Last Review Date: 08/01/2024

Date of Origin: 05/13/2019

Dates Reviewed: 05/2019, 07/2019, 02/2020, 10/2020, 02/2021, 02/2022, 06/2023, 08/2024

1. Length of Authorization

     Initial coverage will be provided for 6 months and may be renewed annually thereafter.

2. Dosing Limits

 A. Quantity Limit (max daily dose) [NDC unit]:

    [56 mg Dose Kit]

• Treatment Resistant Depression (TRD)

• Induction (weeks 1 to 4): 2 kits per week
• Maintenance (weeks 5 and after): 1 kit per week

• Depressive Symptoms In Patients With Major Depressive Disorder (MDD) With Acute Suicidal Ideation/Behavior:  2 kits per week

  [84 mg Dose Kit]

• Treatment Resistant Depression (TRD)

• Induction (weeks 1 to 4): 1 kit, week 1; 2 kits per week, weeks 2 to 4  
• Maintenance (weeks 5 and after): 1 kit per week

• Depressive Symptoms In Patients With Major Depressive Disorder (MDD) With Acute Suicidal Ideation/Behavior:  2 kits per week

B. Max Units (per dose and over time) [HCPCS Unit]:

   [G2082/G2083]

• Treatment Resistant Depression (TRD)

• Induction (weeks 1 to 4): 1 billable unit twice weekly
• Maintenance (weeks 5 and after): 1 billable unit weekly

• Depressive Symptoms In Patients With Major Depressive Disorder (MDD) With Acute Suicidal Ideation/Behavior:  1 billable unit twice weekly

 [S0013]

• Treatment Resistant Depression (TRD)

• Induction (weeks 1 to 4): 56 billable units on Day 1, then 84 billable units twice weekly
• Maintenance (weeks 5 and after): 84 billable units weekly

• Depressive Symptoms In Patients With Major Depressive Disorder (MDD) With Acute Suicidal Ideation/Behavior:  168 billable units weekly

3. Initial Approval Criteria ^1,15

Coverage is provided in the following conditions:

• Patient is at least 18 years old; AND
• Patient must have a baseline assessment using any validated depression rating scale (e.g., Montgomery-Asberg Depression Rating Scale [MADRS], Hamilton Depression Rating Scale [HAM-D], Patient Health Questionnaire Depression Scale [PHQ-9], Beck Depression Inventory [BDI], Quick Inventory of Depressive Symptomatology [QIDS], etc.); AND
• Prescriber’s healthcare setting is certified in the Spravato Risk Evaluation and Mitigation Strategies (REMS) program; AND

Universal Criteria ^1,11

• Patient has a diagnosis of major depressive disorder (MDD) according to the current version of the Diagnostic and Statistical Manual of Mental Disorders (e.g., DSM-5-TR); AND
• Patient must not have any of the following:
  • Aneurysmal vascular disease
  • Arteriovenous malformation
  • History of intracerebral hemorrhage
  • Known hypersensitivity to ketamine; AND
• Patient is not receiving concomitant ketamine therapy; AND
• Must be used in conjunction with an oral antidepressant; AND

Treatment-Resistant Depression (TRD) † ^{1,7,8,12-13,16}

• Patient has tried psychotherapy alone or in combination with an oral antidepressant, if psychotherapy resources are available; AND
• Patient is NOT receiving concomitant electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), or deep brain stimulation (DBS); AND
• Patient has failed a trial of at least 2 antidepressants of different classes for a duration of at least 6 weeks each with adequate adherence at generally accepted doses in the current depressive episode, unless contraindicated or clinically significant adverse effects are experienced (‘Failed trial’ is defined as less than or equal to 25% reduction in symptom severity using any validated depression rating scale)

Depressive Symptoms In Patients With Major Depressive Disorder (MDD) With Acute Suicidal Ideation/Behavior † ^1,9,10

• Patient is experiencing acute suicidal ideation or behavior; OR
• Patient has recently been discharged from a hospital in which treatment with esketamine has been initiated

† FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug

4. Renewal Criteria ^1,15

Coverage can be renewed based upon the following criteria:

• Patient continues to meet the universal and indication specific criteria as identified in section III; AND

• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: sedation, dissociation, respiratory depression, signs of abuse/dependance, severe cognitive impairment, ulcerative/interstitial cystitis, suicidal thoughts/behavior, severe hypertension, etc.; AND
• Patient has demonstrated disease improvement and/or stabilization as evidenced by a reduction in symptom severity, compared to baseline, using any validated depression rating scale.

5. Dosage/Administration ¹

6. Billing Code/Availability Information

HCPCS(s):

• J3490 – Unclassified drugs
• C9399 – Unclassified drugs or biologicals
• S0013 – Esketamine, nasal spray, 1 mg; 1 billable unit = 1 mg
• *G2082 – Office or other outpatient visit for the evaluation and management of an established patient that requires the supervision of a physician or other qualified health care professional and provision of up to 56 mg of esketamine nasal self-administration, includes 2 hours post-administration observation
• *G2083 – Office or other outpatient visit for the evaluation and management of an established patient that requires the supervision of a physician or other qualified health care professional and provision of greater than 56 mg esketamine nasal self-administration, includes 2 hours post-administration observation

* Required for Medicare part B claims. For non-Medicare, those that do not accept the G Codes, providers may continue to report separate codes for the drug and service using the unclassified drug codes (J3490 or C9399) for Spravato and the most appropriate E/M CPT® code for the service.

NDC(s):

• 56 mg Dose Kit: Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose): 50458-0028-xx
• 84 mg Dose Kit: Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose): 50458-0028-xx

7. References

1. Spravato [package insert]. Titusville, NJ; Janssen Pharm., Inc.; October 2023. Accessed June 2024.
2. Papakostas GI. Incidence, impact, and current management strategies for treatment-resistant major depressive disorder. Medscape. Available at: https://www.medscape.org/viewarticle/574817_1. Accessed July 3, 2024.
3. American Psychiatric Association Work Group on Major Depressive Disorder. Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. October 2010. Available at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed July 3, 2024.
4. Major Depression. National Institute of Mental Health. Available at: https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Accessed July 3, 2024.
5. Johnston KM, Powell LC, Anderson IM, et al. The burden of treatment-resistant depression: a systematic review of the economic and quality of life literature. J Affect Disord. 2019; 242: 195-210. DOI: 10.1016/j.jad.2018.06.045.
6. Socci C, Medda P, Toni C, et al. Electroconvulsive therapy and age: age-related clinical features and effectiveness in treatment resistant major depressive episode. J Affect Disord. 2018; 227:627-632.
7. Starr HL, Abell J, Larish A, et al. Self-reported review of the value of esketamine in patients with treatment-resistant depression: Understanding the patient experience in the STRIVE Study. Psychiatry Res. 2020 Nov;293:113376. doi: 10.1016/j.psychres.2020.113376. Epub 2020 Aug 8. PMID: 32818917.
8. Jha MK, Williamson DJ, Magharehabed G, et al. Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability. J Affect Disord. 2023 Jan 15;321:153-160. doi: 10.1016/j.jad.2022.10.020. Epub 2022 Oct 20. PMID: 36273682.
9. Fu D-J, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191.
10. Rozjabek, H., Li, N., Hartmann, H. et al. Assessing the meaningful change threshold of Quality of Life in Depression Scale using data from two phase 3 studies of esketamine nasal spray. J Patient Rep Outcomes 6, 74 (2022). https://doi.org/10.1186/s41687-022-00453-y
11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), 2022.
12. Reif A, Bitter I, Buyze J, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med 2023; 389:1298.
13. McIntyre RS, Rosenblat JD, et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry. 2021 May 1;178(5):383-399. doi: 10.1176/appi.ajp.2020.20081251. Epub 2021 Mar 17. PMID: 33726522; PMCID: PMC9635017.
14. Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, Tufte J, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023;176(2):239. Epub 2023 Jan 24.
15. American Psychological Association. Depression Assessment Instruments. January 2023. Available at: https://www.apa.org/depression-guideline/assessment. Accessed on July 3, 2024.
16. Rush AJ, Thase ME. Improving Depression Outcome by Patient-Centered Medical Management. Am J Psychiatry. 2018 Dec 1;175(12):1187-1198. doi: 10.1176/appi.ajp.2018.18040398. Epub 2018 Sep 17. PMID: 30220219.
17. Novitas Solutions, Inc. Local Coverage Article: Billing and Coding: Esketamine (A59249). Centers for Medicare & Medicaid Services, Inc. Updated on 09/23/2022 with effective date 11/14/2022. Accessed June 2024.
18. First Coast Service Options, Inc. Local Coverage Article: Billing and Coding: Esketamine (A59250). Centers for Medicare & Medicaid Services, Inc. Updated on 09/23/2022 with effective date 11/14/2022. Accessed June 2024.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

The preceding information is intended for non-Medicare coverage determinations. Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.