Medical Policies - Prescription Drugs
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
Edaravone (Radicava™) may be considered medically necessary for the treatment of individuals with amyotrophic lateral sclerosis (ALS) who meet the following criteria:
For initial 6-month therapy, ALL of the following:
• Individuals 18 years of age and older; AND
• Individuals diagnosed with definite or probable ALS based on El Escorial revised criteria (see NOTE); AND
• Individuals have 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 NOTE); AND
• Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] greater than or equal to 80%); AND
• Disease duration of 2 years or less.
For continuation therapy, ALL of the following:
• There is documentation indicating that Edaravone (Radicava™) use has slowed the progression of ALS; AND
• Overall function should be improved/superior relative to that projected for the natural course of ALS.
Edaravone (Radicava™) is considered experimental, investigational, and/or unproven when the criteria above are not met and for all other indications.
NOTE: Refer to the Description section for definitions of the El Escorial revised criteria and the ALSFRS-R.
Edaravone (Radicava™) is a drug for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. The onset of ALS often involves muscle weakness or stiffness as early symptoms. Progression of weakness, wasting and paralysis of the muscles of the limbs and trunk as well as those that control vital functions such as speech, swallowing and later breathing generally follows. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease. 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. (1,2)
The clinical standard for the diagnosis of ALS is the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria. These criteria allow assignment of diagnostic certainty and were designed for research purposes to ensure appropriate inclusion of patients into clinical trials. (3)
Revised El Escorial Schema for the Clinical Diagnosis of ALS
(The body is divided into four regions: cranial, cervical, thoracic and lumbosacral)
• Clinically Definite ALS: Defined on clinical evidence alone by the presence of upper motor neuron (UMN) signs, as well as lower motor neuron (LMN) signs, in three regions.
• Clinically Probable ALS: Defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to the LMN signs.
• Clinically Probable-Laboratory-Supported ALS: Defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by electromyography (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 one region or UMN signs are found alone in two 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.
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). (4) Each item is scored from 0 to 4, with higher scores representing greater functional ability.
On May 5, 2017, the U.S. Food and Drug Administration (FDA) approved edaravone (Radicava™) (Mitsubishi Tanabe Pharma America, Inc.) for treatment of patients with amyotrophic lateral sclerosis. (5) Edaravone is for intravenous infusion only. Safety and effectiveness in pediatric patients have not been established.
This medical policy was created October 2017 with current literature from the MEDLINE database. Following is a summary of the key literature to date.
The efficacy of edaravone (Radicava™) for the treatment of amyotrophic lateral sclerosis (ALS) was based on a 6-month, phase III, randomized, placebo-controlled, double-blind study. (4) The study was conducted in Japanese patients who lived independently and met the following criteria at screening:
1. Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised (ALSFRS-R);
2. Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] ≥ 80%);
3. Definite or probable ALS based on El Escorial revised criteria;
4. Disease duration of 2 years or less.
The study enrolled 69 patients in the RadicavaTM 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. RadicavaTM was administered as an intravenous 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 2-6).
The primary efficacy endpoint 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 0-4, with higher scores representing greater functional ability. The decline in ALSFRS-R scores from baseline was significantly less in the RadicavaTM -treated patients as compared to placebo. The most common adverse reactions that occurred in > 10% of RadicavaTM treated patients were contusion, gait disturbance, and headache. RadicavaTM 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.
In 2006, Yoshino et al. published results of an early phase II clinical trial which indicated that edaravone may delay the progression of symptoms in some individuals with ALS. (6) In 2014 Abe et al. conducted a 36-week confirmatory study to further evaluate the efficacy and safety of edaravone in subjects with ALS. (7) A total of 206 subjects were randomized to receive either placebo (saline) or edaravone intravenous infusion. The trial consisted of a 12-week pre- observation period followed by 24-week treatment period between May 2006 and September 2008 at 29 Japanese sites. Inclusion criteria included the following: age 20-75 years, diagnosis of definite, probable or probable laboratory-supported ALS, forced vital capacity (FVC) of at least 70%, duration of disease within 3 years, and change in revised ALS functional rate scale score during the pre-observation period of -1 to -4 points. Exclusion criteria included: reduced respiratory function and complaints of dyspnea; complications that might impact evaluation of drug efficacy, such as Parkinson's disease, schizophrenia and dementia; complications that require hospitalization such as liver, cardiac and renal diseases; infections requiring antibiotics; deteriorated general condition; creatinine clearance 50 ml/min or below; and undergoing cancer treatment. The primary efficacy endpoint was change in ALSFRS-R scores during the 24 weeks of treatment. Upon study completion, data failed to demonstrate the efficacy of edaravone for treatment of ALS. Adverse events occurred in 88.5% (92/104) of subjects in the placebo group and 89.2% (91/102) of subjects the edaravone group. The authors indicated that the results of this trial would be helpful to identify the population which edaravone could be expected to show efficacy. On the basis of that information, a phase III study was designed.
The following recommendations is included in an UpToDate literature review for disease modifying treatment of amyotrophic lateral sclerosis: (8)
“For patients with ALS who have a disease duration of two years or less, are living independently, and have an FVC ≥80 percent, we suggest treatment with edaravone (Grade 2B). We also suggest edaravone for patients with more advanced ALS (Grade 2C).”
1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients.
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain.
A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form.
B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other form.
C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with serious flaws.
Summary of Evidence
The evidence is sufficient to support the use of edaravone (Radicava™) for its U.S. Food and Drug Administration (FDA) approved indications, which is based on the clinical trial outcomes documented in the published FDA labeling.
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Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. ALS Association. What is ALS? (2017). Available at <http://www.alsa.org> (accessed - 19 September 2017).
2. FDA – Press Announcements. FDA approves drug to treat ALS. U.S. Food and Drug Administration (May 5, 2017). Available at <https://www.fda.gov> (accessed – 19 September 2017).
3. Elman LB, McCluskey L. Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Available at <http://www.uptodate.com> (accessed 2017 September 19).
4. FDA - Radicava™ (edaravone injection) – Product Label (May 2017). U.S. Food and Drug Administration. Available at <http://www.fda.gov> (accessed - 19 September 2017).
5. FDA - Radicava ™ (edaravone) – FDA Approved Drug Products. U.S. Food and Drug Administration. Available at <http://www.accessdata.fda.gov> (accessed - 20 September 2017).
6. Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler. 2006; 7(4):241-245. PMID 17127563
7. Abe K, Itoyama Y, Sobue G, et al. 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):610-617. PMID 25286015
8. Choudry RB, Galvez-Jimenez N, Cudkowicz ME. Disease modifying treatment of amyotrophic lateral scloerosis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Available at <http://www.uptodate.com> (accessed 2017 September 19).
|7/15/2018||Reviewed. No changes.|
|10/1/2017||New medical document. Edaravone (Radicava™) may be considered medically necessary for the treatment of individuals with amyotrophic lateral sclerosis (ALS) who meet the following criteria: For initial 6-month therapy, ALL of the following: Individuals 18 years of age and older; and Individual is diagnosed with definite or probable ALS based on El Escorial revised criteria; and Individuals have 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; and Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] greater than or equal to 80%); and Disease duration of 2 years or less. For continuation therapy, ALL of the following: There is documentation indicating that edaravone (Radicava™) use has slowed the progression of ALS; and Overall function should be improved/superior relative to that projected for the natural course of ALS. Edaravone (Radicava™) is considered experimental, investigational, and/or unproven when the criteria above are not met and for all other indications.|