Effective Date

Date of Origin   

07-01-2024           

Epidiolex^®

(cannabidiol)

Oral solution

Treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older

1

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy involving several seizure types, with an onset during infancy or early childhood. Many causes of LGS have been identified, including genetic disorders, trauma, cortical malformations, perinatal hypoxia, and meningitis. Tonic, atonic, and atypical absence seizures are the most common seizure types associated with LGS. Clinical features that may be present include cognitive dysfunction, behavioral abnormalities, and neurodevelopmental impairment. Management of LGS is difficult because it is refractory to many treatments, and no specific therapy is effective for all patients. Valproate is generally considered first-line therapy, and if monotherapy is ineffective another drug such as lamotrigine or rufinamide is added to valproate therapy.(4,10) Alternative adjunctive antiseizure medications include topiramate, clobazam, cannabidiol, fenfluramine, or felbamate.(10) Additional therapies, for patients who do not respond to antiseizure medications, include the ketogenic diet and vagal nerve stimulation.(4,10)

Dravet Syndrome

Dravet syndrome (DS) is a severe form of epilepsy with an onset of recurrent, prolonged seizures in infancy that are often triggered by fever or overheating. DS is characterized by lifelong comorbidities, including neurodevelopmental problems and intellectual disability.(7,8,9,15) Mutations in the alpha-1 subunit of the voltage-gated sodium channel (SCN1A) gene are identified in at least 80% of patients with DS.(7,9,15) Status epilepticus is common and is one of the leading causes of premature mortality seen with DS. Patients with DS have an elevated risk of premature mortality, with the most common cause being sudden unexpected death in epilepsy (SUDEP).(7,8,9) Other types of seizures appear before age 5 years and include myoclonic, focal, and atypical absence seizures.(7,9,15) Valproate is considered first-line therapy, with clobazam added if needed.(7,8,9,15) Additional agents include stiripentol, topiramate, cannabidiol, and fenfluramine.(7,8,15) For patients with symptoms refractory to drug therapy, ketogenic diet and vagal nerve stimulation may be beneficial.(7,8,9,15)

Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by a mutation in either the TSC1 gene or the TSC2 gene. TSC is characterized by the development of a variety of benign tumors in multiple organs, including the brain, heart, skin, eyes, kidney, lung, and liver. Seizures are the most frequent presenting neurologic feature of TSC, with more than 80% of patients developing seizures during childhood.(12) Often infantile spasms occur in children with TSC, and vigabatrin is recommended as first-line therapy. Adrenocorticotropic hormone (ACTH), synthetic ACTH, or prednisolone may be used as second-line therapy if an inadequate response to vigabatrin is seen after 2 weeks.(14) Anticonvulsants may be prescribed, with the specific drug being dependent on the type of seizure. Patients with intractable seizures may benefit from a ketogenic diet or vagal nerve stimulation.(11,12,14)

Efficacy

Cannabidiol was studied for treatment of seizures associated with LGS in two published randomized, double-blind, placebo-controlled trials in patients age 2 to 55. Study 1 (GWPCARE4, N=171) compared cannabidiol 20 mg/kg/day vs. placebo.(2) Study 2 (GWPCARE3, N=225) compared cannabidiol 10 mg/kg/day and 20 mg/kg/day vs. placebo.(3) In both studies, LGS patients were inadequately controlled on at least one anti-epileptic drug (AED), with or without vagal nerve stimulation and/or ketogenic diet. In both trials, patients were required to have a minimum of 8 drop seizures (greater than or equal to 2 drop seizures per week) during a 4-week baseline evaluation period. The baseline period was followed by a 2-week titration period and a 12-week maintenance period.(2,3) During Study 1, 94% of patients were taking greater than 2 concomitant AEDs. Most frequently used concomitant AEDs (greater than 25%) were clobazam (49%), valproate (40%), lamotrigine (37%), levetiracetam (34%), and rufinamide (27%).(2) During Study 2, 94% of patients were taking greater than 2 concomitant AEDs. Most frequently used concomitant AEDs (greater than 25%) were clobazam (49%), valproate (38%), levetiracetam (31%), lamotrigine (30%), and rufinamide (29%).(3) In both studies, the primary endpoint was percent change from baseline in frequency (per 28 days) of drop seizures (atonic, tonic, or tonic-clonic seizures) over 14-weeks of treatment. In both studies, median percent change from baseline (reduction) in the frequency of drop seizures was significantly greater for cannabidiol vs. placebo: A reduction in drop seizures was observed within 4 weeks of initiating cannabidiol treatment; the reduction remained generally consistent over the 14-week treatment period. Median percent changes from baseline in drop seizure frequency per 28-day period (cannabidiol vs. placebo):(2,3)

• Study 1- 20 mg/kg/day [-44%]; placebo [-22%] (p equal to 0.01)
• Study 2- 10 mg/kg/day [-37%], 20 mg/kg/day [-42%], placebo [-17%] (both doses p less than 0.01)

An open-label extension study (GWPCARE5, N=366), evaluating the long-term safety and efficacy of cannabidiol, was conducted in patients with LGS who completed either GWPCARE3 or GWPCARE4. Sustained reductions in median drop seizure frequency (48-71%) and median total seizure frequency (48-68%) were observed in 12 week intervals through 156 weeks. Notably, 87-93% of patients/caregivers reported an improvement in the patient’s overall condition per the patient-reported Subject/Caregiver Global Impression of Change (S/CGIC) scale over the 156 week period at various intervals (7 total assessments, with the first assessment at week 24 and the last assessment at week 156).(5)

A single, published, randomized, double-blind, placebo-controlled trial compared cannabidiol 20 mg/kg/day vs. placebo in patients ages 2-18 (N=120) with treatment-resistant DS, inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. During a 4-week baseline period, patients were required to have greater than 4 convulsive seizures while on stable AED therapy. The baseline period was followed by a 2-week titration period and a 12-week maintenance period. During this study, 93% of patients were taking greater than 2 concomitant AEDs; most commonly used concomitant AEDs (greater than 25%) were clobazam (65%), valproate (57%), stiripentol (43%), levetiracetam (28%), and topiramate (26%). Baseline median convulsive seizure frequency was 13 per 28 days for the combined groups. The primary endpoint was the percent change from baseline in the frequency (per 28 days) of convulsive seizures (all countable atonic, tonic, clonic, and tonic-clonic seizures) over the 14-week treatment period. The median percent change in total convulsive seizure frequency per 28-day period (cannabidiol vs. placebo): 20 mg/kg/day [-39%], placebo [-13%]; p equal to 0.01. A reduction in convulsive seizures was observed within 4 weeks of initiating cannabidiol treatment; effect remained generally consistent over the 14-week treatment period.(6)

A randomized, double-blind, placebo-controlled trial compared cannabidiol 25 mg/kg/day and 50 mg/kg/day (two times the recommended maintenance dosage) vs. placebo in patients aged 1-65 years (N=224) with treatment-resistant TSC, inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. During a 4-week baseline period, patients were required to have greater than or equal to 8 seizures while on stable AED therapy. The baseline period was followed by a 4-week titration period and a 12-week maintenance period. During this study, all patients but one were taking 1-2 concomitant AEDs; most commonly used concomitant AEDs (greater than 25%) were valproate (45%), vigabatrin (33%), levetiracetam (29%), and clobazam (27%). Baseline median convulsive seizure frequency was 57 per 28 days for the combined groups. The primary efficacy measure was the percent change from baseline (reduction) in the frequency (per 28 days) of TSC-associated seizures over the 16-week treatment period. The median percentage change in total convulsive seizure frequency per 28-day period (cannabidiol vs. placebo): 25 mg/kg/day [-43%], placebo [-20%]; p less than 0.01. A reduction in convulsive seizures was observed within 4 weeks of initiating cannabidiol treatment; effect remained generally consistent over the 12-week maintenance period.(1)

Safety

Epidiolex carries no boxed warnings. Epidiolex is contraindicated in patients with hypersensitivity to cannabidiol or any of the ingredients in Epidiolex.(1)

1

Epidiolex prescribing information. Jazz Pharmaceuticals, Inc. October 2023.

2

Thiele EA, Marsh ED, French JA, et al. Cannabidiol in Patients with Seizures Associated with Lennox-Gastaut syndrome (GWPCARE4): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial. Lancet. 2018 Mar;391(10125):1085-1096.

3

Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome. N Engl J Med. 2018;378:1888-1897.

4

Wheless JW. Lennox-Gastaut Syndrome. National Organization for Rare Disorders (NORD). Last updated June 2020. Available at https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/.

5

Patel AD, Mazurkiewicz‐Bełdzińska M, Chin R, et al. Long‐term safety and efficacy of add‐on cannabidiol in patients with Lennox–Gastaut syndrome: Results of a long‐term open‐label extension trial. Epilepsia. 2021;62(9):2228-2239.

6

Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376:2011-2020.

7

Sullivan J, Knupp K, Wirrell E, et al. Dravet Syndrome. National Organization for Rare Disorders (NORD). Last updated July 2020. Available at https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum/.

8

Andrade DM, Nascimento FA, et al. Dravet Syndrome: Management and Prognosis. UpToDate. Last updated November 2022. Literature review current through December 2023.

9

Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations from a North American Consensus Panel. Pediatr Neurol. 2017;68:18-34.

10

Wilfong A, et al. Lennox-Gastaut syndrome. UpToDate. Last updated June 2023. Literature review current through December 2023.

11

Randle S, et al. Tuberous Sclerosis Complex: Management and Prognosis. UpToDate. Last updated December 2023. Literature review current through December 2023.

12

DiMario FJ, et al. Tuberous Sclerosis. National Organization for Rare Disorders (NORD). Last updated May 2023. Available at https://rarediseases.org/rare-diseases/tuberous-sclerosis/.

13

Reference no longer used.

14

Northrup H, Aronow ME, Bebin EM, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatric Neurology. 2021;123:50-66.

15

Wirrell E, Hood V, Knupp KG, et al. International Cconsensus on Ddiagnosis and Mmanagement of Dravet Ssyndrome. Epilepsia. 2022 Jul;63(7):1761-1777.

Epidiolex

cannabidiol soln

100 MG/ML

M ; N ; O ; Y

N

Epidiolex

cannabidiol soln

100 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has a diagnosis of seizures associated with ONE of the following:
   1. Lennox-Gastaut syndrome (LGS) OR
   2. Dravet syndrome (DS) OR
   3. Tuberous sclerosis complex (TSC) AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. The requested agent will NOT be used as monotherapy for seizure management AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent AND
6. The requested quantity (dose) is within FDA labeled dosing for the requested indication

Length of Approval:  12 months

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The requested agent will NOT be used as monotherapy for seizure management AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent AND
6. The requested quantity (dose) is within FDA labeled dosing for the requested indication

Length of Approval:  12 months