Coverage Policy Manual
Policy #: 2017026
Category: Pharmacy
Initiated: July 2017
Last Review: August 2023
  Edaravone (e.g., Radicava)

Description:
Edaravone is a free radical scavenger/antioxidant approved for the treatment of amyotrophic lateral sclerosis (ALS). It has been previously investigated for the treatment of ischemic stroke, reperfusion Injury, and myocardial Infarction as it possesses antioxidant and anti-apoptotic properties. Being a low molecular weight molecule with good water and lipid-soluble properties, These are potential therapeutic advantages in crossing the blood-brain barrier to mediate nootropic and neuroprotective effects.
 
Researchers first developed the free radical scavenger edaravone in late 1980s as a treatment for stroke. The approach aimed to prevent the swelling of the brain which may occur after a stroke. It has been marketed in Japan by Mitsubishi Pharma for stroke since 2001 and is now generic.
 
Earlier trials of the drug in patients with all stages of ALS did not demonstrate a benefit.
 
Regulatory Status
 
Radicava™ was FDA approved for the treatment of amyotrophic lateral sclerosis (ALS) in May 2017.
 
Coding
 
See CPT/HCPCS Code section below.
 

Policy/
Coverage:
Effective December 1, 2023, prior approval is required for Edaravone (e.g., Radicava).
 
Effective August 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The initial use of edaravone in the treatment of amyotrophic lateral sclerosis (ALS) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL of the following criteria are met [FDA, 2021; Writing Group; Edaravone (MCI-186) ALS 19 Study Group]:
 
    1. Individual has a diagnosis of definite or probable ALS according to the revised El Escorial criteria of signs of lower motor neuron degeneration and upper motor neuron degeneration in at least 2 topographical regions of the CNS based on the submission of medical records (chart notes, previous medical history, diagnostic testing including: imaging, nerve conduction studies, laboratory values) and seen either primarily or in consultation by a neurologist with expertise in the diagnosis and treatment of ALS,  AND
    2. Indivdiual is age 18 to 75 years, AND
    3. Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below]) (ALS 19 Study Group, 2017), AND
    4. Forced vital capacity greater than or equal to 80% (ALS 19 Study Group, 2017), AND
    5. Disease duration of less than or equal to 2 years (ALS 19 Study Group, 2017), AND
    6. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of edaravone is 60 mg daily for 14 days, followed by a 14 day drug-free period as the initial treatment  cycle administered IV.
 
Then 60mg daily for 10 out of 14 days, followed by a 14 day-drug free period for all  subsequent cycles administered IV.
 
Initial authorization is for 180 days with a limit of <74 doses.
 
Continuation of therapy will require evidence that the individual is not dependent on  invasive ventilation and will be for 180 days with a limit of 70 doses.
 
Edaravone is available as 30 mg/100 mL in a single-dose polypropylene bag.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of edaravone for any indication or circumstance not described above in the treatment of ALS and for all other conditions (including but not limited to stroke, MI, other neurodegenerative disease) does not meet primary coverage criteria that there be evidence of effectiveness in improving health outcomes.
 
For individuals with contracts without primary coverage criteria, the use of edaravone for all other indications in the treatment of ALS and for all other conditions (including but not limited to stoke, MI, other neurodegenerative disease) is considered investigational.
 
Investigational  services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective August 2019 to July 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The initial use of edaravone in the treatment of amyotrophic lateral sclerosis (ALS) meets primary coverage criteria and is covered for members with contracts without primary coverage criteria when all of the following criteria are met [FDA, 2021; Writing Group; Edaravone (MCI-186) ALS 19 Study Group]:
 
        1. A diagnosis of definite or probable ALS according to the revised El Escorial criteria of signs of lower motor neuron degeneration and upper motor neuron degeneration in at least 2 topographical regions of the CNS based on the submission of medical records (chart notes, previous medical history, diagnostic testing including: imaging, nerve conduction studies, laboratory values) and seen either primarily or in consultation by a neurologist with expertise in the diagnosis and treatment of ALS,  AND
        2. Age 18 to 75, AND
        3. Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below]) (ALS 19 Study Group, 2017), AND
        4. Forced vital capacity greater than or equal to 80% (ALS 19 Study Group, 2017), AND
        5. Disease duration of less than or equal to 2 years, AND  (ALS 19 Study Group, 2017)
 
Dosage and Administration (regimen is consistent with FDA labeling)
 
1.  60mg daily for 14 days, followed by a 14 day drug-free period as the initial treatment  cycle administered IV.
2.  Then 60mg daily for 10 out of 14 days, followed by a 14 day-drug free period for all  subsequent cycles administered IV.
3. Initial authorization is for 180 days with a limit of <74 doses.
4. Continuation of therapy will require evidence that the member is not dependent on  invasive ventilation and will be for 180 days with a limit of 70 doses.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of edaravone for all other indications in the treatment of ALS and for all other conditions (including but not limited to stroke, MI, other neurodegenerative disease) does not meet primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of edaravone for all other indications in the treatment of ALS and for all other conditions (including but not limited to stoke, MI, other neurodegenerative disease) is considered investigational.
 
Investigational  services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective 7/12/2017 to July 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
 
The initial use of edaravone in the treatment of amyotrophic lateral sclerosis (ALS) meets primary coverage criteria and is covered for members with contracts without primary coverage criteria when all of the following criteria are met:
 
    1. A diagnosis of definite or probable ALS according to the revised El Escorial criteria of signs of lower motor neuron degeneration and upper motor neuron degeneration in at least 2 topographical regions of the CNS based on the submission of medical records (chart notes, previous medical history, diagnostic testing including: imaging, nerve conduction studies, laboratory values) and seen either primarily or in consultation by a neurologist with expertise in the diagnosis and treatment of ALS,  AND
    2. Age 18 to 75, AND
    3. Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below]), AND
    4. Forced vital capacity greater than or equal to 80%, AND
    5. Disease duration of less than or equal to 2 years, AND
    6. Dosing regimen is consistent with FDA labeling:
        1. 60mg daily for 14 days, followed by a 14 day drug-free period as the initial treatment cycle administered IV
        2. then 60mg daily for 10 out of 14 days, followed by a 14 day-drug free period for all subsequent cycles administered IV.
 
Initial authorization is for 180 days with a limit of <74 doses.
 
Continuation of therapy will require evidence that the member is not dependent on invasive ventilation and will be for 180 days with a limit of 70 doses.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of edaravone for all other indications in the treatment of ALS and for all other conditions (including but not limited to stoke, MI, other neurodegenerative disease) does not meet primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of edaravone for all other indications in the treatment of ALS and for all other conditions (including but not limited to stoke, MI, other neurodegenerative disease) is considered investigational.

Rationale:
Edaravone was evaluated in a phase III study in patients with ALS and did not show a significant difference in the Revised ALS Functional Rating Scale as compared with placebo.  A post-hoc analysis showed that a subset of patients with ALS in the early stage showed a greater effect than the entire study population.  A phase III, randomized, double-blind, parallel-group study was then conducted to confirm the effect on this population subset.  A total of 213 patients were screened and 192 were enrolled as potential participants.  Eligible patients were aged 20 to 75 with definite or probable ALS according to the El Escorial criteria and had grade 1 or 2 ALS according to the Japan ALS Severity Classification, a forced vital capacity of greater than or equal to 80%, and disease duration of two years or less.  Inclusion criteria also required scores of at least 2 points on all 12 items of the Revised ALS Functional Rating Scale and that the patient had a decrease of 1 to 4 points in the Revised ALS Functional Rating Scale score during the 12-week observation period before randomization.  Of the 192 potential participants, 137 completed the observation and were randomized to either edaravone or placebo at a dose of 60mg daily for 14 days, followed by a 14 day drug-free period as the initial treatment cycle, followed by 60mg daily for 10 out of 14 days, followed by a 14 day-drug free period for subsequent cycles.  The primary endpoint was the change in the Revised ALS Functional Rating Scale score from baseline to week 24.  The mean change from baseline in the score in the edaravone group was -5.01 compared with -7.50 (p=0.0013). More patients discontinued treatment in the placebo group as compared to the treatment group (8 vs 2).3
 
Revised ALS Functional Rating Scale
 
The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is scored from 0-4, with higher scores representing greater functional ability.
 
The Revised Functional ALS Rating Scale is a validated questionnaire-based scale that measures physical function in carrying out activities of daily living in 12 domains with the following scoring system:
 
Speech: Scale  4: Normal speech processes, 3: Detectable speech disturbance, 2: Intelligible with repeating, 1: Speech combined with nonvocal communication, 0: Loss of useful speech
 
Salivation:
Scale 4: Normal, 3: Slight but definite excess of saliva in mouth; may have nighttime drooling, 2:  Moderately excessive saliva; may have minimal drooling, 1:  Marked excess of saliva with some drooling, 0: Marked drooling; requires constant tissue or handkerchief
 
Swallowing:  
Scale  4:  Normal eating habits, 3: Early eating problems – occasional choking, 2: Dietary consistency changes, 1: Needs supplemental feeding tube, 0:  NPO (exclusively parenteral/enteral feeding)
 
Handwriting:
Scale  4: Normal, 3: Slow or sloppy:  all words are legible, 2:  Not all words are legible, 1:  Able to grip pen but unable to write, 0: Unable to grip pen
 
Cutting Food & Handling Utensils
Scale:
Patients without Gastronomy   4: Normal, 3: Somewhat slow and clumsy but no help needed, 2: Can cut most foods, although clumsy and slow; some help needed, 1: Food must be cut by someone, but can still feed slowly, 0: Needs to be fed
 
 Patients with Gastronomy 4: Normal, 3: Clumsy but able to perform all manipulations independently, 2: Some help needed with closures and fasteners, 1: Provides minimal assistance to caregiver, 0: Unable to perform any aspect of task
 
Dressing & Hygiene
Scale 4: Normal function, 3: Independent and complete self-care with effort or decreased efficiency, 2: Intermittent assistance or substitute methods, 1: Needs attendant for self-care, 0: Total dependence
 
Turning in bed & Adjusting Bed Clothes
Scale
4: Normal, 3: Somewhat slow and clumsy, but no help needed, 2: Can turn alone or adjust sheets, but with great difficulty, 1: Can initiate, but not turn or adjust sheets alone, 0: Helpless
 
Walking:
Scale  4: Normal,3: Early ambulation difficulties, 2: Walks with assistance, 1: Nonambulatory functional movement, 0: No purposeful leg movement
 
Climbing:
Scale 4: Normal, 3: Slow, 2: Mild unsteadiness or fatigue, 1:  Needs assistance, 0: Cannot do
 
Dyspnea:
Scale 4:  None, 3: Occurs when walking, 2: Occurs with one or more of the following:  eating, bathing, dressing (ADL), 1: Occurs at rest, difficulty breathing when either sitting or lying, 0: Significant difficulty, considering using mechanical respiratory support
 
Orthopnea:
Scale 4: None, 3: Some difficulty sleeping at night due to shortness of breath; does not routinely use more than two pillows, 2: Needs extra pillows in order to sleep (more than two), 1:  Can only sleep sitting up, 0: Unable to sleep
 
Respiratory Insufficiency
Scale  4: None, 3: Intermittent use of BiPAP, 2: Continuous use of BiPAP during the night, 1: Continuous use of BiPAP during the night and day, 0: Invasive mechanical ventilation by intubation and tracheostomy
 
2018 Update
A literature search conducted using the MEDLINE database did not reveal any new
literature that would prompt a change in the coverage statement.
 
2019 Update
A literature search conducted through July 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24-week edaravone vs placebo, followed by open-label treatment for an additional 24 weeks.
Outcome (the change in ALS Functional Rating Scale-Revised, ALSFRS-R, from baseline) was projected for placebo patients through 48 weeks and compared with 48-week edaravone or 24-week edaravone after switching from placebo.
A total of 123 patients received open-label treatment (65 edaravone-edaravone; 58 placebo-edaravone). The projected ALSFRS-R decline for placebo from baseline through week 48 was greater than for 48-week edaravone (P < .0001). For patients switching from placebo to edaravone, ALSFRS-R slope approached that of continued edaravone for 48 weeks. ALSFRS-R decline did not differ between actual and projected edaravone through week 48.
Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 mo of receiving placebo, and efficacy is maintained for up to 1 year. (Shefner J, Heiman-Patterson T, Pioro EP, et al., 2020)
 
Ongoing clinical trials:
The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial (NCT03548311)
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J1301Injection, edaravone, 1 mg
J3490Unclassified drugs
J3590Unclassified biologics

References: Abe K, Itoyama Y, Sobue G, et al.(2014) Edaravone ALS Study Group. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients, Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):610-7. doi: 10.3109/21678421.2014.959024. Epub 2014 Oct 6.

Cedarbaum JM, Stambler N, Malta E, et al.(1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169(1-2):13-21.

Edaravone. Clinical Pharmacology [Internet]. Edaravone. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2017- [cited 2017 June 19]. Available from: http://www.clinicalpharmacology.com

Juan Fernando Ortiz, Sawleha Arshi Khan, Amr Salem, et al.(2020) Post-Marketing Experience of Edaravone in Amyotrophic Lateral Sclerosis: A Clinical Perspective and Comparison With the Clinical Trials of the Drug. Cureus 2020 Oct 6;12(10):e10818. doi: 10.7759/cureus.10818.

Radicava® [package insert]. Jersey City, NJ: MT Pharma America, Inc.,2017

Shefner J, Heiman-Patterson T, Pioro EP, et al.(2020) Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19). Muscle Nerve. 2020;61(2):218-221. doi:10.1002/mus.26740

Writing Group; Edaravone (MCI) ALS 19 Study Group.(2017) Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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