RADICAVA, Edaravone Form

Edaravone (Radicava®, Radicava ORS®) is a member of the substituted 2-pyrazolin-5-one class that acts as a free-radical scavenger of peroxyl radicals and peroxynitrite. FDA Approved Indication(s) Radicava and Radicava ORS are indicated for the treatment of amyotrophic lateral sclerosis (ALS). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Radicava and Radicava ORS are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Amyotrophic Lateral Sclerosis (must meet all):

1. Diagnosis of definite or probable ALS per El Escorial diagnostic criteria (see Appendix D);
2. Prescribed by or in consultation with a neurologist;
   3. Age ≥ 18 years;
   4. Concomitant use of riluzole (at up to maximally indicated doses) unless contraindicated or clinically significant adverse effects are experienced;
3. Independent living status (defined as patients who can eat a meal, excrete, or move with oneself alone, and do not need assistance in everyday life);
4. Percent predicted forced vital capacity (% FVC) ≥ 80%;
   7. Disease duration of ≤ 2 years;
   8. Baseline revised ALS Functional Rating Scale (ALSFRS-R) score with ≥ 2 points in each of the 12 items;

5. Dose does not exceed any of the following (a, b, and c): a. One of the following (i or ii): i. For intravenous administration: 60 mg per day for each treatment cycle; ii. For oral administration: 105 mg per day for each treatment cycle; b. For initial treatment cycle: daily dosing for 14 days followed by a 14-day drug- free period; c. For subsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods. Approval duration: 6 months Page 1 of 8

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   B. Other diagnoses/indications (must meet 1 or 2):

6. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
7. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Amyotrophic Lateral Sclerosis (must meet all):
   
   1. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
   2. Member is responding positively to therapy;
   3. Member continues to meet all of the following criteria (a, b, and c): a. Independent living status; b. Percent predicted forced vital capacity (% FVC) ≥ 80%; c. Revised ALSFRS-R score with ≥ 2 points in each of the 12 items;
8. If request is for a dose increase, new dose does not exceed both of the following (a and b): a. One of the following (i or ii): i. For intravenous administration: 60 mg per day for each treatment cycle; ii. For oral administration: 105 mg per day for each treatment cycle;
   b. Treatment cycle consisting of daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods. Approval duration: 6 months B. Other diagnoses/indications (1 or 2):

9. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): Page 2 of 8

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   a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

10. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALS: amyotrophic lateral sclerosis ALSFRS-F: revised ALS Functional Rating Scale FDA: Food and Drug Administration FVC: forced vital capacity LMN: lower motor neuron UMN: upper motor neuron Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization. Drug Name Dosing Regimen riluzole (Rilutek®) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. 50 mg PO BID Dose Limit/ Maximum Dose 100 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): hypersensitivity to edaravone or any of the inactive ingredients in Radicava and/or Radicava ORS • Boxed warning(s): none reported Appendix D: General Information • Revised El Escorial diagnostic criteria for ALS requires the presence of:

11. Signs of lower motor neuron (LMN) degeneration by clinical, electrophysiological or neuropathologic examination, Page 3 of 8

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12. Signs of upper motor neuron (UMN) degeneration by clinical examination, and

    3. Progressive spread of signs within a region or to other regions, together with the absence of: a. Electrophysiological evidence of other disease processes that might explain the signs of LMN and/or UMN degenerations; and b. Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs. • The definitions of ALS diagnoses provided by the El Escorial criteria are as follows: Definite ALS Probable ALS Possible ALS Suspected ALS El Escorial criteria, 1994 Upper and lower motor neuron signs in three regions Upper and lower motor neuron signs in at least two regions, with upper motor neuron signs rostral to lower motor neuron signs Upper and lower motor neuron signs in one region, upper motor neuron signs alone in two or more regions, or lower motor neuron signs rostral to upper motor neuron signs Lower motor neuron signs only, in two or more regions • Two pivotal phase III trials that were conducted in Japan were used for the approval of Radicava in the USA. One of the phase III trials of Radicava found no statistically significant difference in delay of ALS progression, but a post-hoc analysis found that a certain subset of patients may benefit. Based on the post-hoc analysis, the second phase III was performed with a much more strict eligibility criteria and found a statistically significant difference in ALS progression in favor of Radicava. Therefore, patients not meeting the strict eligibility criteria at any time (at the time of initial or continued approval) can be assumed that no benefit will be provided by the use of Radicava for the treatment of ALS until further studies support its use in a wider population with ALS. • The revised ALS Functional Rating Scale (ALSFRS-R) score consists of a total of 12 items and 48 points. It is a physician-generated estimate of the patient’s degree of functional impairment. Each item assesses the patient’s functional ability on daily tasks, such as walking and hand-writing. Each item is scored from 0 to 4 points, with 0 indicating no ability and 4 indicating normal ability.
       V. Dosage and Administration
       Indication Dosing Regimen ALS Oral: 105 mg PO in the morning per initial and subsequent treatment cycles below IV: 60 mg IV (60 mg dose as an intravenous infusion over a total of 60 minutes at an infusion rate approximately 1 mg per minute) per initial and subsequent treatment cycles below Maximum Dose Oral: 105 mg/day IV: 60 mg/day Page 4 of 8

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    Indication Dosing Regimen Maximum Dose Treatment cycles for oral and IV administrations: • 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. Patients treated with 60 mg of Radicava IV infusion may be switched to 105 mg (5 mL) Radicava ORS using the same dosing frequency. VI. Product Availability
    • Single-dose polypropylene bag for injection: 30 mg/100 mL • Multi-dose oral suspension: 105 mg/5 mL VII.