Prior Authorization Review Panel MCO Policy Submission

Transcription

1 Prior Authorization Review Panel MCO Policy Submission A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review. Plan: Aetna Better Health Submission Date: 11/01/2018 Policy Number: 0918 Policy Name: Edaravone (Radicava) Effective Date: Revision Date: Type of Submission Check all that apply: New Policy* Revised Policy Annual Review No Revisions *All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below: CPB 0918 Edaravone (Radicava) Policy is new to Aetna Better Health of Pennsylvania. Name of Authorized Individual (Please type or print): Signature of Authorized Individual: Dr. Bernard Lewin, M.D.

2 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 1 of 17 Edaravone (Radicava) Number: 0918 Policy *Please see amendment forpennsylvaniamedicaid at theend of this CPB. Notes: PRECERTIFICATION REQUIRED * Site of Care Utilization Management Policy applies. For Policy History Last Review: 04/06/2018 Effective: 07/21/2017 Next Review: 10/25/2018 Review History information on site of service for edaravone, see Utilization Management Policy on Site of Care for Specialty Drug Infusions ( Definitions Aetna considers edaravone (Radicava) medically necessary for the treatment of individuals with amyotrophic lateral sclerosis (ALS) when all the following criteria are met: Additional Information 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; see Appendix)); and Normal respiratory function (defined as percentpredicted forced vital capacity values of [%FVC] greater than or equal to 80%); and Clinical Policy Bulletin Notes

3 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 2 of 17 Definite or probable ALS based on El Escorial revised criteria (see Appendix); and Disease duration of 2 years or less Aetna considers edaravone experimental and investigational for the following (not an all-inclusive list): Acute ischemic stroke Choroidal neovascularization Intra-cerebral hemorrhage Myocardial damage after ischemia and re-perfusion Nephropathy Osteoarthritis Continuation Criteria: Aetna considers continued use of edaravone medically necessary when the following criteria are met: There is documentation indicating that edaravone use has slowed the progression of ALS; and Overall function should be improved/superior relative to that projected for the natural course of ALS. * Precertification of edaravone is required of all Aetna participating providers and members in applicable plan designs. For precertification of edaravone, call (866) , or fax (866) Background 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

4 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 3 of 17 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 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 preobservation 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 ± 0.84 in the placebo group and ± 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 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

5 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 4 of 17 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 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

6 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 5 of 17 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, placebocontrolled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening: 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 percentpredicted forced vital capacity values of [%FVC] greater than or equal to 80 %) Definite or Probable ALS based on El Escorial revised criteria

7 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 6 of 17 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 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.

8 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 7 of 17 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 ± 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 ± 0.66; p = ). 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

9 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 8 of 17 significantly different between the edaravone-treated and placebo-treated groups (-6.52 ± 1.78 versus ± 1.83; p = ). *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. 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 < ), and ICH (MD = -4.32; 95 % CI: to -3.29, p < ). 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 longterm disability for AIS and ICH.

10 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 9 of 17 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 (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. 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

11 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 10 of 17 eligible trials, assessed trial quality and independently extracted the data. A total of 7 clinical trials were eventually 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

12 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 11 of 17 kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a 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 proinflammatory 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-αinduced 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)

13 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 12 of 17 and expression of interferon regulatory factor 1 (IRF-1); these findings suggested a potential protective effect of edaravone in OA. Appendix 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 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 ( 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.

14 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 13 of 17 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 CPT Codes / HCPCS Codes / ICD-10 Codes Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

15 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 14 of 17 Code Code Description Other CPT codes related to the CPB: Intravenous infusion, for therapy, prophylaxis, or diagnosis(specify substance or drug); initial, up to 1 hour HCPCS codes covered if selection criteria are met: C9493 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: H31.8 Other specified disorders of choroid [choroidal neovascularization] I25.5 Ischemic cardiomyopathy [myocardial damage after ischemia and re-perfusion] I Nontraumatic intracerebral hemorrhage I61.9 I Cerebral infarction [acute ischemic stroke] I63.9 M Osteoarthritis M19.93 N Glomerular diseases [nephropathy] N08 N10 - Renal tubulo-interstitial diseases [nephropathy] N16 N N19 N N29 Acute kidney failure and chronic kidney disease [nephropathy] Other disorders of kidney and ureter [nephropathy]

16 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 15 of 17 Code Code Description S06.340A - S06.369S Traumatic hemorrhage of cerebrum 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 patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(7-8): 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): 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): 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): Masuda T, Shimazawa M, Takata S, et al. Edaravone is a free radical scavenger that protects against laserinduced choroidal neovascularization in mice and common marmosets. Exp Eye Res. 2016;146: 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):

17 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 16 of Huang C, Liao G, Han J, et al. Edaravone suppresses degradation of type II collagen. Biochem Biophys Res Commun. 2016;473(4): 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: Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother. 2017;18(7): 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): Food and Drug Administration. FDA approves drug to treat ALS. May 5, FDA: Silver Spring, MD. Available at: source=govdelivery&utm_medium= &utm_source=govdelivery. Accessed May 10, 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 Approval No AMZ th Version D15a. Osaka, Japan; Mitsubishi Tanabe Pharma Corporation; Revised: June 2015.

18 Edaravone (Radicava) - Medical Clinical Policy Bulletins Aetna Page 17 of 17 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 Aetna Inc.

19 AETNA BETTER HEALTH OF PENNSYLVANIA Amendment to Aetna Clinical Policy Bulletin Number: 0918 Edaravone (Radicava) There are no amendments for Medicaid. new 11/01/2018