0918 edaravone (radicava) (3)
TRANSCRIPT
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 1 of 45
(https://www.aetna.com/)
Edaravone (Radicava)
Proprietary
Policy History
Last Review
07/21/2020
Effective: 07/21/2017
Next
Review: 10/28/2021
Review History
Definitions
Additional Information
Clinical Policy Bulletin
Notes
Number: 0918
Policy *Please see amendment forPennsylvaniaMedicaid
at the end of this CPB.
Notes: PRECERTIFICATION REQUIRED
Precertification of edaravone is required of all Aetna
participating providers and members in applicable plan
designs. For precertification of edaravone, call (866) 752-7021
(Commercial), (866) 503-0857 (Medicare), or fax (866) 267
3277.
Site of Care Utilization Management Policy applies. For
information on site of service for edaravone, see Utilization
Management Policy on Site of Care for Specialty Drug
Infusions (https://www.aetna.com/health-care
professionals/utilization-management/drug-infusion-site
of-care-policy.html).
Aetna considers edaravone (Radicava) medically necessary
for the treatment of individuals with amyotrophic lateral
sclerosis (ALS) when all the following criteria are met:
▪ Diagnosis of definite or probable ALS; and
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 2 of 45
▪ Member has scores of at least 2 points on all 12 areas of
the revised ALS Functional Rating Scale (ALSFRS-R); and
▪ Continuous use of ventilatory support during the day
and night is not required (noninvasive or invasive).
Aetna considers edaravone experimental and investigational
for the following (not an all-inclusive list):
▪ Acute encephalopathy
▪ Acute ischemic stroke
▪ Acute kidney injury
▪ Acute lung injury
▪ Acute pancreatitis-induced pancreatic and intestinal
injury
▪ Alzheimer's disease
▪ Asthma
▪ Autoimmune thyroiditis
▪ Brain radionecrosis
▪ Choroidal neovascularization
▪ Cisplatin-induced chronic renal injury
▪ Doxorubicin-induced cardiotoxicity / nephrotoxicity
▪ Intra-cerebral hemorrhage
▪ Multiple sclerosis
▪ Myocardial damage after ischemia and re-perfusion
▪ Nephropathy
▪ Osteoarthritis
▪ Parkinson disease
▪ Post-stroke depression
▪ Rheumatoid arthritis
▪ Seizure
▪ Stroke
▪ Subarachnoid hemorrhage
▪ Traumatic brain injury
▪ Wound healing.
Continuation Criteria
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 3 of 45
Aetna considers continued use of edaravone medically
necessary when the following criteria are met:
▪ Diagnosis of definite or probable ALS; and
▪ There is a clinical benefit from edaravone therapy; and
▪ Invasive ventilation is not required.
Dosing Recommendations
The recommended dosage of edaravone (Radicava) is 60 mg
administered as an IV infusion over 60 minutes as follows:
Initial treatment cycle: Daily dosing for 14 days followed by a
14-day drug-free period
Subsequent treatment cycles: Daily dosing for 10 days out of
14-day periods, followed by 14-day drug-free periods.
Source: MT Pharma America 2019.
Background
Acute Encephalopathy
Hayakawa and colleagues (2020) noted that treatments for
pediatric acute encephalopathy are largely empiric with limited
evidence to support. These investigators examined recent
trends in clinical practice patterns for pediatric acute
encephalopathy at a national level. Discharge records were
extracted for children with acute encephalopathy from 2010 to
2015 using a national inpatient database in Japan. They
ascertained the secular trends in medications, diagnostic and
therapeutic procedures, healthcare costs, in-hospital mortality,
and length of hospital stays (LOS), using mixed effect linear or
logistic regression models. These researchers also
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 4 of 45
ascertained variations and clustering of the practice patterns
across different hospitals using hierarchical cluster analyses.
A total of 4692 eligible inpatients were identified, these
investigators observed increasing trends in hospitalization
costs, corticosteroid and edaravone use and a decreasing
trend in LOS. Despite changes in treatments, the rates of
home respiratory support and in-hospital mortality were
constant during the study period. Hierarchical cluster analyses
showed that 6 hospital groups showed largely different
therapeutic strategies to the same disease regardless of
mortality rates. Hospitals with more intensive treatment
practices were likely to have higher mortality, while hospitals
with less intensive treatment practices were likely to have the
lower mortality. However, hospitals in one group (group 1)
had less intensive treatment practice even though they had the
highest mortality. The authors provided novel insights into the
recent trends in treatments for pediatric acute encephalopathy;
therapeutic strategies varied among hospitals, suggesting the
importance of pursuing evidence-based therapeutic strategy
and promoting standardized practices to pediatric acute
encephalopathy.
Furthermore, UpToDate reviews on “Acute toxic-metabolic
encephalopathy in children” (Chiriboga, 2019) and “Clinical
features, diagnosis, and treatment of neonatal
encephalopathy” (Wu, 2019) do not mention edaravone as a
therapeutic option.
Acute Kidney Injury
In a rat resuscitation model, Fu and colleagues (2020)
examined if edaravone (5-methyl-2-phenyl-2,4-dihydro-3H
pyrazol3-one, EDR) can ameliorate renal warm ischemia
reperfusion injury (IRI) by modulating endoplasmic reticulum
stress (ERS) and its down-stream effector after cardiac arrest
(CA) and cardiopulmonary resuscitation (CPR). Rats (n = 10)
experienced anesthesia and intubation followed by no CA
inducement were defined as the sham group. Trans-
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 5 of 45
esophageal alternating current stimulation was employed to
establish 8-min of CA followed by conventional CPR for a
resuscitation model. The rats with successful restoration of
spontaneous circulation (ROSC) randomly received EDR (3
mg/kg, EDR group, n = 10) or equal volume normal saline
solution (the NS group, n = 10). At 24 hours after ROSC,
serum creatinine (SCR), blood urea nitrogen (BUN) levels, and
cystatin-C (Cys-C) levels were determined and the protein
level of glucose-regulated protein (GRP78), C/EBP
homologous protein (CHOP), extracellular signal-regulated
kinase (ERK), phosphorylated extracellular signal-regulated
kinase 1/2 (p-ERK1/2), Bax/Bcl-2, and caspase-3 were
detected by Western blot method. At 24 hours after ROSC,
SCR, BUN and Cys-C were obviously increased and the
proteins expression, including GRP78, CHOP and p-ERK1/2,
cleaved-caspase 3 Bax/Bcl-2 ratio, were significantly up-
regulated in the NS group compared with the sham group (p <
0.05). The remarkable improvement of these adverse
outcomes was observed in the EDR group (p < 0.05). The
authors concluded that EDR ameliorated renal warm IRI by
down-regulating ERS and its down-stream effectors in a rat
AKI model evoked by CA/CPR. These data may provide
evidence for future therapeutic benefits of EDR against acute
kidney injury (AKI) induced by CA/CPR.
Acute Lung Injury
Kassab and colleagues (2020) stated that EDR is a potent free
radical scavenger that has a promising role in combating many
acute lung injuries. Ischemia/reperfusion (i/R) process is a
serious condition that may lead to multiple-organ dysfunctions.
These investigators examined the novel mechanisms
underlying I/R-induced lung injury and assessed the protective
role of EDR. A total of 30 adult male rats were divided into 3
experimental groups: operated with no ischemia (sham-group),
I/R group, and EDR-I/R group. Hind-limb ischemia was carried
out by clamping the femoral artery. After 2 hours of ischemia
for the hind-limb, the rat underwent 24-hour of reperfusion.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 6 of 45
Rats in the EDR-I/R group received EDR (3 mg/kg), 30 mins
before induction of ischemia. At the end of the I/R trial,
specimens from the lungs were processed for histological,
immunohistochemical, enzyme assay, and RT-qPCR studies.
Specimens from I/R group showed focal disruption of the
alveolar architecture. Extensive mononuclear cellular
infiltration particularly with neutrophils and dilated congested
blood capillaries were observed. A significant increase in
inducible nitric oxide synthase (iNOS), nuclear factor-κB
(NFκB), and cyclooxygenase-2 (COX-2) immunoreaction was
detected and confirmed by RT-qPCR. Ultra-structural
examination showed red blood cells (RBCs) and fluid inside
alveoli, cellular infiltration, and vacuolations of the inter-
alveolar septum. In contrast, minimal changes were observed
in rats that received EDR before the onset of the ischemia.
The authors concluded that EDR exerted a potent protective
effect against lung injury induced by a hind-limb I/R in rats
through its antioxidant and anti-inflammatory activities.
Acute Pancreatitis-Induced Pancreatic and Intestinal Injury
Wang and Lin (2020) noted that acute pancreatitis (AP) is a
type of acute surgical abdominal disease in the world. It
causes intestinal damage with subsequent bacterial migration,
endotoxemia and secondary pancreatic infections. These
investigators examined if EDR could reduce pancreatic and
intestinal injury after AP in mice. This was demonstrated by a
reduction in histological score, apoptosis, interleukin (IL)-6, IL
1β and tumor necrosis factor-alpha (TNF-α), along with
obstructing activation of Toll-like receptor 4 (TLR4) and NFκB.
The authors concluded that the findings of this study
suggested that EDR exerted its protective effects against
pancreatic and intestinal injury after AP via regulation of the
TLR4/NFκB pathway. These researchers stated that the
findings provided the basis for EDR to treat AP-induced
pancreatic and intestinal injury, even might develop as a
potential therapy for other inflammatory diseases.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 7 of 45
Acute Stroke (e.g., Acute Ischemic Stroke and Intra-Cerebral Hemorrhage)
Yang and colleagues (2015) evaluated the effectiveness of
edaravone for acute stroke including acute ischemic stroke
(AIS) and intra-cerebral hemorrhage (ICH). These
investigators identified RCTs with comprehensive searches
and performed systematic reviews according to the Cochrane
methods of systematical reviews. Edaravone can reduce the
rate of death or long-term disability significantly for AIS
(relative risk [RR] = 0.65; 95 % confidence intervals [CI]: 0.48
to 0.89, p = 0.007). However, sensitivity analysis yielded a
different result. Edaravone can also improve the short-term
neurological impairment of AIS (mean difference (MD) = 7.09;
95 % CI: 5.12 to 9.05, p < 0.00001), and ICH (MD = -4.32; 95
% CI: -5.35 to -3.29, p < 0.00001). The authors concluded that
edaravone is beneficial in improving neurological impairment
resulting from AIS and ICH. However, there is currently
insufficient evidence that edaravone reduces death or long
term disability for AIS and ICH.
Bao and associates (2018) stated that cerebral vasculature
and neuronal networks will be largely destroyed due to the
oxidative damage by over-produced reactive oxygen species
(ROS) during a stroke, accompanied by the symptoms of
ischemic injury and blood-brain barrier (BBB) disruption. Ceria
nanoparticles, acting as an effective and recyclable ROS
scavenger, have been shown to be highly effective in neuro
protection. However, the brain access of nanoparticles can
only be achieved by targeting the damaged area of BBB,
leading to the disrupted BBB being unprotected and to
turbulence of the micro-environment in the brain.
Nevertheless, the integrity of the BBB will cause very limited
accumulation of therapeutic nanoparticles in brain lesions.
This dilemma is a great challenge in the development of
efficient stroke nano-therapeutics. These researchers
developed an effective stroke treatment agent based on
monodisperse ceria nanoparticles, which were loaded with
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 8 of 45
edaravone and modified with Angiopep-2 and poly(ethylene
glycol) on their surface (E-A/P-CeO2). The as-designed
E-A/P-CeO2 features highly effective BBB crossing via
receptor-mediated transcytosis to access brain tissues and
synergistic elimination of ROS by both the loaded edaravone
and ceria nanoparticles. As a result, the E-A/P-CeO2 with low
toxicity and excellent hemo-/histo-compatibility can be used to
effectively treat strokes due to great intra-cephalic uptake
enhancement and, in the meantime, effectively protect the
BBB, holding great potentials in stroke therapy with much
mitigated harmful side effects and sequelae.
Oguru and co-workers (2018) noted that argatroban is a
thrombin inhibitor agent for acute non-cardioembolic ischemic
stroke in Japan. These researchers studied the prognosis in
patients with acute stroke treated by argatroban in comparison
with the control group with ozagrel. A total of 513 patients with
acute non-cardioembolic ischemic stroke were enrolled
retrospectively from the authors’ hospital database. Of all
patients with stroke, 353 were administered with argatroban.
The other 160 control patients were administered with
ozagrel. Patients were examined as to their stroke types, the
neurological severity according to the National Institutes of
Health Stroke Scale (NIHSS), and clinical outcomes on
discharge were determined according to the modified Rankin
Scale (mRS). A total of 353 patients with acute non
cardioembolic stroke, including 138 with lacunar infarction
(LIs) and 215 with athero-thrombotic infarction (ATI) showed
functional recovery by argatroban, but the effectiveness of
argatroban was not superior to ozagrel therapy defined by the
control group. A total of 255 patients with ATI who were
treated with both argatroban and ozagrel showed improvement
by 1 point. These investigators could not find any significant
difference between argatroban and ozagrel in the 2 stroke
subtypes, LI and ATI. They also found that combination
therapy of argatroban and edaravone was not superior to
argatroban monotherapy in clinical outcome. The authors
concluded that argatroban therapy was not superior to control
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 9 of 45
with ozagrel therapy in acute non-cardioembolic ischemic
stroke, including LI and ATI, regardless of the use of
edaravone.
Naganuma and associates (2018) stated that uric acid (UA),
an anti-oxidant with neuroprotective effects, favorably affects
stroke outcome. However, the effect has not been examined
in patients treated with edaravone, a frequently used free
radical scavenger. These investigators examined if the use of
edaravone affected the relationship between UA levels and
outcome in acute ischemic stroke (AIS). They retrospectively
evaluated 1,114 consecutive ischemic stroke patients with pre
morbid mRS scores of less than 2 admitted within 24 hours of
onset (mean age of 74 years; median UA levels, 333 μmol/L).
These researchers divided the patients into 2 groups using the
median UA value as a cut-off, a low UA group (less than or
equal to 333 μmol/L; n = 566) and a high UA group (greater
than 333 μmol/L; n = 548), and compared their clinical
characteristics and favorable outcomes (mRS less than 2) at
90 days. These researchers examined the associations
between UA levels and 90-day stroke outcome in patients with
and without edaravone treatment. The high UA group had a
higher proportion of men, hypertension, atrial fibrillation, and
cardio-embolic stroke than the low UA group. The high UA
group also had a higher proportion of patients with mRS of
less than 2 at 90 days (61.5 versus 54.1 %, p = 0.013), but the
significance was diminished in multi-variate analysis (OR 1.30,
95 % CI: 0.94 to 1.71). In subgroup analysis, the high UA
group without edaravone exhibited a higher proportion of
patients with mRS of less than 2 at 90 days than the low UA
group (OR 2.87, 95 % CI: 1.20 to 7.16). The high UA group
with edaravone did not exhibit this difference. The authors
concluded that in AIS, the favorable association between high
UA levels and outcome at 90 days was not evident in patients
treated with edaravone.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 10 of 45
Kobayashi and colleagues (2019) examined the effect of
edaravone on neurological symptoms in patients with ischemic
stroke stratified by stroke subtype. Subjects were 61,048
patients aged 18 years or older who were hospitalized for less
than or equal to 14 days after onset of an AIS and were
registered in the Japan Stroke Data Bank, a hospital-based
multi-center stroke registration database, between June 2001
and July 2013. Patients were stratified according to ischemic
stroke subtype (large-artery atherosclerosis, cardio-embolism,
small-vessel occlusion, and cryptogenic/undetermined) and
then divided into 2 groups (edaravone-treated and no
edaravone). Neurological symptoms were evaluated using the
NIHSS. The primary outcome was changed in neurological
symptoms during the hospital stay (ΔNIHSS=NIHSS score at
discharge-NIHSS score at admission). Data were analyzed
using multi-variate linear regression with inverse probability of
treatment weighting after adjusting for the following
confounding factors: age, gender, and systolic and diastolic
blood pressure at the start of treatment, NIHSS score at
admission, time from stroke onset to hospital admission, infarct
size, co-morbidities, concomitant medication, clinical
department, history of smoking, alcohol consumption, and
history of stroke. After adjusting for potential confounders, the
improvement in NIHSS score from admission to discharge was
greater in the edaravone-treated group than in the no
edaravone group for all ischemic stroke subtypes (mean [95 %
CI] difference in ΔNIHSS: -0.46 [-0.75 to -0.16] for large-artery
atherosclerosis, -0.64 [-1.09 to -0.2] for cardio-embolism, and
-0.25 [-0.4 to -0.09] for small-vessel occlusion). The authors
concluded that for any ischemic stroke subtype, edaravone
use (compared with no use) was associated with a greater
improvement in neurological symptoms, although the
difference was small (less than 1 point NIHSS) and of limited
clinical significance.
Alzheimer's Disease
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 11 of 45
Parikh and associates (2018) stated that Alzheimer's disease
(AD) is a devastating neurodegenerative disorder that lacks
any disease-modifying drug for the prevention and treatment.
Edaravone (EDR), an approved free radical scavenger, has
proven to have potential against AD by targeting multiple key
pathologies including amyloid-beta (Aβ), tau phosphorylation,
oxidative stress, and neuro-inflammation. To enable its oral
use, novel edaravone formulation (NEF) was previously
developed. These researchers evaluated the safety and
efficacy of NEF by using in-vitro/in-vivo disease model. In-vitro
therapeutic potential of NEF over EDR was studied against the
cytotoxicity induced by copper metal ion, H2O2 and Aβ42
oligomer, and cellular uptake on SH-SY5Y695 amyloid-β
precursor protein (APP) human neuroblastoma cell line. For i-
vivo safety and efficacy assessment, a total of 7 groups of
APP/PS1 (5 treatment groups, 1 each as a basal and sham
control) and 1 group of C57BL/6 mice as a positive control for
behavior tests were used; 3 groups were orally treated for 3
months with NEF at an equivalent dose of EDR 46, 138, and
414 µmol/kg, whereas 1 group was supplied with each
Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF
of 414 µmol/kg dose of EDR). Behavior tests were conducted
to assess motor function (open-field), anxiety-related behavior
(open-field), and cognitive function (novel objective recognition
test, Y-maze, and Morris water maze). For the safety
assessment, general behavior, adverse effects, and mortality
were recorded during the treatment period. Moreover,
biochemical, hematological, and morphological parameters
were determined. Compared to EDR, NEF showed superior
cellular uptake and neuroprotective effect in SH-SY5Y695
APP cell line. Furthermore, it showed nontoxicity of NEF up to
414 µM/kg dose of EDR and its potential to reverse AD-like
behavior deficits of APP/PS1 mice in a dose-dependent
manner. The authors concluded that these findings indicated
that oral delivery of NEF holds promise as a safe and effective
therapeutic agent for AD.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 12 of 45
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), commonly known as Lou
Gehrig’s disease, is a progressive, neurodegenerative disease
that destroys motor neurons. Patients with ALS gradually lose
their ability to control voluntary muscles that are involved in
breathing, chewing, talking, and walking; resulting in paralysis
and finally death. The Centers for Disease Control and
Prevention estimates that approximately 12,000 to 15,000
Americans have ALS; and the majority of patients with ALS die
from respiratory failure, usually within 3 to 5 years from when
the symptoms first commence. Riluzole is the only currently
approved mildly effective treatment; it received marketing
authorization in the U.S. in 1995 in the U.S. and in Europe in
1996. In the years that followed, over 60 molecules have been
investigated as a possible treatment for ALS. Despite
significant research efforts, the majority of clinical studies have
failed to demonstrate clinical effectiveness. In the past year,
oral masitinib and intravenous (IV) edaravone (a synthetic-free
radical scavenger) have emerged as promising new
therapeutic agent for the treatment of ALS (Petrov et al,
2017).
In a double-blind, parallel-group, placebo-controlled study, Abe
and colleagues (2014) examined the safety and effectiveness
of edaravone in patients with ALS. These researchers
conducted a 36-week clinical trial, consisting of 12-week pre
observation period followed by 24-week treatment period.
Patients received placebo (n = 104) or edaravone (n= 102) IV
infusion over 60 minutes for the first 14 days in cycle 1, and for
10 of the first 14 days during cycles 2 to 6. The efficacy
primary end-point was changes in the revised ALS functional
rating scale (ALSFRS-R) scores during the 24-week treatment
period. Changes in ALSFRS-R during the 24-week treatment
period were -6.35 ± 0.84 in the placebo group and -5.70 ± 0.85
in the edaravone group, with a difference of 0.65 ± 0.78 (p =
0.411). Adverse events (AEs) amounted to 88.5 % (92/104) in
the placebo group and 89.2 % (91/102) in the edaravone
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 13 of 45
group. The authors concluded that the reduction of
ALSFRS-R was smaller in the edaravone group than in the
placebo group. Levels and frequencies of reported AEs were
similar in the 2 groups. These investigators stated that
although the elimination of free radicals by means of
edaravone to inhibit the degeneration of motor neurons
appeared to be a promising new strategy for the treatment of
ALS, this study did not demonstrate effectiveness of
edaravone in delaying the progression of ALS. They noted
that while the primary end-point was not attained, they
considered that these findings were helpful to identify the
patient population in which edaravone could be expected to
show effectiveness. On the basis of this information, these
researchers designed a phase-III clinical trial.
Noto and associates (2016) stated that therapies that inhibit
neuronal hyper-excitability may be effective in arresting the
progression of ALS. These investigators searched Medline
and ClinicalTrials.gov and selected randomized controlled
trials (RCTs) that covered neuro-protective therapy. Riluzole
has been established to reduce neuronal hyper-excitability.
More recently, initial studies of Na(+) channel blockers
(mexiletine and flecainide) have been investigated.
Separately, a trial of a K(+) channel activator (retigabine) is
underway, while edaravone is currently being considered for
licensing by drug approval agencies based on a hypothesis
that the elimination of free radicals may lead to protection of
motor neurons. The authors concluded that initial clinical trials
with Na(+) channel blockers have not yet established
effectiveness in ALS. Currently, retigabine is under evaluation
as a potential therapy; and edaravone has recently been
approved as a new therapeutic option for ALS in Japan.
Sawada (2017) noted that although the pathogenesis remains
unresolved, oxidative stress is known to play a pivotal role.
Edaravone works in the central nervous system as a potent
scavenger of oxygen radicals. In ALS mouse models,
edaravone suppresses motor functional decline and nitration
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 14 of 45
of tyrosine residues in the cerebro-spinal fluid (CSF). These
investigators reviewed 3 clinical trials: 1 phase-II open-label
trial and 2 phase-III RCTs. In all trials, the primary outcome
measure was the changes in scores on the ALSFRS-R to
evaluate motor function of patients. The phase-II, open-label
trial suggested that edaravone is safe and effective in ALS,
markedly reducing 3-nitrotyrosine levels in the CSF. One of
the 2 RCTs showed beneficial effects in ALSFRS-R, although
the differences were not significant. The last trial
demonstrated that edaravone provided significant
effectiveness in ALSFRS-R scores over 24 weeks where
concomitant use of riluzole was permitted. Eligibility was
restricted to patients with a relatively short disease duration
and preserved vital capacity. Therefore, combination therapy
with edaravone and riluzole should be considered earlier.
Martinez and colleagues (2017) reviewed all the ALS ongoing
clinical trials (up to November 2016). They described them in
a comprehensive way and grouped them in the following
sections: biomarkers, biological therapies, cell therapy, drug
repurposing and new drugs. Despite multiple obstacles that
explain the absence of effective drugs for the treatment of
ALS, joint efforts among patient's associations, public and
private sectors have fueled innovative research in this field,
resulting in several compounds that are in the late stages of
clinical trials. The authors noted that edaravone was recently
approved in Japan and is pending in the U.S.
On May 5, 2017, the Food and Drug Administration (FDA)
approved edaravone (Radicava) for the treatment of patients
with ALS. The effectiveness of edaravone for the treatment of
ALS was demonstrated in a 6-month, randomized, placebo-
controlled, double-blind study conducted in Japanese patients
with ALS who were living independently and met the following
criteria at screening:
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 15 of 45
▪ 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])
▪ Normal respiratory function (defined as percent-
predicted forced vital capacity values of [%FVC] greater
than or equal to 80 %)
▪ Definite or Probable ALS based on El Escorial revised
criteria
▪ Disease duration of 2 years or less.
The study enrolled 69 patients in the Radicava arm and 68 in
the placebo arm. Baseline characteristics were similar
between these groups, with over 90 % of patients in each
group being treated with riluzole. Radicava was administered
as an IV infusion of 60 mg given over a 60-minute period
according to the following schedule:
▪ An initial treatment cycle with daily dosing for 14 days,
followed by a 14-day drug-free period (Cycle 1)
▪ Subsequent treatment cycles with daily dosing for 10
days out of 14-day periods, followed by 14-day drug-free
periods (Cycles 2 to 6).
The primary efficacy end-point was a comparison of the
change between treatment arms in the ALSFRS-R total scores
from baseline to Week 24. 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 to 4, with higher scores representing greater
functional ability. The decline in ALSFRS-R scores from
baseline was significantly less in the Radicava-treated patients
as compared to placebo. The most common AEs reported by
subjects receiving edaravone were contusion and gait
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 16 of 45
disturbance. Radicava is also associated with serious risks
that require immediate medical care, such as hives, swelling,
or shortness of breath, and allergic reactions to sodium
bisulfite, an ingredient in the drug. Sodium bisulfite may cause
anaphylactic symptoms that can be life-threatening in people
with sulfite sensitivity. The FDA granted Radicava orphan
drug designation, which provides incentives to assist and
encourage the development of drugs for rare diseases.
Mitsubishi Tanabe Pharma Corporation’s Package Insert on
“Radicut Injection” (2015) lists 3 clinical studies regarding the
use of edaravone injection for the treatment of ALS.
1st Confirmatory Study:
When edaravone or placebo was intravenously administered
at 60 mg in patients with ALS (warranting “Definite”, “Probable”
or “Probable-laboratory-supported” according to the El Escorial
and the revised Airlie House diagnostic criteria for ALS, rated
as grade 1 or 2 in Japan ALS severity classification, having %
FVC not less than 70 %, and illness duration within 3 years) in
6 cycles of treatment*1, mean changes from baseline in the
ALSFRS-R as primary end-point were not significantly different
between the edaravone-treated and placebo-treated groups
(-5.70 ± 0.85 versus -6.35 ± 0.84; p = 0.411).
2nd Confirmatory Study:
When edaravone or placebo was intravenously administered
at 60 mg in patients with ALS (warranting “Definite” or
“Probable” according to the El Escorial and the revised Airlie
House diagnostic criteria for ALS, rated as grade 1 or 2 in
Japan ALS severity classification, having %FVC not less than
80 % and illness duration within 2 years) in 6 cycles of
treatment*1, there were significant differences in mean changes
from baseline in the ALSFRS-R as primary end-point between
the edaravone-treated and placebo-treated groups (-5.01 ±
0.64 versus -7.50 ± 0.66; p = 0.0013).
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 17 of 45
A Placebo-Controlled Double-Blind Comparative Study in Patients with Japan ALS Severity Classification of Grade 3:
When edaravone or placebo was intravenously administered
at 60 mg in patients with Japan ALS severity classification of
grade 3 ALS in 6 cycles of treatment*1, mean changes from
baseline in the ALSFRS-R as primary end-point were
significantly different between the edaravone-treated and
placebo-treated groups (-6.52 ± 1.78 versus -6.00 ± 1.83; p =
0.8347).
*1: Once-daily consecutive administration for 14 days and
subsequent cessation for 14 days of this product were
combined in the 1st cycle of treatment. After completion of the
1st cycle, this product was administered for 10 of 14 days
followed by cessation for 14 days from the 2nd to 6th cycle
(the treatment cycle was repeated 5 times).
Edaravone is also being investigated in the treatment of
various conditions/diseases (e.g., acute ischemic stroke,
choroidal neovascularization, intra-cerebral hemorrhage,
myocardial damage after ischemia and re-perfusion,
nephropathy, and osteoarthritis); however, its effectiveness for
these indications has not been established.
Asthma
Pan and colleagues (2020) noted that asthma is a chronic
disease that threatens public health worldwide. Multiple
studies have shown that oxidative stress plays an important
role in the pathogenesis of asthma. Edaravone has been
shown to have a protective effect against lung injury due to its
ability to eliminate reactive oxygen species. These
investigators examined the effect of EDR on asthma and the
mechanism underlying its actions. An experimental asthma
model was induced in mice, before they were treated with
different doses of EDR. Measurements of airway
responsiveness to methacholine (Mch), cell counts and
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 18 of 45
cytokine levels in broncho-alveolar lavage fluid (BALF) and of
the oxidative products and antioxidant enzymes in lung tissue
were taken in these asthma model mice and compared with
control mice. Protein levels of kelch-like ECH-associated
protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2
(Nrf2) and hemeoxygenase-1 (HO-1) were determined in the
lung tissue of normal mice and Nrf2 and HO-1-deficient mice
subject to the asthma model to examine the mechanisms
underlying EDR action. The results indicated that EDR
effectively reduced airway responsiveness to Mch. The total
number of cells and the numbers of eosinophils, lymphocytes
and neutrophils in BALF of asthma model mice were also
significantly reduced by EDR treatment when compared with
normal saline treatment. EDR treatment significantly alleviated
peri-vascular edema, peri-bronchial inflammation and
macrophage infiltration in the alveolar space and decreased
the levels of inflammatory cytokines released in BALF
compared with control. EDR also significantly reduced the
levels of oxidative stress markers in BALF and restored the
levels of antioxidative enzyme, superoxide dismutase, when
compared with control. The Keap1/Nrf2 ratio was significantly
decreased with EDR compared with control due to an increase
in Nrf2 and a decrease in Keap1 expression. HO-1 expression
was increased by EDR. The airway responsiveness of Nrf2-/
mice or HO-1-/- mice to Mch was significantly higher compared
with normal mice treated with EDR. The authors concluded
that the findings of the this study showed that EDR exerted anti-
inflammatory and antioxidative effects, which suggested a
potential use for EDR in reduction of asthma severity. The
activated Keap1/Nrf2 pathway and HO-1 may be involved in
the anti-asthmatic effect of EDR.
Autoimmune Thyroiditis
Li and co-workers (2018) noted that autoimmune thyroiditis is
among the most prevalent of all the auto-immunities in
population. It is characterized as both cellular immune
responses with T, B cells infiltrating to the thyroid gland
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 19 of 45
followed by hypothyroidism as a result of destruction of the
thyroid follicles and fibrous replacement of the parenchymal
tissue, as well as immune response for TPO and Tg-antibody
production. Experimental autoimmune thyroiditis (EAT) has
been proven to be an ideal model to study autoimmune
thyroiditis. In the present study, these researchers induced an
EAT model in rats and examined the effect of edaravone on
EAT severity and explored the mechanism. The results
showed that edaravone reduced the severity score of
thyroiditis dose-dependently and the levels of serum TPOAb,
TgAb, T3 and T4. Edaravone significantly decreased the
mRNA level of IL-17, but increased the mRNA level of IL-10, IL
4, TNF-α and IFN-γ. EAT model significantly induced oxidative
stress, which was inhibited by the treatment of 10 mg/kg, 20
mg/kg or 40 mg/kg of edaravone. The EAT model
significantly increased the Akt and STAT3 phosphorylation, but
when rats were treated with 20 mg/kg or 40 mg/kg edaravone,
they were significantly inhibited. The HO-1 expression was
greatly increased by 20 mg/kg or 40 mg/kg edaravone. The
PI3K inhibitor LY294002, Akt inhibitor triciribine or STAT3
inhibitor WP1066 all significantly decreased the severity score
of thyroiditis in the EAT model group, while the HO-1 inhibitor
ZnPP-IX increased the severity score of thyroiditis. The
authors concluded that these findings confirmed the
involvement of ROS and HO-1-dependent STAT3/PI3K/Akt
pathway in the process of Hashimoto's thyroiditis and
suggested the potential usage of edaravone in the therapy of
it.
Brain Radionecrosis
Chung and colleagues (2018) stated that brain radionecrosis
can occur following high-dose radiotherapy to brain tissue and
can have a significant impact on a person's quality of life
(QOL) and function. The underlying pathophysiological
mechanism remains unclear for this condition, which makes
establishing effective treatments challenging. In a Cochrane
review, these investigators evaluated the effectiveness of
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 20 of 45
interventions used for the treatment of brain radionecrosis in
adults over 18 years old. In October 2017, these researchers
searched the Cochrane Register of Controlled Trials
(CENTRAL), Medline, Embase and the Cumulative Index to
Nursing and Allied Health Literature (CINAHL) for eligible
studies. They also searched unpublished data through
Physicians Data Query, www.controlled-trials.com/rct,
www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for
ongoing trials and hand-searched relevant conference
material. These investigators included RCTs of any
intervention directed to treat brain radionecrosis in adults over
18 years old previously treated with radiation therapy to the
brain. These investigators anticipated a limited number of
RCTs, so they also planned to include all comparative
prospective intervention trials and quasi-randomized trials of
interventions for brain radionecrosis in adults as long as these
studies had a comparison group that reflects the standard of
care (i.e., placebo or corticosteroids). Selection bias was likely
to be an issue in all the included non-randomized studies
therefore results were interpreted with caution. Two review
authors independently extracted data from selected studies
and completed a “risk of bias” assessment. For dichotomous
outcomes, the odds ratio (OR) for the outcome of interest was
reported. For continuous outcomes, treatment effect was
reported as MD between treatment arms with 95 % CIs. Two
RCTs and 1 prospective non-randomized study evaluating
pharmacological interventions met the inclusion criteria for this
review. As each study evaluated a different drug or
intervention using different end-points, a meta-analysis was
not possible. There were no trials of non-pharmacological
interventions that met the inclusion criteria. A very small
randomized, double-blind, placebo-controlled trial of
bevacizumab versus placebo reported that 100 % (7/7) of
participants on bevacizumab had reduction in brain edema by
at least 25 % and reduction in post-gadolinium enhancement,
whereas all those receiving placebo had clinical or radiological
worsening or both. This was an encouraging finding but due
to the small sample size these researchers did not report a
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 21 of 45
relative effect. The authors also failed to provide adequate
details regarding the randomization and blinding procedures.
Therefore, the certainty of this evidence was low and a larger
RCT adhering to reporting standards is needed. An open-
label RCT demonstrated a greater reduction in brain edema
(T2 hyper-intensity) in the edaravone plus corticosteroid group
than in the corticosteroid alone group (MD was 3.03 (95 % CI:
0.14 to 5.92; low-certainty evidence due to high risk of bias
and imprecision); although the result approached borderline
significance, there was no evidence of any important
difference in the reduction in post-gadolinium enhancement
between arms (MD = 0.47, 95 % CI: - 0.80 to 1.74; low-
certainty evidence due to high risk of bias and imprecision). In
the RCT of bevacizumab versus placebo, all 7 participants
receiving bevacizumab were reported to have neurological
improvement, whereas 5 of 7 participants on placebo had
neurological worsening (very low-certainty evidence due to
small sample size and concerns over validity of analyses).
While no AEs were noted with placebo, 3 severe AEs were
noted with bevacizumab, which included aspiration
pneumonia, pulmonary embolus and superior sagittal sinus
thrombosis. In the RCT of corticosteroids with or without
edaravone, the participants who received the combination
treatment were noted to have significantly greater clinical
improvement than corticosteroids alone based on
LENT/SOMA scale (OR = 2.51, 95 % CI: 1.26 to 5.01; low-
certainty evidence due to open-label design). No differences
in treatment toxicities were observed between arms. One
included prospective non-randomized study of alpha
tocopherol (vitamin E) versus no active treatment was found
but it did not include any radiological assessment. As only 1
included study was a double-blinded RCT, the other studies
were prone to selection and detection biases. None of the
included studies reported QOL outcomes or adequately
reported details about corticosteroid requirements. A limited
number of prospective studies were identified but
subsequently excluded as these studies had a limited number
of participants evaluating different pharmacological
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 22 of 45
interventions using variable end-points. The authors
concluded that there is a lack of good certainty evidence to
help quantify the risks and benefits of interventions for the
treatment of brain radionecrosis after radiotherapy or
radiosurgery. In an RCT of 14 patients, bevacizumab showed
radiological response that was associated with minimal
improvement in cognition or symptom severity. Although it
was a randomized trial by design, the small sample size limited
the quality of data. A trial of edaravone plus corticosteroids
versus corticosteroids alone reported greater reduction in the
surrounding edema with combination treatment but no effect
on the enhancing radionecrosis lesion. Due to the open-label
design and wide CIs in the results, the quality of this data was
also low. There was no evidence to support any non-
pharmacological interventions for the treatment of
radionecrosis. They stated that further prospective
randomized studies of pharmacological and non-
pharmacological interventions are needed to generate
stronger evidence; 2 ongoing RCTs, 1 evaluating
bevacizumab and 1 evaluating hyperbaric oxygen therapy
were identified.
Choroidal Neovascularization
Masuda and colleagues (2016) stated that choroidal neo
vascularization (CNV) is a main characteristic in exudative
type of age-related macular degeneration. These researchers
examined the effects of edaravone on laser-induced CNV,
which was induced by laser photocoagulation to the subretinal
choroidal area of mice and common marmosets. Edaravone
was administered either intra-peritoneally (IP) twice-daily for 2
weeks or intravenously just once after laser photocoagulation.
The effects of edaravone on laser-induced CNV were
evaluated by fundus fluorescein angiography, CNV area
measurements, and the expression of 4-hydroxy-2-nonenal
(4-HNE) modified proteins, a marker of oxidative stress.
Furthermore, the effects of edaravone on the production of
hydrogen peroxide (H2O2)-induced reactive oxygen species
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 23 of 45
(ROS) and vascular endothelial growth factor (VEGF)-induced
cell proliferation were evaluated using human retinal pigment
epithelium cells (ARPE-19) and human retinal microvascular
endothelial cells, respectively. Choroidal neo-vascularization
areas in the edaravone-treated group were significantly
smaller in mice and common marmosets. The expression of 4
HNE modified proteins was up-regulated 3 hours after laser
photocoagulation, and intravenously administered edaravone
decreased it. In in-vitro studies, edaravone inhibited H2O2
induced ROS production and VEGF-induced cell proliferation.
The authors concluded that these findings suggested that
edaravone may protect against laser-induced CNV by
inhibiting oxidative stress and endothelial cell proliferation.
Cisplatin-Induced Chronic Renal Injury
Koike and colleagues (2019) noted that cisplatin has been
widely used as an anti-cancer agent for a wide range of
tumors, however, it had nephrotoxicity that was mainly caused
by oxidative stress. Edaravone has reportedly been validated
to have a protective effect against renal injury induced by
reactive oxygen species. However, most of these reports were
against AKI, and few studies have examined the effect of
chronic renal injury. These investigators examined the effect
of edaravone on cisplatin nephropathy in the chronic phase. A
total of 25 male Wistar rats were divided into 5 groups: control,
cisplatin, cisplatin + edaravone 1 mg kg-1, cisplatin + edaravone
10 mg kg-1, and cisplatin + edaravone 100 mg kg-1.
Edaravone was administrated intra-peritoneally every other
day for 5 weeks, starting 1 week before cisplatin administration
(6 mg kg-1, i.p.). As a result, proximal tubule injury, interstitial
fibrosis, and mononuclear cell infiltration were ameliorated
histologically in the group of rats treated with high edaravone
dose. In the cisplatin group, the number of α-SMA-, CD68-,
and CD3-positive cells increased markedly compared with the
control group, but these numbers were significantly decreased
by higher doses of co-administered edaravone. The authors
concluded that while there was no clear mRNA expression
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 24 of 45
variation in antioxidant enzymes, the apoptosis-promoting
factors, caspase8, were markedly reduced in the high-dose
edaravone co-administration group compared with the cisplatin
group. These researchers stated that these findings
suggested that cisplatin-induced renal injury in the chronic
phase was ameliorated by edaravone.
Doxorubicin-Induced Cardiotoxicity / Nephrotoxicity
Hassan and associates (2019) stated that doxorubicin (DOX)
is a potential chemotherapeutic agent but its use is restricted
due to cardiotoxicity. Edaravone is a potent-free radical
scavenging agent used in cerebral ischemia. Benidipine is a
triple calcium channel blocker (CCB). These investigators
examined the potential cardio-protective effects of EDR and
benidipine alone and their combination against DOX-induced
cardiotoxicity. Cardiotoxicity was induced by administering 6
equal injections of DOX (2.5 mg/kg) on alternative days for 2
weeks. DOX-treated group showed significant increase level
of lipid peroxide and decrease in antioxidant status along with
mitochondrial enzymatic activity. Cardiotoxic effect of DOX
illustrated by significantly increased the cardiac biomarkers
such as cardiac troponin-I, brain natriuretic peptide (BNP),
creatine kinase-MB in serum. Significant increased activation
of TNF-α, caspase-3 activity and myocardial infarct (MI) size in
DOX-treated group. Histopathological evaluation also
confirmed the DOX-induced cardiotoxicity. Pre-treated with
EDR and benidipine significantly attenuated level of
thiobarbituric acid reactive substance, endogenous enzymes,
mitochondrial enzyme activities and cardiac biomarkers.
Furthermore, pre-treated group showed decreased activation
of TNF-α, caspase-3 activity along with reduction in the MI
size. Histopathological evaluation also strengthened the
above results. The authors concluded that these findings
suggested that the pre-treatment with EDR and benidipine
have potential protective effect against DOX-induced
cardiotoxicity.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 25 of 45
Demir and colleagues (2020) examined the nephroprotective
effect of EDR on DOX-induced nephrotoxicity. A total of 28
Wistar male rats were used; they were separated into 4 groups
(n = 7 for each group). Group І (control) rats were treated with
saline (4 ml/kg); in group ІІ (DOX), nephrotoxicity was induced
by 3 doses of 18 mg/kg/i.p. DOX, at a 24-hour interval on the
12th, 13th, and 14th days; in group ІІІ (EDR), rats were treated
with EDR (30 mg/kg/for 14 days), and in group ІV (EDR +
DOX), rats were treated with EDR (30 mg/kg/for 14 days) and
DOX were injected (18 mg/kg/for 3 days; at a 24-hour interval
on the 12th, 13th, and 14th days). On the 15th day of the
experiment, technetium-99m-labeled dimercaptosuccinic acid
([99mTc]DMSA) uptake was obtained in both kidneys and
biochemical parameters from serum and kidney tissue were
measured. DOX led to nephrotoxicity through elevation of
serum BUN, creatinine and TNF-α, NO, and IL-6 in kidney
tissue and decreased [99mTc]DMSA uptake level in the kidney
when compared with control group (p < 0.01). The authors
concluded that pre-treatment EDR significantly decreased
BUN and creatinine, also kidney tissue TNF-α, IL-6, NO, and
increased [99mTc]DMSA uptake level compared with the
DOX; EDR had a significant nephron-protective effect through
the attenuation of oxidative stress and inflammatory markers
during DOX-induced nephrotoxicity in rats.
Multiple Sclerosis
Agresti and colleagues (2019) stated that multiple sclerosis
(MS) is a chronic inflammatory disease of the central nervous
system (CNS) leading to demyelination and
neurodegeneration, with a complex and still to be clarified
etiology. Data coming from patients' samples and from animal
models showed that oxidative status (OS) plays an important
role in MS pathogenesis. Over-production of reactive
oxidative species by macrophages/microglia could bring about
cellular injury and ensuing cell death by oxidizing cardinal
cellular components. Oxidized molecules are present in active
MS lesions and are associated with neurodegeneration.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 26 of 45
These researchers undertook a structured search of
bibliographic databases for peer-reviewed research literature
focusing on OS in MS. The contents of the selected papers
were described in the context of a conceptual framework. A
special emphasis was given to the results of the authors’ study
in the field. The results of their 3 recent studies were put in the
context and discussed taking into account the literature on the
topic. Oxidative damage underpinned an imbalance shared by
MS and neurodegenerative diseases such as AD and PD. In
people with clinically isolated syndrome (an early phase of MS)
oxidative stress proved to contribute to disease
pathophysiology and to provide biomarkers that may help
predict disease evolution. A drug screening platform based on
multiple assays to test the re-myelinating potential of library of
approved compounds showed 2 anti-oxidants, edaravone and 5
methyl-7-methoxyisoflavone, as active drugs. Moreover, an
analysis of “structure activity relationship” showed off-targets
sites of these compounds that accounted for their re
myelinating activity, irrespective of their antioxidant action.
The authors concluded that edaravone emerged as a
candidate to treat complex disease such as MS, where
inflammation, oxidative stress and neurodegeneration
contribute to disease progression, together or individually, in
different phases and disease types. Furthermore, approaches
based on drug re-positioning appeared to maintain the
promise of helping discover novel treatment for complex
diseases, where molecular targets are largely unknown.
Myocardial Damage After Ischemia and Re-Perfusion
Zheng and associates (2015) evaluated the safety and
effectiveness of edaravone for myocardial damage during
myocardial ischemia and reperfusion (I/R). These researchers
included RCTs that compared edaravone with placebo or no
intervention in patients with acute myocardial infarction (MI) or
undergoing coronary artery bypass. Two authors selected
eligible trials, assessed trial quality and independently
extracted the data. A total of 7 clinical trials were eventually
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 27 of 45
included and analyzed in this study, involving 148 participants;
4 trials were defined as waiting assessment. All of the 3
remaining trials compared edaravone and another treatment
combined with other treatment alone, used the same dose of
edaravone injections (60 mg/day) and course of treatment (14
days), evaluated the effect of edaravone at different times,
applied different methods, reported AEs, and showed no
differences between the treatment group and the control
group. When pooling all of the trials in 1 dataset, edaravone
appeared to decrease the proportion of participant with
marked myocardial damage during I/R as compared with the
control group. The meta-analysis also revealed decreased
cardiac markers such as creatine kinase myocardial b fraction
(CK-MB), cardiac troponin I (cTnI) and erythrocyte membrane
malonyldialdehyde (MDA), and increased content of
superoxide dismutase (SOD). The authors concluded that as
a consequence of the moderate risk of bias and small sample,
the observation of an effective treatment trend of edaravone
for I/R requires future larger, high-quality trials to confirm.
Nephropathy
Varatharajan and colleagues (2016) stated that edaravone has
been reported to reduce ischemia-reperfusion-induced renal
injury by improving tubular cell function, and lowering serum
creatinine (Cr) and renal vascular resistance. These
researchers examined the effect of edaravone in diabetes
mellitus-induced nephropathy in rats. A single administration
of streptozotocin (STZ, 55 mg/kg, IP) was employed to induce
diabetes mellitus in rats. The STZ-administered diabetic rats
were allowed for 10 weeks to develop nephropathy. Mean
body weight, lipid alteration, renal functional and
histopathology were analyzed. Diabetic rats developed
nephropathy as evidenced by a significant increase in serum
Cr and urea, and marked renal histopathological abnormalities
like glomerulo-sclerosis and tubular cell degeneration. The
kidney weight to body weight ratio was increased. Moreover,
diabetic rats showed lipid alteration as evidenced by a
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 28 of 45
significant increase in serum triglycerides and decrease in
serum high-density lipoproteins (HDLs). Edaravone (10
mg/kg, IP, last 4-weeks) treatment markedly prevented the
development of nephropathy in diabetic rats by reducing
serum Cr and urea and preventing renal structural
abnormalities. In addition, this treatment, without significantly
altering the elevated glucose level in diabetic rats, prevented
diabetes mellitus-induced lipid alteration by reducing serum
triglycerides and increasing serum HDLs. Interestingly, the
reno-protective effect of edaravone was comparable to that of
lisinopril (5 mg/kg, P.O. 4 weeks, standard drug). The authors
concluded that edaravone prevented renal structural and
functional abnormalities and lipid alteration associated with
experimental diabetes mellitus; it has the potential to prevent
nephropathy without showing an anti-diabetic action,
implicating its direct reno-protection in diabetic rats.
Osteoarthritis
Huang and colleagues (2016) stated that osteoarthritis (OA) is
a degenerative joint disease affecting millions of people. The
degradation and loss of type II collagen induced by pro-
inflammatory cytokines secreted by chondrocytes, such as
tumor necrosis factor-alpha (TNF-α) is an important
pathological mechanism to the progression of OA. Whether
edaravone has a protective effect in articular cartilage has not
been reported. These researchers examined the chondrocyte
protective effects of edaravone on TNF-α induced degradation
of type II collagen, and found that TNF-α treatment resulted in
degradation of type II collagen, which can be ameliorated by
treatment with edaravone in a dose-dependent manner. It
was found that the inhibitory effects of edaravone on TNF-α
induced reduction of type II collagen were mediated by matrix
metalloproteinase 3 (MMP-3) and MMP-13. The authors
concluded that edaravone alleviated TNF-α induced activation
of signal transducer and activator of transcription 1 (STAT1)
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 29 of 45
and expression of interferon regulatory factor 1 (IRF-1); these
findings suggested a potential protective effect of edaravone in
OA.
Parkinson Disease
Karba and colleagues (2018) noted that Parkinson's disease
(PD) is one of the most common neurodegenerative disorder
with intricate progressive pathology. Currently, available
conventional options for PD have certain limitations of their
own, and as a result, patient compliance and satisfaction are
low. Current therapeutic options provide only symptomatic
relief with limited control to prevent disease progression,
resulting in poor patient compliance and satisfaction. Several
emerging pharmacotherapies for PD are in different stages of
clinical development. These therapies include adenosine A2A
receptor antagonists, glutamate receptor antagonists,
monoamine oxidase inhibitors, anti-apoptotic agents, and
antioxidants such as coenzyme Q10, N-acetyl cysteine, and
edaravone. Other emerging non-pharmacotherapies include
viral vector gene therapy, microRNAs, transglutaminases,
RTP801, stem cells and glial-derived neurotrophic factor
(GDNF). In addition, surgical procedures including deep brain
stimulation, pallidotomy, thalamotomy and Gamma Knife
surgery have emerged as alternative interventions for
advanced PD patients who have completely utilized standard
treatments and still suffer from persistent motor fluctuations.
Complementary and alternative medicine (CAM) modalities
such as Yoga, acupuncture, Tai Chi, music therapies etc. are
highly practiced in several countries, offer some of the safer
and effective treatment modalities for PD. While several of
these therapies hold much promise in delaying the onset of the
disease and slowing its progression, more pharmacotherapies
and surgical interventions need to be investigated in different
stages of PD. It is hoped that these emerging therapies and
surgical procedures will strengthen our clinical armamentarium
for improved treatment of PD.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 30 of 45
Post-Stroke Depression
Kong and colleagues (2020) examined the effect of EDR on
depression relief in symptomatic patients with intra-cranial
stenosis and its relationship with the expression of sex
hormones. These investigators recruited 112 patients with
symptomatic intra-cranial arterial stenosis from Renmin
Hospital, Wuhan University, between October 2014 and
October 2017. All patients were divided into the traditional or
experimental (traditional treatment + intravenous infusion of
EDR 30 mg twice-daily for 14 days) treatment groups. The
general clinical data were collected, and neurological
functional recovery using the mRS and NIHSS scores were
recorded. Symptom Checklist 90 (SCL-90) was used to
assess the general psychological changes of the patient,
followed by the 24 Hamilton Depression Scale (HAMD) to
examine the incidence of post-stroke depression (PSD). This
divided the patients into the mild, moderate, and severe
depression groups. These researchers also measured the
serum protein expression of the sex hormones estradiol (E2),
testosterone (T), follicle stimulating hormone (FSH), prolactin
(PRL), and luteinizing hormone (LH). The mRS and NIHSS
scores were significantly lower in the experimental group than
in the control group (p <0.05). There was no significant
difference in SCL90 score before intervention (p >0.05); the
scores were significantly lower in the experimental group after
intervention (p <0.05)> There was a significant difference in
SCL-90 and HAMD scores between groups before treatment
(p <0.05), with significantly lower scores in the experimental
group post-treatment (p <0.05). The incidence of depression
was significantly reduced in the experimental group post-
treatment. Furthermore, the expression of E2 and FSH was
significantly higher (p <0.01) and lower (p < 0.001),
respectively, in women than in men in the experimental group
post-treatment. Interestingly, the expression of T was
significantly lower in men in the experimental group post-
treatment (p <0.001). The authors concluded that EDR
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 31 of 45
significantly improved the clinical efficacy of stent implantation
in intra-cranial artery stenosis treatment by alleviating
depression and reducing the incidence of PSD.
The authors stated that there were some drawbacks in this
study, such as the lack of long-term continuity, further clinical
follow-up, and prospective clinical data. In this trial, these
investigators collected clinical data from patients at 7 days and
4 weeks post-treatment. Further prospective studies will be
carried out to collect clinical data at baseline, and 3, 6, 12, and
24 months after intervention to further evaluate the clinical
efficacy of EDR and its relationship with the sex hormones. In
addition, the study lacked further clinical follow-up data, such
as sub-group analyses of the specific infarct location, degree
of arterial stenosis, and location of the symptomatic intra-
cranial arterial stenosis. Finally, there was a lack of
prospective clinical data.
Rheumatoid Arthritis
Zhang and colleagues (2020) stated that current research
suggests that synovial phagocytic cells remove excessive
amounts of free oxygen radicals (reactive oxygen species
[ROS]), thereby preventing damage to synovial tissues.
Moreover, ROS may affect the expression of growth arrest
and DNA damage inducible α (GADD45A), thus further
promoting the activation of synovial fibroblasts. In this study,
male adult rats were examined for progression of collagen-
induced arthritis (CIA) using a macroscopic arthritis scoring
system of the hind-paws and by measuring the changes in the
rat's body weight, and activity level before and after diagnosis
of CIA. Rats were intraperitoneally injected twice-daily with
EDR at doses of 3, 6, and 9 ml/kg. Samples were taken at 2,
4, and 6 weeks, respectively. EDR was found to significantly
reduce macroscopic arthritis and microscopic pathology scores
in CIA rats. The concentration of endothelial NOS-6,
glutathione, and heme oxygenase-1 in the serum of rats
decreased, as was the production of ROS around the
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 32 of 45
synovium and inflammatory factors. Moreover, ROS-1
increased the expression of the NF-κB p65 protein by altering
the expression level of GADD45A, causing aggravation of
tissue damage. EDR also significantly improved the
physiological condition of CIA rats, including appetite, weight
changes, and loss of fur, as well as limb mobility. The authors
believed that EDR acted to reduce the expression of NF-ĸB
p65 by clearing ROS, which causes reduced expression of
GADD45A, and subsequently reduced the level of apoptosis
and inflammatory response proteins, thus, reducing the
symptoms of CIA. These researchers proposed that EDR is
an effective option for clinical treatment of rheumatoid arthritis.
Seizure
Hao and colleagues (2020) stated that previous studies have
demonstrated that excessive free radicals play an essential
role in the initiation and progression of epilepsy and that a
novel exogenous free radical scavenger EDR exerts some
neuroprotective effects on seizure-induced neuronal damage.
These researchers examined the possible molecular
mechanisms of EDR associated with procaspase-3
denitrosylation and activation through the FasL-Trx2 pathway
in seizures rats. They examined the effects of EDR on the
regulation of the combination of Fas ligand/Fas receptor and
the major components of the death-inducing signaling complex
(DISC) in the hippocampus of kainic acid (KA)-treated Sprague-
Dawley (SD) rats. Treatment with EDR could attenuate the
increased expression of FasL induced by KA and prevent
procaspase-3 denitrosylation and activation via suppression of
the FasL-Trx2 signaling pathway, which alleviated the neuronal
damage in seizures. The authors concluded that these findings
provided experimental evidence that EDR functions by
preventing the denitrosylation and activation of procaspase-3
and that EDR acts as a therapeutic option for epilepsy.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 33 of 45
Subarachnoid Hemorrhage
Cai and colleagues (2020) examined the effects of EDR
combined with cinepazide maleate on neurocyte autophagy
and neurological function in rats with subarachnoid
hemorrhage (SAH). A total of 80 Sprague Dawley rats were
selected to establish SAH rat models, which were divided into
sham operation group, SAH group, MCI group and combined
group. Hippocampal tissue of each group was taken to
observe the number of neurocytes. The expression levels of
Beclin-1 and (light chain LC3)-II of rats in each group were
detected by ELISA. Pearson's correlation factors were used to
analyze the correlation between Beclin-1 and LC3-11, and
neurological function tests were performed on rats of each
group 14 and 28 days after administration. The morphological
and structural damage of nerve cells in the combined group
was further alleviated, and the survival rate of neurons
significantly increased at all time-points (p < 0.05). The
expression levels of Beclin-1 and LC3-11 in combined group
was significantly higher than those in SAH group and CMI
group (p < 0.05), and Beclin-1 was positively correlated with
LC3-11 (r = 0.9454). Longa score of the combined group was
significantly lower than that of the other 2 groups, and muscle
strength score was significantly higher than that of the other 2
groups (p < 0.05). The authors concluded that EDR combined
with cinepazide maleate could enhance the survival rate of
brain cells and promote the volatilization of neurological
function in the treatment of hemorrhage in the subretinal space
of the omentum, which is worthy of popularization and
application.
Traumatic Brain Injury
Zhang and colleagues (2019) stated that traumatic brain injury
(TBI) is among the leading causes of irreversible neurological
damage and death worldwide. These investigators examined
if edaravone (EDA) had a neuroprotective effect on TBI and
identified the potential mechanism. Results demonstrated that
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 34 of 45
EDA suppressed inflammatory and oxidative responses in
mice following TBI. This was evidenced by a reduction in
glutathione peroxidase, interleukin 6 (IL-6), tumor necrosis
factor-alpha (TNF-α) and hydrogen peroxide levels, in addition
to an increase in hemeoxygenase-1, quinone oxidoreductase
1 and superoxide dismutase levels, thus mitigating
neurofunctional deficits, cell apoptosis and structural damage.
These researchers found that EDA prevented the transfer of
NF-κB protein from the cytoplasm to the nucleus, while
promoting the expression of nuclear factor erythroid 2-related
factor 2 (Nrf2) protein in mice following TBI. The authors
concluded that these findings indicated that EDA exerted
neuroprotective effects, including impeding neurofunctional
deficits, cell apoptosis and structural damage, in mice with TBI,
potentially via suppression of NF-κB-mediated inflammatory
activation and promotion of the Nrf2 antioxidant pathway.
These researchers stated that these findings provided
evidence for the potential clinical application of EDA in the
treatment of TBI.
Wound Healing
Tamer and colleagues (2018) noted that a novel wound
healing material composed of chitosan (Ch) and hyaluronan
(HA) boosted with edaravone (Ed) as an anti-inflammatory
drug was developed. The fabricated membranes were verified
using FT-IR, and the thermal properties were estimated
employing TGA instrument. Moreover, physical
characterizations of the prepared membranes demonstrated a
decrease in the membrane wettability, whereas an increase in
membrane roughness was monitored due to the effect of
edaravone supplementation. A comparative study of free-
radical scavenging activity of edaravone itself was carried out
by 2 in-vitro approaches: uninhibited/inhibited hyaluronan
degradation and de-colorization of ABTS methods in normal
and simulated inflammation condition (acidic condition).
Accordingly, the scavenging activity of edaravone was
significantly diminished to OH and peroxy-/alkoxy-type radicals
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 35 of 45
in acidic conditions in compared to the neutral reactions. The
biochemical studies evidenced the hemo-compatibility of the
examined membranes. The consequence of membranes
composed of Ch/HA/Ed on the wound healing of the rat's skin
was studied, and the macroscopic and microscopic
investigations revealed remarkable healing at 21st day post-
surgery compared with injuries treated with cotton gauze as a
negative control in addition to Ch/HA membrane without
edaravone. For these reasons, the Ch/HA/Ed membrane
could be implemented as wound dressing material.
Appendix
ALS Functional Rating Scale-Revised [ALSFRS-R]
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 to 4, with higher
scores representing greater functional ability.
ALSFRS-R Scale and Calculator (http://www.outcomes
umassmed.org/ALS/alsscale.aspx)
Revised El Escorial Schema for the Clinical Diagnosis of ALS
The body is divided into 4 regions: (i) cranial, (ii) cervical, (iii)
thoracic and (iv) lumbosacral.
▪ Clinically Definite ALS: Defined on clinical evidence alone
by the presence of UMN, as well as LMN signs, in 3
regions.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 36 of 45
▪ Clinically Probable ALS: Defined on clinical evidence
alone by UMN and LMN signs in at least 2 regions with
some UMN signs necessarily rostral to (above) the LMN
signs.
▪ Clinically Probable-Laboratory-Supported ALS: Defined
when clinical signs of UMN and LMN dysfunction are in
only 1 region, or when UMN signs alone are present in 1
region, and LMN signs defined by EMG criteria are
present in at least 2 limbs, with proper application of
neuroimaging and clinical laboratory protocols to
exclude other causes.
▪ Clinically Possible ALS: Defined when clinical signs of
UMN and LMN dysfunction are found together in only 1
region or UMN signs are found alone in 2 or more
regions; or LMN signs are found rostral to UMN signs
and the diagnosis of Clinically Probable-Laboratory-
Supported ALS cannot be proven by evidence on clinical
grounds in conjunction with electrodiagnostic,
neurophysiologic, neuroimaging or clinical laboratory
studies. Other diagnoses must have been excluded to
accept a diagnosis of Clinically Possible ALS.
▪ Clinically Suspected ALS: Defined as a pure LMN
syndrome, wherein the diagnosis of ALS could not be
regarded as sufficiently certain to include the patient in
a research study.
LMN: lower motor neuron sign(s); UMN: upper motor neuron
sign(s).
Source: Elman LB, McCluskey L. Diagnosis of amyotrophic
lateral sclerosis and other forms of motor neuron disease.
UpToDate Inc., April 2017.
CPT Codes / HCPCS Codes / ICD-10 Codes
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 37 of 45
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
Other CPT codes related to the CPB:
96365 Intravenous infusion, for therapy, prophylaxis,
or diagnosis(specify substance or drug); initial,
up to 1 hour
HCPCS codes covered if selection criteria are met:
J1301 Injection, edaravone, 1 mg
ICD-10 codes covered if selection criteria are met:
G12.21 Amyotrophic lateral sclerosis
ICD-10 codes not covered for indications listed in the CPB:
E06.3 Autoimmune thyroiditis
F06.31 Mood disorder due to known physiological
condition with depressive features
G20 Parkinson's disease
G30.0 -
G30.9
Alzheimer's disease
G35 Multiple sclerosis
G40.001 -
G40.919
Epilepsy and recurrent seizures
G93.40 Encephalopathy, unspecified
H31.8 Other specified disorders of choroid [choroidal
neovascularization]
I25.5 Ischemic cardiomyopathy [myocardial damage
after ischemia and re-perfusion]
I60.00 -
I60.9
Nontraumatic subarachnoid hemorrhage
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 38 of 45
Code Code Description
I61.0 -
I61.9
Nontraumatic intracerebral hemorrhage
I63.00 -
I63.9
Cerebral infarction
I69.398 Other sequelae of cerebral infarction
J45.20 -
J45.998
Asthma
K85.00 -
K85.92
Acute pancreatitis
M05.00 -
M06.9
Rheumatoid arthritis
M15.0 -
M19.93
Osteoarthritis
N00.0 -
N08
Glomerular diseases [nephropathy]
N10 -
N16
Renal tubulo-interstitial diseases [nephropathy]
N14.1 Nephropathy induced by other drugs,
medicaments and biological substances
[cisplatin-induced chronic renal injury]
[doxorubicin-induced nephrotoxicity]
N17.0 -
N19
Acute kidney failure and chronic kidney disease
[nephropathy]
N25.0 -
N29
Other disorders of kidney and ureter
[nephropathy]
R56.00 -
R56.9
Convulsions, not elsewhere classified
Numerous
Options
Wound healing
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 39 of 45
Code Code Description
S06.340A
-
S06.369S
Traumatic hemorrhage of cerebrum
S06.9x0A
-
S06.9x9S
TBI (traumatic brain injury)
S27.301A
-
S27.399S
Other and unspecified injuries of lung
S36.200A
-
S36.299S
Injury of pancreas
S36.500A
-
S36.599S
Injury of colon
T46.991A
-
T46.996S
Poisoning by, adverse effect of and
underdosing of other agents primarily affecting
the cardiovascular system [doxorubicin-induced
cardiotoxicity]
T66.xxxA
-
T66.xxxS
Radiation sickness [brain radionecrosis]
The above policy is based on the following references:
1. Abe K, Itoyama Y, Sobue G, et al; Edaravone ALS Study
Group. Confirmatory double-blind, parallel-group,
placebo-controlled study of efficacy and safety of
edaravone (MCI-186) in amyotrophic lateral sclerosis
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 40 of 45
patients. Amyotroph Lateral Scler Frontotemporal
Degener. 2014;15(7-8):610-617.
2. Agresti C, Mechelli R, Olla S, et al. Oxidative status in
multiple sclerosis and off-targets of antioxidants: The
case of edaravone. Curr Med Chem. 2019 Jan 24 [Epub
ahead of print].
3. Bao Q, Hu P, Xu Y, et al. Simultaneous blood-brain
barrier crossing and protection for stroke treatment
based on edaravone-loaded ceria nanoparticles. ACS
Nano. 2018;12(7):6794-6805.
4. Cai Z, Zhang H, Song H, et al. Edaravone combined
with cinepazide maleate on neurocyte autophagy and
neurological function in rats with subarachnoid
hemorrhage. Exp Ther Med. 2020;19(1):646-650.
5. Chiriboga CA. Acute toxic-metabolic encephalopathy in
children. UpToDate [online serial]. Waltham, MA:
UpToDate; reviewed August 2019.
6. Chung C, Bryant A, Brown PD. Interventions for the
treatment of brain radionecrosis after radiotherapy or
radiosurgery. Cochrane Database Syst Rev.
2018;7:CD011492.
7. Demir F, Demir M, Aygun H. Evaluation of the
protective effect of edaravone on doxorubicin
nephrotoxicity by [99mTc]DMSA renal scintigraphy
and biochemical methods. Naunyn Schmiedebergs
Arch Pharmacol. 2020 Feb 8 [Epub ahead of print].
8. EFNS Task Force on Diagnosis and Management of
Amyotrophic Lateral Sclerosis: Andersen PM,
Abrahams S, Borasio GD, 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(3):360-375.
9. Fu ZY, Wu ZJ, Zheng JH, et al. Edaravone ameliorates
renal warm ischemia-reperfusion injury by
downregulating endoplasmic reticulum stress in a rat
resuscitation model. Drug Des Devel Ther.
2020;14:175-183.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 41 of 45
10. Hao L, Dong L, Yu Q, et al. Edaravone inhibits
procaspase-3 denitrosylation and activation through
FasL-Trx2 pathway in KA-induced seizure. Fundam Clin
Pharmacol. 2020 Mar 25 [Epub ahead of print].
11. Hassan MQ, Akhtar MS, Afzal O, et al. Edaravone and
benidipine protect myocardial damage by regulating
mitochondrial stress, apoptosis signalling and cardiac
biomarkers against doxorubicin-induced
cardiotoxicity. Clin Exp Hypertens. 2019 Oct 20:1-12
[Epub ahead of print].
12. Hayakawa I, Okubo Y, Nariai H, et al. Recent treatment
patterns and variations for pediatric acute
encephalopathy in Japan. Brain Dev. 2020;42(1):48-55.
13. Huang C, Liao G, Han J, et al. Edaravone suppresses
degradation of type II collagen. Biochem Biophys Res
Commun. 2016;473(4):840-844.
14. Kabra A, Sharma R, Kabra R, Baghel US. Emerging and
alternative therapies for Parkinson disease: An
updated review. Curr Pharm Des. 2018;24(22):2573
2582.
15. Kassab AA, Aboregela AM, Shalaby AM. Edaravone
attenuates lung injury in a hind limb ischemia
reperfusion rat model: A histological,
immunohistochemical and biochemical study. Ann
Anat. 2020;228:151433.
16. Kobayashi S, Fukuma S, Ikenoue T, et al. Effect of
edaravone on neurological symptoms in real-world
patients with acute ischemic stroke. Stroke. 2019;50
(7):1805-1811.
17. Koike N, Sasaki A, Murakami T, Suzuki K. Effect of
edaravone against cisplatin-induced chronic renal
injury. Drug Chem Toxicol. 2019 May 7:1-10 [Epub
ahead of print].
18. Kong Z, Jiang J, Deng M, et al. Edaravone reduces
depression severity in patients with symptomatic
intracranial stenosis and is associated with the serum
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 42 of 45
expression of sex hormones. Medicine (Baltimore).
2020;99(8):e19316.
19. Li H, Min J, Mao X, et al. Edaravone ameliorates
experimental autoimmune thyroiditis in rats through
HO-1-dependent STAT3/PI3K/Akt pathway. Am J Transl
Res. 2018;10(7):2037-2046.
20. Martinez A, Palomo Ruiz MD, Perez DI, Gil C. Drugs in
clinical development for the treatment of amyotrophic
lateral sclerosis. Expert Opin Investig Drugs. 2017;26
(4):403-414.
21. Masuda T, Shimazawa M, Takata S, et al. Edaravone is
a free radical scavenger that protects against laser-
induced choroidal neovascularization in mice and
common marmosets. Exp Eye Res. 2016;146:196-205.
22. Mitsubishi Tanabe Pharma Corporation. Radicut
Injection 30 mg. The Japanese Pharmacopoeia
Edaravone Injection. Prescription Drug. Package Insert
[English translation]. Standard Commodity
Classification No. of Japan 87119. Approval No.
21300AMZ00377000. 18th Version D15a. Osaka, Japan;
Mitsubishi Tanabe Pharma Corporation; Revised: June
2015.
23. Mitsubishi Tanabe Pharma Corporation. Radicava
(edavarone injection) for intravenous use. Prescribing
Information. 118839-W. Jersey City, NJ: Mitsubishi
Tanabe Pharma America; August 2017.
24. Mitsubishi Tanabe Pharma Corporation. Radicava
(edavarone injection) for intravenous use. Prescribing
Information. Jersey City, NJ: Mitsubishi Tanabe Pharma
America; August 2018.
25. Mitsubishi Tanabe Pharma Corporation. Radicava
(edavarone injection) for intravenous use. Prescribing
Information. Jersey City, NJ: Mitsubishi Tanabe Pharma
America; July 2019.
26. Naganuma M, Inatomi Y, Nakajima M, et al.
Associations between uric acid level and 3-month
functional outcome in acute ischemic stroke patients
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 43 of 45
treated with/without edaravone. Cerebrovasc Dis.
2018;45(3-4):115-123.
27. Noto Y, Shibuya K, Vucic S, Kiernan MC. Novel
therapies in development that inhibit motor neuron
hyperexcitability in amyotrophic lateral sclerosis.
Expert Rev Neurother. 2016;16(10):1147-1154.
28. Oguro H, Mitaki S, Takayoshi H, et al. Retrospective
analysis of argatroban in 353 patients with acute
noncardioembolic stroke. J Stroke Cerebrovasc Dis.
2018;27(8):2175-2181.
29. Pan Y, Li W, Feng Y, et al. Edaravone attenuates
experimental asthma in mice through induction of
HO-1 and the Keap1/Nrf2 pathway. Exp Ther Med.
2020;19(2):1407-1416.
30. Parikh A, Kathawala K, Li J, et al. Self-nanomicellizing
solid dispersion of edaravone: Part II: In vivo
assessment of efficacy against behavior deficits and
safety in Alzheimer's disease model. Drug Des Devel
Ther. 2018;12:2111-2128.
31. Petrov D, Mansfield C, Moussy A, Hermine O. ALS
clinical trials review: 20 years of failure. Are we any
closer to registering a new treatment? Front Aging
Neurosci. 2017;9:68.
32. Radicava [package insert]. Jersey City, NJ: MT Pharma
America, Inc.; August 2018.
33. Sawada H. Clinical efficacy of edaravone for the
treatment of amyotrophic lateral sclerosis. Expert
Opin Pharmacother. 2017;18(7):735-738.
34. Tamer TM, Valachová K, Hassan MA, et al.
Chitosan/hyaluronan/edaravone membranes for anti-
inflammatory wound dressing: In vitro and in vivo
evaluation studies. Mater Sci Eng C Mater Biol Appl.
2018;90:227-235.
35. U.S. Food and Drug Administration. FDA approves
drug to treat ALS. FDA News. Silver Spring, MD: FDA;
May 5, 2017.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 44 of 45
36. Varatharajan R, Lim LX, Tan K, et al. Effect of
edaravone in diabetes mellitus-induced nephropathy
in rats. Korean J Physiol Pharmacol. 2016;20(4):333
340.
37. Wang B, Lin W. Edaravone protects against pancreatic
and intestinal injury after acute pancreatitis via
nuclear factor-κB signaling in mice. Biol Pharm Bull.
2020;43(3):509-515.
38. Writing Group; Edaravone (MCI-186) ALS 19 Study
Group. Safety and efficacy of edaravone in well
defined patients with amyotrophic lateral sclerosis: A
randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2017;16(7):505-512.
39. Wu Y. Clinical features, diagnosis, and treatment of
neonatal encephalopathy. UpToDate [online serial].
Waltham, MA: UpToDate; reviewed August 2019.
40. Yang J, Cui X, Li J, et al. Edaravone for acute stroke:
Meta-analyses of data from randomized controlled
trials. Dev Neurorehabil. 2015;18(5):330-335.
41. Zhang M, Teng CH, Wu FF, et al. Edaravone attenuates
traumatic brain injury through anti-inflammatory and
anti-oxidative modulation. Exp Ther Med. 2019;18
(1):467-474.
42. Zhang X, Ye G, Wu Z, et al. The therapeutic effects of
edaravone on collagen-induced arthritis in rats. J Cell
Biochem. 2020;121(2):1463-1474.
43. Zheng C, Liu S, Geng P, et al. Efficacy of edaravone on
coronary artery bypass patients with myocardial
damage after ischemia and reperfusion: A meta
analysis. Int J Clin Exp Med. 2015;8(2):2205-2211.
Proprietary
Edaravone (Radicava) - Medical Clinical Policy Bulletins | Aetna Page 45 of 45
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors
in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely
responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is
subject to change.
Copyright © 2001-2020 Aetna Inc.
Proprietary
Proprietary
AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0918 Edaravone
(Radicava)
The Site of Care Utilization Management Policy does not apply to Edaravone (Radicava) for the Pennsylvania Medical Assistance Plan.
Continuation Criteria:
Aetna considers continued use of edaravone medically necessary when the following criteria are met:
• Diagnosis of definite or probable ALS; and • There is a clinical benefit from edaravone therapy; and • Continuous use of invasive ventilatory support is not required.
www.aetnabetterhealth.com/pennsylvania revised 07/21/2020
Proprietary