This policy version was replaced June 5, 2023. To find the newest version, go to https://www.bluecrossmn.com/providers/medical-policy-and-utilization-management, read and accept the Blue Cross Medical Policy Statement, then select “Blue Cross and Blue Shield of Minnesota Medical Policies.” This will bring up the Medical Policy search screen. Enter the policy number without the version number (last 3 digits).

Esketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist.  Esketamine is administered intranasally (nasal spray) under the supervision of a health care provider.

The U.S. Food and Drug Administration (FDA) has approved esketamine (Spravato™), in conjunction with an oral antidepressant, for the following indications:

• Treatment of treatment resistant depression (TRD) in adults. 
• Treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

Treatment resistant depression (TRD) is a form of major depressive disorder in which a patient’s depressive episodes have not responded satisfactorily to antidepressant therapy, including four trials from at least two different classes of medications. 

Serious adverse reactions have occurred in patients receiving esketamine, including dissociation, sedation, abuse and misuse, and suicidal thoughts and behaviors. Due to these safety concerns, the FDA regulates esketamine through a restricted distribution program under a risk evaluation and mitigation strategy (REMS) called the SPRAVATO™ REMS program. Under the SPRAVATO™ REMS, only certified providers can dispense and administer esketamine. The prescribing information for esketamine also includes a black box warning. Health care providers should consider the risks and benefits of prescribing prior to treatment of patients at higher risk of abuse, and should continue to monitor patients for signs and symptoms of abuse and misuse.

Definitions:

An augmentation trial in pharmacological management of psychiatric conditions refers to the concurrent use of an antidepressant and an additional drug as an adjunctive agent.

I.    Initial Review for Esketamine (Spravato™)

Esketamine may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Age 18 years or older; AND
• Diagnosis of major depressive disorder (MDD); AND 
• Documentation from standardized rating scales that reliably measure depressive symptoms (e.g., Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, or PHQ-9); AND
• ONE of the following:
  • Treatment resistant depression (TRD) AND ONE of the following:
    • Inadequate response to three or more trials of antidepressants from at least two different therapeutic classes (e.g. selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs]), including at least one failed trial of augmentation, in the current depressive episode; OR
    • Documented intolerance, FDA labeled contraindication, or hypersensitivity to four or more antidepressants from at least two different therapeutic classes; 
  • OR
  • Acute suicidal ideation or behavior;
• AND
• Esketamine will be used in combination with an oral antidepressant; AND
• Esketamine will not be used in combination with other ketamine products; AND
• Prescribed by or in consultation with a psychiatrist; AND
• No FDA labeled contraindications to esketamine (see table 1 below); AND
• The dose is within the FDA labeled dose (see table 2 below).

II.   Renewal Review for Esketamine (Spravato™) for Treatment Resistant Depression (TRD)

Esketamine may be considered MEDICALLY NECESSARY AND APPROPRIATE for TRD when ALL of the following criteria are met:

• Previously approved for esketamine through the initial review process; AND
• Continued positive clinical response to esketamine (e.g. > 50% reduction in PHQ-9 score from baseline); AND
• Esketamine will be used in combination with an oral antidepressant; AND
• Esketamine will not be used in combination with other ketamine products; AND
• Prescribed by or in consultation with a psychiatrist; AND
• No FDA labeled contraindications to esketamine (see table 1 below); AND
• The dose is within the FDA labeled dose for the indication (see table 2 below).

III.    Renewal Review for Esketamine (Spravato™) for Major Depressive Disorder (MDD) with Acute Suicidal Ideation or Behavior

• Renewal of esketamine for treatment for MDD with acute suicidal ideation or behavior is considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes.
• Note: If depressive symptoms associated with major depressive disorder (MDD) with acute suicidal ideation or behavior have not been successfully treated in 4 weeks, esketamine may be considered for treatment resistant depression (TRD) after trials of other therapies. (See criteria in Section I)

IV.    Experimental/Investigative Uses

All other uses of esketamine are considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

Table 1. FDA Labeled Contraindications

Table 2. Dosing

NOTE: See documentation submission requirements below if the requested dose is higher or more frequent than the dosing criteria provided in this table.

Documentation Submission:

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization, when prior authorization is required. In addition, the following documentation must also be submitted:

Initial Review

1. Clinical notes describing the diagnosis and clinical features of the diagnosis.
2. If being prescribed for treatment resistant depression, documentation of failed medication trials including the drug, dosage, duration, and reason for discontinuation.
   
3. The dose being requested. If the requested dose is higher or more frequent than the dosing guidelines provided in the table above, a clear explanation for the medical necessity of the requested dose MUST be submitted, including prior dosing (strength and frequency) associated with inadequate response.

Renewal Review

1. Documentation of prior approval for the requested agent through the initial review process.
2. Documentation, since most recent approval, supporting continued positive clinical response.
3. The dose being requested. If the requested dose is higher or more frequent than the dosing guidelines provided in the table above, a clear explanation for the medical necessity of the requested dose MUST be submitted, including prior dosing (strength and frequency) associated with inadequate response.