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Cannabidiol Prior Authorization Program Summary

Policy Number: PH-1100

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies. 

 

POLICY REVIEW CYCLE                                                                                                                                                                           

               

Effective Date

Date of Origin 

7/1/2023

FDA APPROVED INDICATIONS AND DOSAGE

Agent(s)

FDA Indication(s)

Notes

Ref#

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

See package insert for FDA prescribing information:  https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. The syndrome has many causes, including genetic disorders, cortical malformations, tumors, encephalopathies following hypoxic-ischemic insults, meningitis, and head injuries. Affected children experience several different types of seizures; atonic, clonic, and atypical absence seizures are the most common. Children with LGS may develop cognitive dysfunction, delays in reaching developmental milestones, and behavioral problems. LGS is difficult to treat because no specific therapy is effective in all cases, and the disorder has proven particularly resistant to most therapeutic options. Valproate is generally considered first-line therapy, and if monotherapy is ineffective another drug such as lamotrigine or rufinamide is added to valproate therapy. Alternative adjunctive antiseizure medications include topiramate, clobazam, cannabidiol, fenfluramine, or felbamate. Additional therapies combined with drug therapy, for patients who do not respond, include the ketogenic diet and vagal nerve stimulation.(4,10)

Dravet Syndrome

Dravet syndrome (DS) is a severe form of epilepsy characterized by frequent, prolonged seizures and neurodevelopmental problems beginning in infancy. Mutations in the alpha-1 subunit of the voltage-gated sodium channel (SCN1A) gene are identified in 70-85% of patients with DS. Status epilepticus, or a seizure lasting longer than 5 minutes and sometimes 30 minutes or more, is common. Additional seizure types, including myoclonic, atypical absence, and complex partial seizures, appear before age 5 years. Mortality in DS is elevated above that found in the general epilepsy population, with an estimated mortality of 15-20% by adulthood. First-line treatment is typically valproate, with clobazam added if needed. Additional agents include stiripentol, topiramate, cannabidiol, and fenfluramine. 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) According to the 2012 International Tuberous Sclerosis Complex Consensus, first-line therapy is vigabatrin for infantile-onset seizures, and second-line therapy is adjunctive or alternative adrenocorticotropin hormone (ACTH).(12,13,14) Other anticonvulsants may be prescribed and depend on the specific type of seizure; for example, simple-partial or complex-partial seizures would be treated with oxcarbazepine or carbamazepine.(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 less than 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=681), evaluating the long-term safety and efficacy of cannabidiol, is being conducted in patients with LGS who completed either GWPCARE3 or GWPCARE4. Study completion date is June 2020, but an interim analysis has been issued. Median treatment duration was 38 weeks, with 208 patients receiving 48 weeks of treatment. Treatment-emergent adverse events were most commonly diarrhea (26.8%), somnolence (23.5%), and convulsion (23.1%). Sustained reductions in drop seizure (48-60%) and total seizures (48-57%) were observed through 48 weeks. Notably, 88% 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.(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 black box warnings. Epidiolex is contraindicated in patients with hypersensitivity to cannabidiol or any of the ingredients in Epidiolex.(1)

REFERENCES                                                                                                                                                                           

Number

Reference

1

Epidiolex prescribing information. Jazz Pharmaceuticals, Inc. January 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 2020. Available at https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/.

5

Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, et al. Cannabidiol in Patients with Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study. Epilepsia. 2019;60(3):i-vii.

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 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 2022.

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. Epilepsy Syndromes in Children. UpToDate. Last updated June 2022. Literature review current through December 2022.

11

Randle S, et al. Tuberous Sclerosis Complex: Management and Prognosis. UpToDate. Last updated August 2022. Literature review current through December 2022.

12

DiMario FJ, et al. Tuberous Sclerosis. National Organization for Rare Disorders (NORD). Last updated 2020. Available at https://rarediseases.org/rare-diseases/tuberous-sclerosis/.

13

Krueger DA, Northrup H, et al. International Tuberous Sclerosis Complex Consensus Group Recommendations for Tuberous Sclerosis Complex Surveillance and Management. Pediatr Neurol. 2012;49(4):P255-265.

14

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021;123:50.

15

International Consensus on Diagnosis and Management of Dravet Syndrome. Epilepsia. 2022 Jul;63(7):1761-1777.

 

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)

Target Generic Agent(s)

Strength

Targeted MSC

Available MSC

Final Age Limit

Preferred Status

Epidiolex

cannabidiol soln

100 MG/ML

M ; N ; O ; Y

N

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

Client Formulary

Epidiolex

cannabidiol soln

100 MG/ML

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

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

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 approved indication, ONE of the following:
    1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
    2. The prescriber has provided information in support of 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 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

 

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.


The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

           

Commercial _ PS _ Cannabidiol Prior Authorization _ProgSum_ 7/1/2023