomit None Frequency ≥ 10% (and greater treatment gradually to decrease the risk of than placebo) more frequent seizures and status • Somnolence, decreased epilepticus appetite, weight Stiripentol2 • Suicidal behavior and ideation decreased, agitation, • Somnolence ataxia, hypotonia, nausea, • Decreased appetite and decreased weight tremor, dysarthria, • Neutropenia and thrombocytopenia insomnia • Risks in patients with phenylketonuria Abbreviations: AEDs, antiepileptic drugs

15

Clinical Trial and Systematic Review Evidence

Appendix E outlines the efficacy results from clinical trials evaluating cannabidiol and stiripentol agents in LGS and DS.

A. Cannabidiol (CBD) Clinical Development The efficacy of CBD as add-on therapy to conventional AEDs for the treatment of LGS and DS has been demonstrated in 3 pivotal randomized controlled trials (RCTs) [GWPCAREI, GWPCARE3, and GWPCARE4 studies].51 All trials had a 4-week baseline period to establish a baseline seizure frequency, followed by a 2-week CBD titration period and a 12-week maintenance period (ie, a 14-week treatment period).1,51

Additional safety information comes from other studies, including expanded access programs (EAPs) in patients with refractory epilepsies.51 Dravet Syndrome Population

A 14-week RCT compared CBD 20 mg/kg/day as add-on therapy versus placebo in patients (2 to 18 years old) with treatment-resistant DS (GWPCAREI study).51

The following inclusion criteria were required 1,4,51:

1. Age between 2 and 18 years old 2. Have a clinical diagnosis of DS not adequately controlled with current AED therapy (at least one concomitant AED). The presence of SCN1A mutations was not considered as an inclusion criteria 3. Experience ≥4 convulsive seizures (eg, tonic-clonic, tonic, clonic, atonic seizures) during the 4- week baseline period while receiving stable AED treatment 4. Receiving one or more AEDs at a stable dose

Patients with a “history or presence of alcohol or substance abuse within the last 2 years” were excluded from the trial.4 In addition, patients at high risk for suicidal ideation or behavior were excluded.4

Regarding baseline characteristics, the median number of convulsive seizures during the 4-week baseline period was 13, with 90% of them being classified as tonic-clonic seizures.1,4 Regarding concomitant AED therapy, the majority of patients (93%) were taking at least 2 concomitant AEDs (eg, 65% of patients were on clobazam, 55% on valproate, 43% on stiripentol, 28% on levetiracetam, and 26% on topiramate).1,51

Efficacy results from the GWPCAREI trial showed significant improvements in favor of CBD with regard to the primary endpoint: the percent change from baseline in the average monthly (per 28 days) frequency of convulsive seizures over the 14-week treatment period, as evaluated by patients or caregiver using seizure diaries.51 Convulsive seizures included atonic, tonic, clonic, and tonic-clonic seizures.51 Patients receiving CBD 20 mg/kg/day (maximum recommended dosage) experienced a 38.9% reduction in convulsive seizures compared to a 13.3% reduction in patients receiving placebo.51 Regarding the key secondary endpoint, a higher percentage of patients treated with CBD had at least 50% reduction in convulsive seizure frequency (43%) compared to placebo (27%); however, these results were not statistically significant.51Other secondary endpoints such as the percentage change from

16

baseline in the number of total seizures and Caregiver Global Impression of Change [CGIC] showed significant improvements with CBD therapy compared to placebo.51 Lennox-Gastaut Syndrome Population

A 14-week RCT compared CBD 20 mg/kg/day as add-on therapy versus placebo in patients (2 to 55 years old) with treatment-resistant LGS (GWPCARE4 study).51 A second 14-week RCT compared 2 doses of CBD (10 mg/kg/day and 20 mg/kg/day) as add-on therapy versus placebo in patients (2 to 55 years old) with treatment-resistant LGS (GWPCARE3 study).51

The following inclusion criteria were required1,4,51:

1. Age between 2 and 55 years old 2. Have a clinical diagnosis of LGS not adequately controlled with current AED therapy (at least one concomitant AED). “Documentation of the patient having met EEG diagnostic criteria and evidence of more than 1 type of generalized seizure, including drop seizures (atonic, tonic or tonic-clonic) for at least 6 months” was required 3. Experience ≥ 2 drop seizures (ie, atonic, tonic, or tonic-clonic seizures) per week during the 4- week baseline period 4. Receiving one or more AEDs at a stable dose (4 AEDs maximum)

Patients with a “history or presence of alcohol or substance abuse within the last 2 years” were excluded from trials.4 In addition, patients at high risk for suicidal ideation or behavior were excluded.4

Regarding baseline characteristics, the median percentage of drop seizures during the 4-week baseline period was 85%.4 Regarding concomitant AED therapy, the majority of patients (94%) were taking at least 2 concomitant AEDs, with clobazam, valproate, lamotrigine, levetiracetam, and rufinamide being the most common concomitant AEDs.1

Efficacy results from the GWPCARE4 trial showed significant improvements in favor of CBD 20 mg/kg/day regarding the primary endpoint (ie, “percentage change from baseline in drop seizure frequency [average per 28 days] during the 14-week treatment period”, as evaluated by seizure diaries51). Patients on CBD 20 mg/kg/day experienced a decrease in drop seizure frequency of 44% compared to 22% in the placebo group.51 The GWPCARE3 trial additionally showed significant improvements in the frequency of drop seizures in favor of CBD (both doses) compared to placebo.51 Patients on both CBD 20 mg/kg/day (maximum recommended dosage) and CBD 10 mg/kg/day (maintenance dosage) reported a reduction in drop seizure frequency of 41.9% and 37.2%, respectively, compared to a 17.2% reduction in patients receiving placebo.51 Regarding the three key secondary endpoints in both trials (≥ 50% reduction in drop seizure frequency from baseline to 14-week treatment period, percentage change from baseline in the number of total seizures [drop seizures and non-drop seizures], and Subject/Caregiver Global Impression of Change [S/CGIC]), significant improvements were observed with CBD therapy compared to placebo.51

A systematic review/meta-analysis combining results from the 2 pivotal studies in patients with LGS (GWPCARE3 and GWPCARE4 studies) showed that 40% of patients on CBD compared to 19% of patients in the placebo group (p< 0.001) experienced a ≥ 50% reduction in drop seizure frequency during the treatment.52 Concerning non-drop seizures, a significantly higher percentage of patients in the CBD

17

group reported a ≥ 50% reduction in non-drop seizure frequency compared to placebo group (49% vs. 30.4%; p=0.018).52

B. Stiripentol (STP) Clinical Development The efficacy of STP for the treatment of seizures associated with DS has been demonstrated in 2 small pivotal RCTs with similar study design (STICLO France and STICLO Italy).2,5,7 Both trials had a 4-week baseline period to measure seizure frequency, followed by a 2-month maintenance period in which patients received STP 50mg/kg/day or placebo, as add-on therapy to clobazam and valproate.2,5,7 Patients and caregivers used a diary to record the frequency of seizures.5

To enter these trials, the following inclusion criteria were required for patients2,5:

1. Age between 3 years and < 18 years old 2. Have Dravet syndrome, according to the 1989 ILAE classification of epilepsy 3. Be “inadequately controlled on clobazam and valproate, with at least 4 generalized clonic or tonic-clonic seizures per month despite optimized therapy”2,5

Regarding baseline characteristics, the median number of monthly seizures at baseline was 18 to 19 in the STICLO France trial and 25 in STICLO Italy.7,53

Efficacy results from the STICLO studies showed significant improvements in the 50% responder rate (primary endpoint), defined as the percentage of patients “who experienced a greater than 50% decrease in the frequency (per 30 days) of generalized clonic or tonic-clonic seizures during month 2 of the double-blind treatment period compared to the 4-week baseline period (i.e., placebo run-in).”2,5 The 50% responder rates were 71% with STP versus 5% with placebo in STICLO France study (p=0.0001) and 67% with STP versus 9.1% with placebo in STICLO Italy (p=0.0094).2,5 The percentage reduction in the frequency of generalized tonic-clonic or clonic seizures during month 2 (secondary endpoint) with STP therapy was significantly greater compared to placebo (-91% vs. 7.4% in STICLO FRANCE and -81% vs. - 27% in STICLO Italy).2,5 Of note, 43% of patients on STP in the STICLO France trial and 25% of patients on STP in the STICLO Italy trial reported no generalized clonic or tonic-clonic seizures compared to none in the placebo group.5,53

Although clinical trials evaluated patients with DS treated with STP in combination with clobazam and valproate, the FDA approved STP in patients taking clobazam only.7 This decision was mainly based on the effect of STP on the of clobazam and valproate.7 STP significantly increases plasma levels of clobazam (2-2.5 fold) and its active metabolite (4-5 fold), which probably contribute to the treatment effect of STP.7 The increase in valproate concentrations is 11%, which was considered “unlikely to influence seizure frequency” by FDA reviewers.7 Utah Medicaid Utilization Data

No pharmacy claims were found for cannabidiol and sitirpentol in the Medicaid fee-for-service population from January 2018 through January 2019.

Regarding pharmacy data for accountable care organization (ACO) patients, there were fewer than 5 patients (ages 23 to 40 years) receiving cannabidiol in 2019 and none receiving stiripentol.

18

Discussion Topics and Potential Prior Authorization Criteria

A. Cannabidiol Potential Prior Authorization Criteria • Patient is 2 years of age or older

• Cannabidiol is prescribed according to the FDA approved dosage (maximum recommended maintenance dose: 20 mg/kg/day)

• Cannabidiol is prescribed as an adjunctive treatment to conventional AEDs

• Diagnosis of seizures associated with LGS or DS that have not responded to treatment with at least 2 AEDs:

o Diagnosis may be based on physician’s clinical judgement OR

o Documentation regarding the frequency of specific seizure types, as detailed in clinical trials, may be considered:

. LGS clinical trials required patients to have more than 1 type of generalized seizures (including drop seizures) for at least 6 months and at least 2 drop seizures per week during the 4-week baseline period

. DS clinical trials required patients to have at least 4 convulsive seizures (tonic-clonic, tonic, clonic, or atonic seizures) during the 4-week baseline period

o Seizures are inadequately controlled with at least 2 AEDs: . Clinical trials evaluated cannabidiol as add-on therapy to at least one conventional AEDs (eg, clobazam or valproate). More than 90% of patients were taking at least 2 AEDs at the initiation of cannabidiol treatment

. Treatment-resistant epilepsy is defined by the ILAE as “failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom”22

• For the management of LGS, consider a trial and failure of at least one FDA-approved conventional AEDs (see table below), unless contraindication, drug-drug interaction, or intolerance: FDA-approved agents for LGS apart from cannabidiol Off-label agents for LGS (Utah Medicaid PDL) (AAN Level of Evidence/Utah Medicaid PDL) Clobazam (Level B/NP) Valproic acid (P) (generally used as first-line in Clonazepam (Not available/P) clinical practice) Felbamate (limited use due to safety concerns) (Level A/NP) Levetiracetam (P) Lamotrigine (Level A/P) Other AEDs Rufinamide (Level A/NP) Topiramate (Level A/P) Abbreviations: AAN, American Academy of Neurology; LGS, Lennox-Gastaut syndrome; NP, non-preferred; P, preferred; PDL, Preferred Drug List

19

• For the management of DS, consider a trial and failure of at least two AEDs with evidence supporting their use in patients with DS (see table below), unless contraindication, drug-drug interaction, or intolerance: FDA-approved agents for DS apart from Off-label agents for DS, supported by low-quality studies (see cannabidiol tables 6 and 7 for further information) (Utah Medicaid PDL) (AAN Level of Evidence/Utah Medicaid PDL) Stiripentol (Level A/not included in the PDL) Clobazam (NP) (generally used as first-line in clinical practice) Valproate (P) (generally used as first-line in clinical practice) Topiramate (P) Zonisamide (P) Bromides Levetiracetam (P) Rufinamide (NP) Abbreviations: AAN, American Academy of Neurology; DS, Dravet syndrome; NP, non-preferred; P, preferred; PDL, Preferred Drug List

• Serum transaminases (ALT and AST) and total bilirubin levels obtained prior to starting treatment

B. Stiripentol Potential Prior Authorization Criteria • Patient is 2 years of age or older

• Stiripentol is prescribed for the FDA approved indication of “treatment of seizures associated with DS in patients 2 years of age and older taking clobazam.”2 The efficacy and safety of stiripentol as monotherapy have not been established

• Stiripentol is prescribed according to the FDA approved dosage

• Diagnosis of seizures associated with DS that have not responded to treatment with at least 2 AEDs:

o Diagnosis may be based on physician’s clinical judgement OR

o Documentation regarding the frequency of specific seizure types, as detailed in clinical trials, may be considered:

. Clinical trials required patients to have at least 4 generalized clonic or tonic-clonic seizures per month that were not controlled with clobazam AND valproate therapy

o Seizures are inadequately controlled with at least 2 AEDs. Consider a trial and failure of a regimen containing valproate AND clobazam, unless contraindication, drug-drug interaction, or intolerance:

. Stiripentol is approved as adjunctive treatment to clobazam, based on clinical trials studying the three-drug regimen of stiripentol, clobazam, and valproic acid. While the labeling does not specify use of a regimen containing stripentol, clobazam, and valproic acid, experts in the field strongly recommend stiripentol as adjunctive therapy to valproate and clobazam

. Clinical trials included patients that had failed therapy with a valproate AND clobazam regimen

20

Re-authorization criteria for cannabidiol and stiripentol:

• Documentation demonstrating positive clinical response (reduction in drop seizure frequency in LGS patients or convulsive seizures in DS patients) after at least 3 months of therapy may be required

• Most recent serum transaminase (ALT and AST) and total bilirubin levels should be submitted for patients taking cannabidiol

o The labeling of cannabidiol states that “serum transaminases (ALT and AST) and total bilirubin levels should be obtained at month 1, 3, and 6 after initiation of treatment with Epidiolex, and periodically thereafter or as clinically indicated”1

Summary

Cannabidiol (Epidiolex) and stiripentol (Diacomit) have been recently FDA-approved for the treatment of seizures associated with LGS or DS, increasing the treatment options for these 2 severe epileptic encephalopathies that are commonly resistant to multiple AEDs. Both agents have been studied as add- on therapies to conventional AEDs.

Current therapeutic options with FDA approval for the treatment of seizures in patients with LGS include clobazam, felbamate, lamotrigine, rufinamide, topiramate, clonazepam, and the recently approved agent, cannabidiol. Treatment-resistant epilepsy guidelines from the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) recommend rufinamide, clobazam, lamotrigine, topiramate, and felbamate as effective for the treatment of seizures in patients with LGS, based on moderate to strong quality evidence. These guidelines predated cannabidiol approval. Experts in the field suggest the use of valproate (off-label use), lamotrigine, and topiramate as initial therapies for patients with LGS. Non-pharmacological interventions such as ketogenic diet, vagus nerve stimulation, and surgical intervention may be added to the AED armamentarium.

For patients with DS, stiripentol and cannabidiol are the first and only products approved by the FDA for the treatment of seizures in DS. Evidence supporting the efficacy of off-label agents for DS is very limited. A 2017 North American consensus panel suggests valproic acid or clobazam (as monotherapy or in combination) as first-line agents and stiripentol or topiramate as second-line add-on agents. Stiripentol is recommended for use in combination with valproic acid and clobazam. Evidence for cannabidiol was limited when these consensus panel’s recommendations were published.

Cannabidiol is the first FDA-approved product containing a purified extract from the cannabis plant. It displays anti-seizure properties and lacks psychoactive effects. Clinical trials with cannabidiol as an add- on therapy to conventional AEDs have demonstrated a significant reduction (17% to 23%) in the frequency of the most disabling seizures (ie, drop seizures in patients with LGS and convulsive seizures in patients with DS) with cannabidiol compared to placebo after 14 weeks of treatment. The Caregiver Global Impression of Change score was significantly improved with cannabidiol compared to placebo. Common adverse events with the use of cannabidiol include somnolence, gastrointestinal effects, and elevated liver transaminases. Drug-drug interactions are important, especially when cannabidiol is co- administered with clobazam (increased risk for somnolence) and (increased risk for elevated liver transaminases). Cannabidiol is minimally associated with psychoactive or euphoric effects, abuse

21

potential, and physical dependence because it has low affinity for cannabinoid receptors. The US DEA has rescheduled cannabidiol to Schedule V controlled substance.

Clinical trials with stiripentol as add-on therapy to clobazam and valproate in DS patients showed that around 70% of patients on stiripentol therapy achieved more than 50% reduction in the frequency of generalized clonic or tonic-clonic seizures compared to 6.5% of patients in the placebo group after 2 months of treatment. A large significant effect was additionally reported for the percentage reduction in the frequency of generalized seizures from baseline (84% reduction with stiripentol compared to 6% with placebo). Identified risks associated with stiripentol include somnolence, decreased appetite with weight loss, neutropenia, and thrombocytopenia. Stiripentol increases the plasma levels of adjunctive AEDs, especially clobazam, via cytochrome P450 inhibition. Reduction in the dose of concomitant clobazam may be considered if adverse events such as somnolence occur.

The Utah Medicaid utilization data documented fewer than 5 ACO patients receiving cannabidiol in 2019 and none receiving stiripentol. No utilization data was documented for FFS patients. Prior authorization criteria may include matching FDA approved indication and dosage, confirmation for diagnosis of LGS or DS that has not responded to treatment with at least 2 AEDs, and use of cannabidiol and stiripentol as adjunctive treatments.

22

References

1. Epidiolex (cannabidiol) oral solution [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; revised June 2018. 2. Diacomit (stiripentol) capsules for oral use and powder for oral suspension [package insert]. Beauvais, France: BIOCODEX; revised August 2018. 3. U.S. Food & Drug Administration. Search Orphan Drug Designations and Approvals. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/. Accessed January 29, 2019. 4. Getzoff N and Ling X. Center for Drug Evaluation and Research. Application number: 210365Orig1s000. Clinical Review. Epidiolex (cannabidiol). Review completion date: June 2018. . 5. Sheridan PH, Bastings E, and Temple R. Center for Drug Evaluation and Research. Application number: 206709Orig1s000 and 207223Orig1s000. Summary Review. Diacomit (stiripentol). August 2018. 6. Chiron C. Stiripentol and vigabatrin current roles in the treatment of epilepsy. Expert opinion on pharmacotherapy. 2016;17(8):1091-1101. 7. Dinsmore S. Center for Drug Evaluation and Research. Application number: 206709Orig1s000 and 207223Orig1s000. Clinical Review. Diacomit (stiripentol). Review completion date: May 2018. 8. Chen JW, Borgelt LM, Blackmer AB. Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes. The Annals of pharmacotherapy. 2019:1060028018822124. 9. National Institutes of Health (NIH). U.S. National Library of Medicine. Genetics Home Reference. Lennox-Gastaut syndrome. https://ghr.nlm.nih.gov/condition/lennox-gastaut- syndrome#statistics. Reviewed: September 2018. Published: February 5, 2019. Accessed February 5, 2019. 10. Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert Opinion on the Management of Lennox-Gastaut Syndrome: Treatment Algorithms and Practical Considerations. Frontiers in neurology. 2017;8:505. 11. Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. The Lancet Neurology. 2009;8(1):82-93. 12. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. 13. Asadi-Pooya AA. Lennox-Gastaut syndrome: a comprehensive review. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;39(3):403-414. 14. Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatric neurology. 2017;68:18-34.e13. 15. Drug Monographs. Lexi-Drugs. Lexicomp. Wolters Kluwer; 2018. https://online.lexi.com/lco/action/home. Accessed February 4, 2019. 16. Vossler DG, Weingarten M, Gidal BE. Summary of Antiepileptic Drugs Available in the United States of America: WORKING TOWARD A WORLD WITHOUT EPILEPSY. Epilepsy currents. 2018;18(4 Suppl 1):1-26. 17. Zack MM, Kobau R. National and State Estimates of the Numbers of Adults and Children with Active Epilepsy - United States, 2015. MMWR Morbidity and mortality weekly report. 2017;66(31):821-825.

23

18. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482. 19. Engel J, Jr. Report of the ILAE classification core group. Epilepsia. 2006;47(9):1558-1568. 20. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522-530. 21. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005- 2009. Epilepsia. 2010;51(4):676-685. 22. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077. 23. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics. 2015;12(4):747-768. 24. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-1523. 25. Jahngir MU, Ahmad MQ, Jahangir M. Lennox-Gastaut Syndrome: In a Nutshell. Cureus. 2018;10(8):e3134. 26. U.S. Department of Health & Human Services. National Institutes of Health (NIH). National Center for Advancing Translational Sciences. Genetic and Rare Diseases Information Center (GARD). Dravet Syndrome. https://rarediseases.info.nih.gov/diseases/10430/dravet-syndrome. Accessed February 8, 2019. 27. Brigo F, Igwe SC, Bragazzi NL. Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy. Cochrane Database of Systematic Reviews. 2017(5). 28. McTague A, Cross JH. Treatment of epileptic encephalopathies. CNS Drugs. 2013;27(3):175-184. 29. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989;30(4):389-399. 30. Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015;136(5):e1310-1315. 31. Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: A review. Epilepsy & behavior : E&B. 2016;64(Pt A):69-74. 32. Centers for Disease Control and Prevention. Epilepsy. Sudden Unexpected Death in Epilepsy (SUDEP). https://www.cdc.gov/epilepsy/about/sudep/index.htm. Last reviewed: May 17, 2018. Accessed February 14, 2019. 33. Dulac O, Lassonde M, Sarnat HB. Pediatric Neurology, Part I. Edinburgh: Elsevier; 2013. 34. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(24):1117. 35. Michoulas A, Farrell K. Medical management of Lennox-Gastaut syndrome. CNS Drugs. 2010;24(5):363-374. 36. Morris GL, 3rd, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;81(16):1453-1459. 37. Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome. The Cochrane database of systematic reviews. 2013(2):Cd003277.

24

38. French J, Smith M, Faught E, Brown L. Practice advisory: The use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999;52(8):1540-1545. 39. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62(8):1261-1273. 40. Gronseth GS, Cox J, Gloss D, et al.; on behalf of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. 2017. Clinical Practice Guideline Process Manual, 2017 ed. Minneapolis, MN: The American Academy of Neurology. 41. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia. 2015;56(8):1185-1197. 42. Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy & behavior : E&B. 2017;70(Pt B):313-318. 43. United States Drug Enforcement Administration. What we do. Drug Information. Drug Scheduling. https://www.dea.gov/drug-scheduling. Accessed February 15, 2019. 44. Department of Health and Human Services. Food and Drug Administration. Supplement Approval. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/210365Orig1s002ltr.pdf. Accessed February 15, 2019. 45. United States Drug Enforcement Administration. Press Releases 2018/09/27. FDA-approved drug Epidiolex placed in schedule V of Controlled Substance Act. https://www.dea.gov/press- releases/2018/09/27/fda-approved-drug-epidiolex-placed-schedule-v-controlled-substance-act. Accessed February 15, 2019. 46. Utah State Legislature. Chapter 37. Utah Controlled Substances Act. https://le.utah.gov/xcode/Title58/Chapter37/C58-37_1800010118000101.pdf. Accessed February 15, 2019. 47. Epidiolex (cannabidiol). Getting Started on Epidiolex. https://www.epidiolex.com/getting- started/prescription. Accessed February 22, 2019. 48. Epidiolex (cannabidiol). Start a patient with EPIDIOLEX® Engage™ support. https://www.epidiolexhcp.com/epidiolex-engage-support. Accessded February 22, 2019. 49. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels. Epilepsia. 2006;47(4):704-716. 50. Chiron C. Stiripentol. Expert opinion on investigational drugs. 2005;14(7):905-911. 51. Buracchio TJ, Dunn WH, and Unger EF. Center for Drug Evaluation and Research. Application number: 210365Orig1s000. Summary Review. Epidiolex (cannabidiol). June 2018. 52. Lattanzi S, Brigo F, Cagnetti C, Trinka E, Silvestrini M. Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox-Gastaut Syndrome: A Systematic Review and Meta-Analysis. CNS Drugs. 2018;32(10):905-916. 53. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000;356(9242):1638-1642. 54. Marinol (dronabinol) capsules [package insert]. North Chicago, IL: AbbVie Inc.; revised August 2017. 55. Syndrol (dronabinol) oral solution [package insert]. Chandler, AZ: Insys Therapeutics, Inc.; revised September 2018.

25

56. Cesamet (nabilone) capsules [package insert]. Somerset, New Jersey: Meda Pharmaceuticals Inc.; revised May 2015. 57. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. The New England journal of medicine. 2017;376(21):2011-2020. 58. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet (london, england). 2018;391(10125):1085‐1096. 59. Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox- Gastaut Syndrome. New England journal of medicine. 2018;378(20):1888‐1897.

26

Appendix A: FDA-Approved Antiepileptic Drugs as of January 2019

Table 1. FDA-Approved Antiepileptic Drugs as of January 201915,16 Antiepileptic Drug Labeled Indication(s) Proposed MoA Adrenocorticotropic Infantile spasm (children < 2 years) Unknown. “Stimulates adrenal secretion hormone (ACTH) of cortisol, corticosterone, aldosterone IM injection and other steroids” Brivaracepam (oral Focal onset seizures (oral formulations: Inhibits synaptic vesicle protein 2A and injectable patients ≥ 4 years, injectable (SV2A) in the brain formulations) formulation: children ≥ 16 years) Cannabidiol (oral LGS or DS in patients ≥ 2 years Unknown. It does not interact with formulations) cannabinoid receptors. It is thought to act on key targets associated with a reduction in seizure frequency Carbamazepine Focal onset seizures; GTCS; mixed types “Enhances rapid inactivation of sodium (oral formulations) channels; block L-type calcium channel” Clobazam (oral LGS (adjunctive treatment) in children GABAA receptor agonist formulations) ≥ 2 years Clonazepam (oral LGS (monotherapy or adjunctive GABAA receptor agonist formulations) therapy), akinetic and myoclonic seizures, and absence seizures unresponsive to (oral and Adjunct in convulsive disorders (oral); GABAA receptor agonist injectable adjunct in severe recurrent convulsive formulations) seizures (injection) Eslicarbazepine Focal onset seizures (patients ≥ 4 years) Unknown. It is thought to inhibit sodium (oral formulations) channels Ethosuximide (oral Absence “Increases the seizure threshold and formulations) suppresses paroxysmal spike-and-wave pattern” Everolimus (oral Focal-onset seizures associated with Mechanistic target of rapamycin formulations) tuberous sclerosis complex in patients (mTOR) inhibitor ≥ 2 years Felbamate (oral Focal-onset epilepsy (patients ≥ 4 years), “Enhances rapid inactivation of sodium formulations) LGS (as add-on therapy). Felbamate is channels; block calcium channel, recommended for use only in those inhibits NMDA receptor, potentiates patients who respond inadequately to GABAA conductance” alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use (oral Focal-onset seizures (as add-on therapy) Binds to calcium channels to modulate formulations) in patients ≥ 3 years calcium current (oral Focal-onset seizures in patients ≥ 4 years “Enhances sodium channel slow and injectable (injectable formulation for patients ≥ 17 inactivation” formulations) years) Lamotrigine (oral Focal-onset seizures in patients ≥ 16 “Enhances sodium channel rapid formulations) years, LGS, primary TCS inactivation; inhibits calcium channels”

27

Table 1. FDA-Approved Antiepileptic Drugs as of January 201915,16 Antiepileptic Drug Labeled Indication(s) Proposed MoA Levetiracepam (oral Focal-onset seizures, myoclonic in JME, “Inhibits synaptic vesicle SV2A protein; and injectable primary TCS partially inhibits N-type Ca2+ currents” formulations) Methsuximide (oral Absence seizures “Affects low-threshold, slow, T- Ca2+ formulation) thalamic currents“ Oxcarbazepine (oral Focal-onset seizures (as monotherapy in “Enhances sodium channel rapid formulations) patients ≥ 4 years and as add-on therapy inactivation, block calcium channels, in patients ≥ 2 years) and enhances potassium conductance” (oral Focal-onset seizures (patients ≥ 12 “Selective, noncompetitive antagonist formulations) years), primary TCS (as add-on therapy) of AMPA glutamate receptor “ in patients ≥ 12 years Phenobarbital (oral Focal-onset and generalized-onset “Binds synaptic and extrasynaptic and injectable seizures GABAA receptors” formulations) Phenytoin and Generalized tonic clonic status “Enhances rapid inactivation of sodium (oral epilepticus channels” and injectable Focal-onset seizures formulations) (oral Focal-onset seizures (as add-on therapy) Binds calcium channels formulation) in adults (oral Focal-onset seizures and TCS “Binds synaptic and extrasynaptic formulation) GABAA receptors” Rufinamide (oral LGS (as add-on therapy) in patients ≥ 1 “Enhances sodium channel rapid formulations) year inactivation” Stiripentol (oral DS Unknown. It is thought to enhance the formulations) GABAergic inhibitory action and increase the plasma levels of adjunctive AEDs by inhibiting CYP450 Tiagabine (oral Focal-onset seizures (as add-on therapy) “Selective GABA reuptake inhibitor” formulations) in patients ≥ 12 years Topiramate (oral Focal and primary GTCS (patients ≥ 2 “Inhibits sodium channels, kainite formulations) years) and LGS (as add-on therapy in receptors and carbonic anhydrase. patients ≥ 2 years) Enhances GABAA” Valproic Focal-onset seizures and absences “Inhibits voltage-dependent sodium and acid/divalproex (patients ≥ 10 years). Mixed seizure types T-type calcium channels, enhances (oral and injectable GABA transmission” formulations) Vigabatrin (oral Refractory focal impaired awareness GABA transaminase inhibitor formulations) seizure (as add-on therapy in patients >10 years), infantile spasms Zonisamide (oral Focal-onset seizures (as add-on therapy) “Enhances rapid inactivation of Na+ formulation) in patients ≥ 16 years channels; ↓low-threshold T-type Ca2+ current; binds GABAA ionophore; carbonic anhydrase inhibition“ Abbreviations: AED, antiepileptic drug; AMPA, aminohydroxy methylisoxazole propionic acid; CYP, cytochrome; DS, Dravet syndrome; FDA, Food and Drug Administration; GABA, gamma aminobutyric acid; GTCS, generalized tonic-clonic seizures; IM, intramuscular; JME, juvenile myoclonic epilepsy; LGS, Lennox- Gastaut syndrome; MoA, mechanism of action; NMDA, N-methyl-D-aspartate; TCS, tonic-clonic seizure

28

Appendix B: Literature Search Strategies

Table 1. Cochrane Library Search Strategy Search Date: February 8, 2019 ID Search Hits #1 (dravet syndrome):ti,ab,kw (Word variations have been searched) 36 #2 MeSH descriptor: [Lennox Gastaut Syndrome] this term only 24 #3 ("Lennox Gastaut syndrome"):ti,ab,kw (Word variations have been searched) 167 #4 MeSH descriptor: [Cannabidiol] this term only 91 #5 (cannabidiol):ti,ab,kw (Word variations have been searched) 292 #6 (stiripentol):ti,ab,kw (Word variations have been searched) 23 #7 #1 OR #2 OR #3 197 #8 #4 OR #5 OR #6 313 #9 #7 AND #8 39 [2 Cochrane reviews and 37 trials]

Table 2. Ovid Medline Literature Search Strategy for Systematic Reviews Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to February 14, 2019> Search Strategy: ------1 Cannabidiol/ or cannabidiol.ti,ab,kw,kf. (2276) 2 stiripentol.ti,ab,kw,kf. (228) 3 Anticonvulsants/ (48864) 4 lennox-gastaut syndrome.mp. or Lennox Gastaut Syndrome/ (1263) 5 Dravet syndrome.mp. or Epilepsies, Myoclonic/ (3222) 6 Meta-Analysis/ or "Systematic Review"/ (157829) 7 (metaanaly$ or meta-analy$).ti,ab,kw,kf. or (cochrane$ or systematic review?).jw. or (systematic adj3 review).ti,ab,kw,kf. or systematic review.ti,ab,kw,kf. (231825) 8 (MEDLINE or systematic review).tw. or meta analysis.pt. (232160) [Search filter for “Reviews” (Maximizes specificity) in Ovid Medline from McMaster University] 9 1 or 2 or 3 (51077) 10 4 or 5 (4311) 11 6 or 7 or 8 (280709) 12 9 and 10 and 11 (35) [Total number of potential systematic reviews]

29

Appendix C: FDA-Approved Cannabinoid-Containing Products

Table 1. FDA-Approved Cannabinoid-Containing Products Controlled Brand Name Substance and Agent Labeled Indication(s) Safety Concerns Act Formulation Schedule46 • Anorexia associated with • The use of these Dronabinol weight loss in patients with products at Marinol (a synthetic acquired immune deficiency Schedule III therapeutic doses capsules54 cannabinoid) syndrome (AIDS) may cause central • Nausea and vomiting nervous system associated with cancer adverse reactions Dronabinol chemotherapy in patients such as euphoria or Syndros oral (a synthetic who have failed to respond Schedule III psychiatric solution55 cannabinoid) adequately to conventional disorders antiemetic treatments • Some patients may be at higher risk for abuse or misuse of Nabilone • Treatment of nausea and these products, Cesamet (a synthetic vomiting associated with Schedule II physical capsules56 cannabinoid) cancer chemotherapy dependence, and withdrawal symptoms

30

Appendix D: Drug Interactions with Cannabidiol and Stiripentol

Table 1. Cannabidiol and Stiripentol Interactions1,2 Interacting Medication(s) Interaction Cannabidiol Moderate or strong inhibitor of CYP3A4 or Increased CBD plasma concentrations CYP2C19 Strong CYP3A4 or CYP2C19 inducers Decreased CBD plasma concentrations Increased or decreased plasma concentrations of CYP1A2 substrates (eg, theophylline, caffeine) substrates (CBD inhibits and induces CYP1A2) Increased or decreased plasma concentrations of CYP2B6 substrates (eg, bupropion, ) substrates (CBD inhibits and induces CYP2B6) UGT1A9 substrates (eg, diflunisal, , Increased plasma concentrations of substrates fenofibrate) UGT2B7 substrates (eg, gemfibrozil, Increased plasma concentrations of substrates lamotrigine, morphine, ) CYP2C8 and CYP2C9 substrates (eg, phenytoin) Increased plasma concentrations of substrates Increased plasma concentrations of N- CYP2C19 substrates (clobazam) desmethylclobazam (active metabolite of clobazam) Valproate Increased risk of liver enzyme elevations CNS depressants and alcohol Increased risk of sedation and somnolence Stiripentol STP is both an inhibitor and an inducer of CYP1A2. CYP1A2 substrates (eg, theophylline, caffeine) Plasma concentrations of CYP1A2 substrates may increase or decrease STP is both an inhibitor and an inducer of CYP2B6. CYP2B6 substrates (eg, sertraline, thiotepa) Plasma concentrations of CYP2B6 substrates may increase or decrease STP is both an inhibitor and an inducer of CYP3A4. CYP3A4 substrates (eg, , , Plasma concentrations of CYP3A4 substrates may quinidine) increase or decrease CYP2C8, CYP2C19 substrates (eg, diazepam, Increased plasma concentrations of CYP2C8, CYP2C19 clopidogrel) substrates (STP inhibits enzyme/transporter activity) Increased plasma concentrations of substrates (STP P-gp substrates (eg, carbamazepine) inhibits enzyme/transporter activity) BCRP substrates (eg, methotrexate, prazosin, Increased plasma concentrations of substrates (STP glyburide) inhibits enzyme/transporter activity) Increased plasma concentrations of clobazam and CYP2C19 substrates (clobazam) norclobazam because STP inhibits CYP3A4 and 2C19 Strong CYP1A2, CYP3A4, or CYP2C19 inducers (eg, rifampin, phenytoin, phenobarbital and Decreased plasma concentrations of STP carbamazepine) CNS depressants and alcohol Increased risk of sedation and somnolence Abbreviations: BCRP, Breast Cancer Resistance Protein; CBD, cannabidiol; CYP, cytochrome; STP, stiripentol; UGT, uridine 5' diphospho-glucuronosyltransferase

31

Appendix E: Key Findings in Published Clinical Trials

Table 1. Main Pivotal Clinical Trials Including Cannabidiol and Stiripentol Reference/ Study Design/ Participants Results for Efficacy Endpoints Clinical Study Intervention Cannabidiol as Add-on Therapy 14-week double- DS (age: 2- Primary endpoint: blind, randomized, 18 years) • Percentage change in primary seizure type placebo-controlled (convulsive seizure) trial Adjusted median difference: −22.8% (95% CI = −41.1 to −5.4; p = 0.01) Study arms: Key secondary endpoint: Devinsky 201757 • CBD • ≥50% reduction in convulsive seizure: OR = 2.00 20 mg/kg/day (2 (95% CI = 0.93 to 4.30; p = 0.08) GWPCAREI divided doses) Other secondary endpoints: • PLA • Reduction in total seizures: Difference between groups: −19.2% (95% CI = −39.25 to −1.17; p = 0.03) • Global impression of change: 62% vs 34% reported improved condition, p = 0.02 • 100% reduction in convulsive seizure: Difference 4.9 (95% CI = −0.5 to 10.3, p = 0.08) 14-week randomized, LGS (age: 2- Primary endpoint: double-blind, 55 years) • Percentage change in primary seizure type (drop placebo-controlled seizure) trial Estimated median difference: −17.21 (95% CI = −30.32 to −4.09; p = 0.0135) Study arms: Key secondary endpoints: 58 Thiele 2018 • CBD • ≥50% reduction in drop seizures: OR = 2.57 (95% CI 20 mg/kg/day (2 = 1.33 to 4.97; p = 0.0043) GWPCARE4 divided doses) • Reduction in total seizures (drop seizures and non- • PLA drop seizures): Estimated median difference: −21.1 (95% CI = −33.3 to −9.4; p = 0.0005) • Global impression of change: 58% vs 34% reported improved condition; OR = 2.54 (95% CI = 1.5 to 4.5; p = 0.0012) 14-week double- LGS (age: 2- Primary endpoint: blind, randomized, 55 years) • Percentage change in primary seizure type (drop placebo-controlled seizure) trial - CBD (20) vs PLA: estimated median difference: 21.6 (95% CI = 6.7 to 34.8; p = 0.005) Devinsky 201859 Study arms: - CBD (10) vs PLA: estimated median difference: • CBD 19.2 (95% CI = 7.7 to 31.2; p = 0.002) GWPCARE3 20 mg/kg/day Key secondary endpoints: (2 divided doses) • ≥50% reduction in drop seizures: • CBD - CBD (20) vs PLA: OR = 3.85 (95% CI = 1.75 to 10 mg/kg/day 8.47; p < 0.001) (2 divided doses) - CBD (10) vs PLA: OR = 3.27 (95% CI = 1.47 to • PLA 7.26; p = 0.003)

32

Table 1. Main Pivotal Clinical Trials Including Cannabidiol and Stiripentol Reference/ Study Design/ Participants Results for Efficacy Endpoints Clinical Study Intervention • Reduction in total seizures (drop seizures and non- drop seizures): - CBD (20) vs PLA: - 38.4% vs. – 18.5% (p = 0.009) - CBD (10) vs PLA: - 36.4% vs. – 18.5% (p = 0.002) • Global impression of change score: - CBD (20) vs PLA: 3 vs.3.6 (OR= 1.8, p= 0.044) - CBD (10) vs PLA: 3.2 vs. 3.6 (OR= 2.6, p= 0.002) Stiripentol as Add-on Therapy 2-month RCT DS (Age: Primary endpoint: 50% responder rate (ie, % of 3–21) patients “who experienced a > 50% decrease in the Study arms: monthly frequency of generalized clonic or tonic-clonic seizures during month 2 of the double-blind treatment STP vs. PLA (as add- period compared to the 4-week baseline period: 53 Chiron 2000 on to clobazam and 71% (STP) vs. 5% (PLA); p < 0.0001 valproate) STICLO France Other efficacy endpoints: Median percentage change from baseline in generalized tonic-clonic or clonic seizure frequency -91% (STP) vs. 7.4% (PLA); p=0.0002 2-month RCT (study DS (Age: Primary endpoint: 50% responder rate (see definition was stopped early) 3–19) above)

Guerrini and 67% (STP) vs. 9.1% (PLA), p=0.0094 Study arms: Pons, 2000 Other efficacy endpoints: Median percentage change

STP vs. PLA (as add- from baseline in generalized tonic-clonic or clonic STICLO Italy5,7 on to clobazam and seizure frequency valproate) -81% (STP) vs. -27% (PLA); p=0.0056 Pooled analysis (STICLO France and Primary endpoint: 50% responder rate (see definition STICLO Italy) above) 69.7% (STP) vs. 6.5% (PLA); p < 0.0001 Pooled analysis (STICLO France Other efficacy endpoints: Median percentage change and Italy)7 from baseline in generalized tonic-clonic or clonic seizure frequency -84.4 (STP) vs. -5.8 (PLA); p < 0.0001 Abbreviations: CBD, cannabidiol; DS, Dravet syndrome; LGS, Lennox-Gastaut Syndrome; OR, odds ration; PLA, placebo; RCT, randomized controlled trials; STP, stiripentol

33