Esketamine (Spravato®) Nasal Spray

Restricted Product(s)

• esketamine (Spravato®) intranasal spray for administration under supervision of healthcare professional

FDA Approved Use

• For the treatment of treatment-resistant depression in adults, as monotherapy or in conjunction with an oral antidepressant
• For the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior in conjunction with an oral antidepressant
• Limitations of use:
  • Effectiveness in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated; use of Spravato does not preclude the need for hospitalization if clinically warranted, even if improvement is observed following initial dosing
  • Not approved as an anesthetic agent, as safety and effectiveness for this use have not been established

Criteria for Medical Necessity

The restricted product(s) may be considered medically necessary when the following criteria are met

Initial Criteria for Approval

1. The patient is 18 years of age or older; AND 
2. ONE of the following: 
   1. The patient has a diagnosis of treatment-resistant depression (TRD); AND 
      1. The patient has a confirmed diagnosis of major depressive disorder (MDD) to include one of the following:
         1. Single-episode MDD and the duration has been ≥ 2 years; OR 
         2. Recurrent MDD without psychotic features; AND 
      2. In the current depressive episode, the patient has had an inadequate response (≤ 25% improvement) to at least two antidepressants from at least two different classes (different mechanisms of action) (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs], bupropion, mirtazapine) of adequate dose and duration (typically 6 weeks); OR 
   2. The patient has a diagnosis of major depressive disorder (MDD) with suicidal ideation or behavior; AND 
      1. The suicidal ideation and intent are imminent and warrant potential hospitalization; AND
      2. The patient is receiving esketamine nasal spray in conjunction with an oral antidepressant agent (i.e., esketamine will not be used as monotherapy); AND
3. At initiation of treatment with esketamine nasal spray, the patient has a depression symptom severity of ≥ 28 on the Montgomery-Asberg Depression Rating Scale (MADRS), or as scored by a comparable standardized rating scale that reliably measures depressive symptoms; AND
4. The patient will NOT receive esketamine nasal spray in combination with ketamine of any formulation or route of administration used for the same indication; AND
5. The patient does NOT have any clinical contraindications to esketamine nasal spray therapy (i.e., aneurysmal vascular disease or intracerebral hemorrhage); AND
6. The prescriber is a specialist in the area of the patient’s diagnosis (i.e., psychiatrist); AND
7. The prescribed dose of esketamine nasal spray will be administered under direct supervision of a healthcare professional at a treatment facility that is certified through the Spravato (esketamine) REMS program; AND
8. The requested dose is within FDA labeled dosing for the requested indication, and the requested quantity does NOT exceed the maximum units allowed for the duration of approval (see table below).

Duration of Approval: 90 days (3 months)

Continuation Criteria for Approval

1. The patient was approved through Blue Cross NC initial criteria for approval; OR 
2. The patient would have met initial criteria for approval at the time they started therapy; AND
3. ONE of the following:
   1. The patient has a diagnosis of treatment-resistant depression (TRD); OR
   2. The patient has a diagnosis of major depressive disorder (MDD) with suicidal ideation or behavior; AND
      1. The patient will continue therapy with an oral antidepressant agent in conjunction with esketamine nasal spray; AND
4. Using the MADRS scale or a comparable standardized rating scale that reliably measures depressive symptoms, the patient has demonstrated at least a 50% reduction in depressive symptoms compared to baseline while on esketamine nasal spray therapy; AND
5. The patient will NOT receive esketamine nasal spray in combination with ketamine of any formulation or route of administration used for the same indication; AND
6. The patient does NOT have any clinical contraindications to esketamine therapy (i.e., aneurysmal vascular disease or intracerebral hemorrhage); AND 
7. The prescriber is a specialist in the area of the patient’s diagnosis (i.e., psychiatrist) or has consulted with a specialist in the area of the patient’s diagnosis, AND
8. The prescribed dose of esketamine nasal spray will be administered under direct supervision of a healthcare professional at a treatment facility that is certified through the Spravato (esketamine) REMS program; AND
9. The requested dose is within FDA labeled dosing for the requested indication, and the requested quantity does NOT exceed the maximum units allowed for the duration of approval (see table below).

Duration of Approval: 180 days (6 months)

References

All information referenced is from FDA package insert unless otherwise noted below.

1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition, 2010. 
2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019 Sep;76(9):893-903. 
3. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428-438. 
4. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-17.

Policy Implementation/Update Information

Criteria and treatment protocols are reviewed annually by the Blue Cross NC P&T Committee, regardless of change. This policy is reviewed in Q2 annually.

January 2025: Criteria change: Expanded treatment-resistant depression (TRD) indication to allow for use as monotherapy according to updated FDA label.
October 2024: Criteria change: For treatment-resistant depression indication, adjusted requirement of inadequate response to at least two antidepressants to specify from at least two different drug classes (different mechanisms of action). Policy notification given 8/2/2024 for effective date 10/1/2024.
October 2023: Criteria change: Added requirement for no use in combination with ketamine of any formulation or route of administration used for the same indication within initial and continuation criteria sections. Added requirement within maximum units criteria that the requested dose is within FDA labeled dosing for the requested indication. Updated maximum units for clarity. Minor adjustments made to formatting throughout policy for clarity. Policy notification given 8/2/2023 for effective date 10/1/2023.
June 2021: Coding change: Added applicable HCPCS codes G2082 and G2083, and description of billing scenarios.
June 2021: Criteria change: Added maximum units; medical policy formatting change. Policy notification given 4/16/2021 for effective date 6/16/2021.
*Further historical criteria changes and updates available upon request from Medical Policy and/or Corporate Pharmacy.