Effective Date

Date of Origin 

07-01-2024            

01-01-2023

Radicava ORS®

(edaravone)

Oral suspension

Oral suspension starter kit

Treatment of amyotrophic lateral sclerosis (ALS)

1

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease.(2) It is characterized by loss of motor neurons in the spinal cord, brainstem, and motor cortex.(3) Age of onset is between 58-63 years for sporadic disease and 47-52 years for familial disease, with rapidly decreased incidence after 80 years. The clinical hallmark of ALS is the presence of upper and lower motor neuron (UMN and LMN) features involving the brainstem and multiple spinal cord regions of innervation.(2)

ALS is a rapidly progressive disease with 50% of patients dying within 30 months of symptom onset, and about 20% of patients survive between 5 years and 10 years after symptom onset. Older age at symptom onset, early respiratory muscle dysfunction, and bulbar-onset disease are associated with reduced survival, whereas limb-onset disease, younger age at presentation, and longer diagnostic delay are independent predictors of prolonged survival. Dysphagia develops in most patients, with consequent weight loss and malnutrition. Respiratory compromise eventually develops in most cases, leading to exertional dyspnea, orthopnea, hypoventilation with resultant hypercapnia, and early morning headaches. Progressive weakening of the respiratory muscles leads to respiratory failure, often precipitated by pneumonia.(2)

Respiratory function is a critical predictor of survival in ALS. International guidelines recommend the assessment of respiratory function in ALS patients at first visit and every 3 months thereafter.(7) Forced (FVC) and slow (SVC) vital capacities are non-invasive conventional tests used to estimate respiratory function in ALS. Their results depend on age, gender, height, and ethnicity, in addition to the functional integrity of the inspiratory and expiratory muscles. FVC is sensitive to detect hypoventilation in ALS and can be more sensitive in detecting diaphragmatic weakness when performed in the supine position.(8) However, the patient must expel air quickly and forcefully, which may cause fatigue and induce bronchospasm and result in an underestimation of actual lung capacity. SVC is easier for the patient with ALS to perform even in the presence of orofacial paresis because it involves exhalation of air in a slow, gentle manner after a maximal inspiration. FVC and SVC have been shown to be tightly correlated, can be used interchangeably, and decline similarly in ALS (about 2%/month).(8,9)

Symptomatic treatments remain the cornerstone for management of patients with ALS. Disease modifying treatment options for ALS are limited. Riluzole is the only agent shown to have any impact on survival in ALS. The American Academy of Neurology (AAN) has recommended that riluzole be offered to slow disease progression in patients with ALS.(2) While edaravone has been shown to slow the decline of functional and quality of life ratings in patients with ALS, the short duration of trials did not allow for the assessment of an effect on survival.(6) According to CADTH Common Drug Review (CDR) of Radicava, Radicava should be considered for the majority of newly diagnosed ALS patients with preserved respiratory function and with functional independence. Patients with advanced ALS with severe disability, such as ventilator-dependence with very little limb function, are unlikely to benefit from therapy and should not be offered Radicava.(5)

Efficacy

The efficacy of edaravone was evaluated in a post-hoc analysis of a 6-month, phase III randomized, placebo-controlled, double-blind study, in patients aged 20 to 75 years with ALS. All study patients had to meet all of the following criteria at screening:

1. 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])
2. Normal respiratory function (defined as percent-predicted forced vital capacity [%FVC] values of greater than or equal to 80%)
3. Definite or probable ALS based on the El Escorial revised criteria
4. Disease duration of 2 years or less

Patients who met the criteria above (n= 137) were randomized to receive either edaravone 60 mg intravenously (IV) or placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off). 91% of patients in both the edaravone and placebo group were also receiving treatment with riluzole. The primary efficacy endpoint was change in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to 24 weeks or therapy discontinuation (if discontinuation occurred after the third cycle) after randomization. The change in ALSFRS-R score was -5.01 (SE 0.64) and -7.50 (0.66) in the edaravone and placebo group respectively. The trial authors concluded edaravone showed efficacy in a small subset of patients (i.e., those meeting the criteria noted above) and that “there is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria”.(1,4)

Safety

Edaravone is contraindicated in patients with history of hypersensitivity to edaravone or any of its inactive ingredients.(1)

1

Radicava prescribing information. Mitsubishi Tanabe Pharma Corporation. November 2022.

2

Kiernan M. C., Vucic S., Cheah B. C., Turner M. R., Eisen A., Hardiman O., et al. (2011). Amyotrophic lateral sclerosis. Lancet 377 942–955. 10.1016/S0140-6736(10)61156-7.

3

Miller R.G., Jackson C.E., Kasarskis E.J., England J.D., Forshew D., Johnston W., Kalra S., Katz J.S., Mitsumoto H., Rosenfeld J., et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): Report of the Quality Standards Subcommittee of the American of Neurology. Neurology. 2009;73:1227–1233.

4

Koji Abe, Mashashi Aoki, Shoji Tsuji, et al. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomized double-blind, placebo-controlled trial. Lancet Neurology. 2017 May 15, S1474-4422(17)30115-1.

5

Clinical Review Report: Edaravone (Radicava): (Mitsubishi Tanabe Pharma Corporation): Indication: For the treatment of amyotrophic lateral sclerosis. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Apr. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542359/.

6

Oskarsson B., Gendron T., Staff N. Amyotrophic Lateral Sclerosis: An Update for 2018. Mayo Clin Proc. 2018;93(11):1617-1628.

7

EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis. Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chio A, et al.. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)–revised report of an EFNS task force. Eur J Neurol. (2012) 19:360–75.

8

Pinto S, de Carvalho M. SVC Is a Marker of Respiratory Decline Function, Similar to FVC, in Patients With ALS. Front Neurol. 2019 Feb 28;10:109. doi: 10.3389/fneur.2019.00109.

9

Andrews JA, Meng L, Kulke SF, et al. Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2018;75(1):58–64. doi:10.1001/jamaneurol.2017.3339.

Radicava ors ; Radicava ors starter kit

edaravone oral susp

105 MG/5ML

M ; N ; O ; Y

N

Radicava ors

edaravone oral susp

105 MG/5ML

50

mLs

28

DAYS

70510232201

Radicava ors starter kit

edaravone oral susp

105 MG/5ML

70

mLs

180

DAYS

70510232101 ; 70510232102

Radicava ors ; Radicava ors starter kit

edaravone oral susp

105 MG/5ML

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

Radicava ors

edaravone oral susp

105 MG/5ML

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

Radicava ors starter kit

edaravone oral susp

105 MG/5ML

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. ONE of the following:
   1. The requested agent is eligible for continuation of therapy AND ONE of the following:

1. The patient has been treated with the requested agent within the past 90 days OR
2. The prescriber states the patient has been treated with the requested agent within the past 90 days AND is at risk if therapy is changed OR
3. ALL of the following:
   1. The patient has a diagnosis of amyotrophic lateral sclerosis (ALS) AND
   2. The patient has had the diagnosis of ALS for a duration of 2 years or less AND
   3. The patient has a baseline percent forced vital capacity (FVC%) or slow vital capacity (SVC) of 80% or greater AND
   4. The patient is able to perform 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] AND   
   5. ONE of the following:
      1. BOTH of the following:
         1. The patient is currently being treated with riluzole AND
         2. The patient will continue riluzole in combination with the requested agent OR
      2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to riluzole 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

Length of Approval:  6 months

NOTE: For patients initiating therapy, approval will include 28 bags per 28 days (initial dose) for the first month and 20 bags per 28 days for the remainder of the 6 months. For patients initiating therapy with oral suspension, approval will include 70 mL starter kit per 180 days (initial dose) and 50 mL per 28 days for the remainder of the 6 months.

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

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 patient is NOT dependent on invasive ventilation or tracheostomy 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

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval:  Initial: up to 6 months; Renewal: up to 12 months