Coverage Policy Manual
Policy #: 2019010
Category: Pharmacy
Initiated: October 2019
Last Review: November 2023
  Esketamine (e.g., SPRAVATO™)

Description:
Esketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Esketamine is the S-enantiomer of racemic ketamine. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.
 
Treatment-resistant depression refers to a major depressive episode with an inadequate response to at least two different antidepressants of adequate dosing and duration. Overall, approximately one in three individuals with depression are considered “treatment-resistant.” Individuals with TRD experience relapse at a higher rate than do those with treatment-responsive depression. Even when individuals with TRD respond to treatment, the overall relapse rate while continuing treatment with the same antidepressant is high after two and three failed trials of medication. Initial treatment may not work or may cause unacceptable side effects and switching to a different therapy is common. Since a trial of a therapy may require dose adjustments and six to 12 weeks to assess response, individuals may find it difficult to remain on therapy long enough for an adequate trial of the treatment, especially if there are side effects or symptoms that are incapacitating. For this reason, TRD can be difficult to define because it includes not only the number of unique treatments tried, but whether the trials were considered adequate.
 
Esketamine nasal spray has a black box warning because of 1) risk for sedation and dissociation after administration 2) potential for abuse and misuse. In order to mitigate these risks, it is available only through a restricted program called the SPRAVATO REMS. The essential features of this program include
• Esketamine nasal spray is only dispensed and administered to individuals in a medically supervised healthcare setting that monitors these individuals.
• Pharmacies and healthcare settings that dispense esketamine nasal spray are certified.
• Ensuring that each individual is informed about the serious adverse outcomes resulting from sedation and dissociation and need for monitoring.
• Enrollment of all individuals in a registry to further characterize the risks and support safe use
 
Evaluation of depression and response to treatment is accomplished utilizing a standard rating scale in order to survey the type and severity of symptoms. There are several standardized rating scales available including the following:
• Beck Depression Inventory (BDI)
• Hamilton Depression Rating Scale (HAM-D)
• Inventory of Depressive Symptomatology-Systems Review (IDS-SR)
• Montgomery-Asberg Depression Rating Scale (MADRS)
• Personal Health Questionnaire Depression Scale (PHQ-9)
• Quick Inventory of Depressive Symptomatology (QIDS)
 
A treatment session for use of esketamine nasal spray must ensure the following:
• Treatment is administered under the direct supervision of a healthcare provider.
• Blood pressure is assessed before and after treatment to ensure safety in accordance with the FDA label.
• Individual receiving treatment should be advised to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.
• Individual receiving treatment should be advised to avoid use of nasal corticosteroid or nasal decongestant one hour prior to treatment.
• Individual is monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the individual is considered clinically stable and ready to leave the healthcare setting.
 
Regulatory Status
 
Esketamine (e.g., SPRAVATO™) was approved by the U.S. Food and Drug Administration (FDA) on March 05, 2019 for the treatment of treatment-resistant depression in adults and on July 31, 2020 for the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior.
 
Coding
 
See CPT/HCPCS Code section below.

Policy/
Coverage:
Esketamine is not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage. This policy applies to members whose plan utilizes AR BCBS pharmacy and has esketamine as a formulary option.
 
Effective November 2023
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
INITIAL AUTHORIZATION FOR 28 DAYS
 
Esketamine meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of each indication when ALL the following conditions are met.
 
Treatment of severe depression in adults (FDA, Spravato, 1979 and 2019):
 
    1. Individual is 18 years of age or older; AND  
 
2. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode by a structured clinical interview for DSM-5 disorders (NIMH, 2017); AND
 
3. Individual’s current depressive episode is considered severe depression based on either of the following (NIMH, 2017; Canuso, 2018):
a. Montgomery-Asberg Depression Rating Scale (MADRS) 35 (see policy guidelines); OR
b. Hamilton Rating Scale for Depression (HAM-D) score 24 (see policy guidelines); OR
c. Other standardized clinician administered rating scale indicating severe depression.  
 
4. Individual meets the following (FDA Spravato, 2019; Canuso, 2018):
Recently (e.g., < 2 years) and/or currently has tried and had an inadequate response to three antidepressant agents   from 3 different antidepressant classes (i.e., selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:
a. The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; AND
b. Individual was 80% adherent to the agent during the trial; AND
 
5. Individual will receive esketamine nasal spray in conjunction with an oral antidepressant that is different from previous therapies (FDA Spravato, 2019; Canuso, 2018);  AND
 
6. Individual does not have current substance use disorder unless in remission (complete abstinence for a month, with a negative drug and alcohol screen) (Canuso, 2018); AND
 
7. Individual does NOT have any Food and Drug Administration (FDA) labeled contraindications to the requested agent (FDA Spravato, 2019):
a. Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
b. Intracerebral hemorrhage.
c. Hypersensitivity to esketamine, ketamine, or any of the excipients; AND
 
8. Esketamine nasal spray is intended to be used consistently with the FDA approved label including meeting Spravato Risk Evaluation and Mitigation Strategy (REMS) program requirements; AND
 
9. The prescriber is a physician specialist in the area of the individual’s diagnosis (e.g., psychiatrist); AND
 
10. Must be dosed in accordance with the FDA label.
 
REAUTHORIZATION for 3 months, with review then reauthorized annually
 
Esketamine nasal spray may be reauthorized for up to 3 months, with review. May then be approved annually if ALL the following conditions are met (FDA Spravato, 2019; Canuso, 2018):
 
    1. Individual has had improvement in depression symptoms as evaluated with an appropriate depression rating scale (e.g., Patient Health Questionnaire 9, Clinically Useful Depression Outcome Scale, Quick Inventory of Depressive SymptomatologySelf Report 16 Item, MADRS, HAMD); AND
 
2. Individual is to receive esketamine nasal spray in conjunction with an oral antidepressant; AND
 
3. Individual does not have current substance use disorder (with a negative drug and alcohol screen); AND
 
4. Individual does NOT develop any FDA labeled contraindications to the requested agent and esketamine nasal spray is intended to be used consistently with the FDA approved label (see policy guidelines) including meeting Spravato REMS program requirements.
 
Treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior:
 
AUTHORIZATION FOR 28 DAYS FROM THE START OF THERAPY
 
    1. Individual is 18 years of age or older; AND
 
2. Individual has a diagnosis of major depressive disorder; AND
 
3. Esketamine was initiated in the Emergency Department or inpatient facility upon diagnosis of major depressive disorder with acute suicidal ideation or behavior (documentation submitted); AND
 
4. Individual will receive esketamine nasal spray in conjunction with a new oral antidepressant or optimizing the current regimen; AND
 
5. Individual does not have current substance use disorder unless in remission (complete abstinence for a month, with a negative drug and alcohol screen; AND
 
6. Individual does NOT have any Food and Drug Administration (FDA) labeled contraindications to the requested agent:
a. Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation
b. Intracerebral hemorrhage  
c. Hypersensitivity to esketamine, ketamine, or any of the excipients; AND
 
7. Esketamine nasal spray is intended to be used consistently with the FDA approved label including meeting Spravato Risk Evaluation and Mitigation Strategy (REMS) program requirements; AND
 
8. The prescriber is a physician specialist in the area of the individual’s diagnosis (e.g., psychiatrist); AND
 
9. Must be dosed in accordance with the FDA label.
 
*Montgomery-Asberg Depression Rating Scale (MADRS)
MADRS is commonly used to evaluate the efficacy of antidepressant by assessing the severity of depression.  It contains 10 items and the total score ranges from 0 to 60.  The following cut-offs were proposed to classify the level of depression severity:
    • 0-6:  No depression (absence of symptoms)
    • 7-19: Mild depression
    • 20-34: Moderate depression
    • 35-62: Severe depression
 
** Hamilton Rating Scale for Depression (HAM-D)
HAM-D is a 17-item rating scale to determine the severity level of depression in an individual before, during and after treatment.  The total score ranges from 0 to 52, with the score corresponding to the following classifications:
    • 0-7 No depression (normal)
    • 8-16: Mild depression
    • 17-23: Moderate depression
    • > 24: Severe depression
 
Dosage and Administration
Dosing per FDA Guidelines
 
Esketamine must be administered under the direct supervision of a healthcare provider. Each treatment session consists of nasal administration of Esketamine and a 2-hour post-administration observation under supervision.  
 
Recommended Dosage for Esketamine in Treatment Resistance Depression:
 
Induction Phase         Weeks 1 – 4: Administer twice per week      Starting dose: 56mg
                                                                                                   Subsequent doses: 56mg or 84mg
 
Maintenance Phase   Weeks 5 – 8: Administer once weekly           56mg or 84mg
 
                                    Week 9 and after: Administer every             56mg or 84mg
                                    2 weeks or once weekly*
 
*Dosing frequency should be individualized to the least frequent dosing to maintain remission/response.
   
Recommended Dosage of Esketamine in Depressive Symptoms in Individuals with Major Depressive disorder with Acute Suicidal Ideation or Behavior:
 
84 mg twice per week for 4 weeks. Dosage may be reduced to 56mg twice per week based on tolerability.
 
Esketamine is available in nasal spray with 28 mg per device. Each nasal spray device delivers two  containing a total of 28 mg of esketamine.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Esketamine, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Esketamine, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 2020 to October 2023
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
Esketamine meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of each indication when ALL of the following conditions are met.
 
Treatment of severe depression in adults (FDA, Spravato, 1979 and 2019):
 
INITIAL AUTHORIZATION FOR 28 DAYS
 
1. Individual is 18 years of age or older AND
 
2. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode by a structured clinical interview for DSM-5 disorders (NIMH, 2017) AND
 
3. Individual’s current depressive episode is considered severe depression based on either of the following (NIMH, 2017; Canuso, 2018):
a. Montgomery-Asberg Depression Rating Scale (MADRS) 35 (see policy guidelines) OR
b. Hamilton Rating Scale for Depression (HAM-D) score 24 (see policy guidelines) OR
c. Other standardized clinician administered rating scale indicating severe depression.  
 
4. Individual meets the following (FDA Spravato, 2019; Canuso, 2018):
Recently (e.g. <2 yrs) and/or currently has tried and had an inadequate response to three antidepressant agents from 3 different antidepressant classes (i.e. selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:
a. The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; AND
b. Individual was 80% adherent to the agent during the trial;
 
5. Individual will receive esketamine nasal spray in conjunction with an oral antidepressant that is different from previous therapies (FDA Spravato, 2019; Canuso, 2018);  AND
 
6. Individual does not have current substance use disorder unless in remission (complete abstinence for a month, with a negative drug and alcohol screen) (Canuso, 2018); AND
 
7. Individual does NOT have any Food and Drug Administration (FDA) labeled contraindications to the requested agent (FDA Spravato, 2019):
      • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
      • Intracerebral hemorrhage.  
      • Hypersensitivity to esketamine, ketamine, or any of the excipients AND
 
8.  Esketamine nasal spray is intended to be used consistently with the FDA approved label including meeting Spravato Risk Evaluation and Mitigation Strategy (REMS) program requirements AND
 
9. The prescriber is a physician specialist in the area of the patient’s diagnosis (e.g. psychiatrist).
 
REAUTHORIZATION for 3 months, with review then reauthorized annually
 
Esketamine nasal spray may be reauthorized for up to 3 months, with review.  May then be approved annually if all of the following conditions are met (FDA Spravato, 2019; Canuso, 2018):
 
1. Individual has had improvement in depression symptoms as evaluated with an appropriate depression rating scale (e.g. Patient Health Questionnaire 9, Clinically Useful Depression Outcome Scale, Quick Inventory of Depressive SymptomatologySelf Report 16 Item, MADRS, HAMD) AND
 
2. Individual is to receive esketamine nasal spray in conjunction with an oral antidepressant AND
 
3. Individual does not have current substance use disorder (with a negative drug and alcohol screen) AND
 
4. Individual does NOT develop any FDA labeled contraindications to the requested agent and esketamine nasal spray is intended to be used consistently with the FDA approved label (see policy guidelines) including meeting Spravato REMS program requirements.
 
Treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior:
 
AUTHORIZATION FOR 28 DAYS FROM THE START OF THERAPY
 
    1. Individual is 18 years of age or older AND
 
2. Individual has a diagnosis of major depressive disorder AND
 
3. Esketamine was initiated in the Emergency Department or inpatient facility upon diagnosis of major depressive disorder with acute suicidal ideation or behavior (documentation submitted) AND
 
4. Individual will receive esketamine nasal spray in conjunction with a new oral antidepressant or optimizing the current regimen AND
 
5. Individual does not have current substance use disorder unless in remission (complete abstinence for a month, with a negative drug and alcohol screen AND
 
6. Individual does NOT have any Food and Drug Administration (FDA) labeled contraindications to the requested agent:
      • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation
      • Intracerebral hemorrhage  
      • Hypersensitivity to esketamine, ketamine, or any of the excipients AND
 
7. Esketamine nasal spray is intended to be used consistently with the FDA approved label including meeting Spravato Risk Evaluation and Mitigation Strategy (REMS) program requirements AND
 
8. The prescriber is a physician specialist in the area of the patient’s diagnosis (e.g. psychiatrist).
 
*Montgomery-Asberg Depression Rating Scale (MADRS)
MADRS is commonly used to evaluate the efficacy of antidepressant by assessing the severity of depression.  It contains 10 items and the total score ranges from 0 to 60.  The following cut-offs were proposed to classify the level of depression severity:
    • 0-6:  No depression (absence of symptoms)
    • 7-19: Mild depression
    • 20-34: Moderate depression
    • 35-62: Severe depression
 
** Hamilton Rating Scale for Depression (HAM-D)
HAM-D is a 17-item rating scale to determine the severity level of depression in a patient before, during and after treatment.  The total score ranges from 0 to 52, with the score corresponding to the following classifications:
    • 0-7 No depression (normal)
    • 8-16: Mild depression
    • 17-23: Moderate depression
    • >24: Severe depression
 
Dosage and Administration
 
Esketamine must be administered under the direct supervision of a healthcare provider. Each treatment session consists of nasal administration of Esketamine and a 2-hour post-administration observation under supervision.  
 
Recommended Dosage for Esketamine in Treatment Resistance Depression:
 
Induction Phase           Weeks 1 – 4: Administer twice per week      Starting dose: 56mg
                                                                                                     Subsequent doses:
                                                                                                      56mg or 84mg
 
Maintenance Phase     Weeks 5 – 8: Administer once weekly          56mg or 84mg
 
                                      Week 9 and after: Administer every              56mg or 84mg
                                       2 weeks or once weekly*
 
*Dosing frequency should be individualized to the least frequent dosing to maintain remission/response.
   
Recommended Dosage of Esketamine in Depressive Symptoms in Patients with Major Depressive disorder with Acute Suicidal Ideation or Behavior:
84 mg twice per week for 4 weeks. Dosage may be reduced to 56mg twice per week based on tolerability.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Esketamine does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than severe depression.  
 
For members with contracts without primary coverage criteria, Esketamine is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective April 2020 to October 2020
 
The use of esketamine is not covered under the medical benefit.  
 
The use of esketamine is addressed under the pharmacy benefit using the following criteria:
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
Esketamine meets primary coverage criteria that there be scientific evidence of effectiveness for the treatment of severe depression in adults when ALL of the following conditions are met.
 
INITIAL AUTHORIZATION FOR 28 DAYS
 
1. Individual is 18 years of age or older AND
 
2. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode by a structured clinical interview for DSM-5 disorders. AND
 
3. Individual’s current depressive episode is considered severe depression based on either of the following:
a. Montgomery-Asberg Depression Rating Scale (MADRS) 35 (see policy guidelines) OR
b. Hamilton Rating Scale for Depression (HAM-D) score 24 (see policy guidelines) OR
c. Other standardized clinician administered rating scale indicating severe depression.  
 
4. Individual meets the following:
Recently (e.g. <2 yrs) and/or currently has tried and had an inadequate response to three antidepressant agents from 3 different antidepressant classes (i.e. selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:
a. The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; AND
b. Individual was 80% adherent to the agent during the trial;
 
5. Individual will receive esketamine nasal spray in conjunction with an oral antidepressant that is different from previous therapies. AND
 
6. Individual does not have current substance use disorder unless in remission (complete abstinence for a month, with a negative drug and alcohol screen). AND
 
7. Individual does NOT have any Food and Drug Administration (FDA) labeled contraindications to the requested agent:
    • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
    • Intracerebral hemorrhage.  
    • Hypersensitivity to esketamine, ketamine, or any of the excipients.  
 
8.  Esketamine nasal spray is intended to be used consistently with the FDA approved label including meeting Spravato Risk Evaluation and Mitigation Strategy (REMS) program requirements AND
 
9. The prescriber is a physician specialist in the area of the patient’s diagnosis (e.g. psychiatrist).
 
REAUTHORIZATION for 3 months, with review then reauthorized annually
 
Esketamine nasal spray may be reauthorized for up to 3 months, with review.  May then be approved annually if all of the following conditions are met:
 
1. Individual has had improvement in depression symptoms as evaluated with an appropriate depression rating scale (e.g. Patient Health Questionnaire 9, Clinically Useful Depression Outcome Scale, Quick Inventory of Depressive SymptomatologySelf Report 16 Item, MADRS, HAMD).
 
2. Individual is to receive esketamine nasal spray in conjunction with an oral antidepressant.
 
3. Individual does not have current substance use disorder (with a negative drug and alcohol screen).
 
4. Individual does NOT develop any FDA labeled contraindications to the requested agent and esketamine nasal spray is intended to be used consistently with the FDA approved label (see policy guidelines) including meeting Spravato REMS program requirements.
 
*Montgomery-Asberg Depression Rating Scale (MADRS)
MADRS is commonly used to evaluate the efficacy of antidepressant by assessing the severity of depression.  It contains 10 items and the total score ranges from 0 to 60.  The following cut-offs were proposed to classify the level of depression severity:
    • 0-6:  No depression (absence of symptoms)
    • 7-19: Mild depression
    • 20-34: Moderate depression
    • 35-62: Severe depression
 
** Hamilton Rating Scale for Depression (HAM-D)
HAM-D is a 17-item rating scale to determine the severity level of depression in a patient before, during and after treatment.  The total score ranges from 0 to 52, with the score corresponding to the following classifications:
    • 0-7 No depression (normal)
    • 8-16: Mild depression
    • 17-23: Moderate depression
    • >24: Severe depression
 
Dosage and Administration
 
Esketamine must be administered under the direct supervision of a healthcare provider. Each treatment session consists of nasal administration of Esketamine and a 2-hour post-administration observation under supervision.  
 
Recommended Dosage for Esketamine
 
Induction Phase           Weeks 1 – 4: Administer twice per week      Starting dose: 56mg
                                                                                                             Subsequent doses:
                                                                                                             56mg or 84mg
 
Maintenance Phase     Weeks 5 – 8: Administer once weekly          56mg or 84mg
 
                                      Week 9 and after: Administer every              56mg or 84mg
                                       2 weeks or once weekly*
 
*Dosing frequency should be individualized to the least frequent dosing to maintain remission/response.
   
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Esketamine does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than severe depression.  
 
For members with contracts without primary coverage criteria, esketamine is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective October 2019 to March 2020
 
The use of esketamine is not covered under the medical benefit.  
 
The use of esketamine is addressed under the pharmacy benefit using the following criteria:
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
Esketamine meets primary coverage criteria that there be scientific evidence of effectiveness for the treatment of severe depression in adults when ALL of the following conditions are met.
 
INITIAL AUTHORIZATION FOR 28 DAYS
 
1. Individual is 18 years of age or older AND
 
2. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode by a structured clinical interview for DSM-5 disorders. AND
 
3. Individual’s current depressive episode is considered severe depression based on either of the following:
a. Montgomery-Asberg Depression Rating Scale (MADRS) 35 (see policy guidelines) OR
b. Hamilton Rating Scale for Depression (HAM-D) score 24 (see policy guidelines) OR
c. Other standardized clinician administered rating scale indicating severe depression.  
 
4. Individual meets the following:
Has tried and had an inadequate response to three antidepressant agents from 3 different antidepressant classes (i.e. selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:
a. The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; AND
b. Individual was 80% adherent to the agent during the trial;
 
5. Individual will receive esketamine nasal spray in conjunction with an oral antidepressant that is different from previous therapies. AND
 
6. Individual does not have current substance use disorder unless in remission (complete abstinence for a month, with a negative drug and alcohol screen). AND
 
7. Individual does NOT have any Food and Drug Administration (FDA) labeled contraindications to the requested agent:
    • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
    • Intracerebral hemorrhage.  
    • Hypersensitivity to esketamine, ketamine, or any of the excipients.  
 
8.  Esketamine nasal spray is intended to be used consistently with the FDA approved label including meeting Spravato Risk Evaluation and Mitigation Strategy (REMS) program requirements AND
 
9. The prescriber is a physician specialist in the area of the patient’s diagnosis (e.g. psychiatrist).
 
REAUTHORIZATION for 3 months, with review then reauthorized annually
 
Esketamine nasal spray may be reauthorized for up to 3 months, with review.  May then be approved annually if all of the following conditions are met:
 
1. Individual has had improvement in depression symptoms as evaluated with an appropriate depression rating scale (e.g. Patient Health Questionnaire 9, Clinically Useful Depression Outcome Scale, Quick Inventory of Depressive SymptomatologySelf Report 16 Item, MADRS, HAMD).
 
2. Individual is to receive esketamine nasal spray in conjunction with an oral antidepressant.
 
3. Individual does not have current substance use disorder (with a negative drug and alcohol screen).
 
4. Individual does NOT develop any FDA labeled contraindications to the requested agent and esketamine nasal spray is intended to be used consistently with the FDA approved label (see policy guidelines) including meeting Spravato REMS program requirements.
*Montgomery-Asberg Depression Rating Scale (MADRS)
MADRS is commonly used to evaluate the efficacy of antidepressant by assessing the severity of depression.  It contains 10 items and the total score ranges from 0 to 60.  The following cut-offs were proposed to classify the level of depression severity:
    • 0-6:  No depression (absence of symptoms)
    • 7-19: Mild depression
    • 20-34: Moderate depression
    • 35-62: Severe depression
 
** Hamilton Rating Scale for Depression (HAM-D)
HAM-D is a 17-item rating scale to determine the severity level of depression in a patient before, during and after treatment.  The total score ranges from 0 to 52, with the score corresponding to the following classifications:
    • 0-7 No depression (normal)
    • 8-16: Mild depression
    • 17-23: Moderate depression
    • >24: Severe depression
 
Dosage and Administration
Esketamine must be administered under the direct supervision of a healthcare provider. Each treatment session consists of nasal administration of Esketamine and a 2-hour post-administration observation under supervision.  
 
Recommended Dosage for Esketamine
 
Induction Phase           Weeks 1 – 4: Administer twice per week      Starting dose: 56mg
                                                                                                             Subsequent doses:
                                                                                                             56mg or 84mg
 
Maintenance Phase     Weeks 5 – 8: Administer once weekly          56mg or 84mg
 
                                      Week 9 and after: Administer every              56mg or 84mg
                                       2 weeks or once weekly*
 
*Dosing frequency should be individualized to the least frequent dosing to maintain remission/response.
   
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Esketamine does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than severe depression.  
 
For members with contracts without primary coverage criteria, esketamine is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
SPRAVATO™ was evaluated in two different studies, a short term and long term. SPRAVATO™ was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week), Phase 3 study (Study 1; NCT02418585) in adult patients 18 to <65 years old with treatment-resistant depression (TRD). Patients in Study 1 met DSM-5 criteria for major depressive disorder (MDD) and in the current depressive episode, had not responded adequately to at least two different antidepressants of adequate dose and duration. After discontinuing prior antidepressant treatments, patients in Study 1 were randomized to receive twice weekly doses of intranasal SPRAVATO™ (flexible dose; 56 mg or 84 mg) or intranasal placebo. All patients also received open-label concomitant treatment with a newly initiated daily oral antidepressant (AD) (duloxetine, escitalopram, sertraline, or extended-release venlafaxine as determined by the investigator based on patient’s prior treatment history). SPRAVATO™ could be titrated up to 84 mg starting with the second dose based on investigator discretion.
 
The demographic and baseline disease characteristics of patients in Study 1 were similar for the SPRAVATO™ and placebo nasal spray groups. Patients had a median age of 47 years (range 19 to 64 years) and were 62% female, 93% Caucasian, and 5% Black. The newly initiated oral AD was an SSRI in 32% of patients and an SNRI in 68% of patients.
 
In Study 1, the primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of the 4-week double-blind induction phase. The MADRS is a ten-item, clinician rated scale used to assess severity of depressive symptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression. SPRAVATO™ plus a newly initiated oral AD demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus a newly initiated oral AD (see Table 8). Most of SPRAVATO™’s treatment difference compared to placebo was observed at 24 hours. Between 24 hours and Day 28, both the SPRAVATO™ and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 28. At Day 28, 67% of the patients randomized to SPRAVATO™ were receiving 84 mg twice weekly.
 
Study 2 (NCT02493868) was a long-term randomized, double-blind, parallel-group, multicenter maintenance-of-effect study in adults 18 to <65 years of age who were known remitters and responders to SPRAVATO™. Patients in this study were responders in one of two short-term controlled trials (Study 1 and another 4-week study) or in an open-label direct-enrollment study in which they received flexibly dosed SPRAVATO™ (56 mg or 84 mg twice weekly) plus daily oral AD in an initial 4-week phase. Stable remission was defined as a MADRS total score ≤ 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction ≥ 50% for the last 2 weeks of optimization and not in remission. After at least 16 initial weeks of treatment with SPRAVATO™ and an oral AD, stable remitters and stable responders were randomized separately to continue intranasal treatment with SPRAVATO™ or switch to placebo nasal spray, in both cases with continuation of their oral AD. The primary study endpoint was time to relapse in the stable remitter group. Relapse was defined as a MADRS total score ≥22 for 2 consecutive weeks or hospitalization for worsening depression or any other clinically relevant event indicative of relapse.
 
The demographic and baseline disease characteristics of the two groups were similar. Patients had a median age of 48 years (range 19 to 64 years) and were 66% female, 90% Caucasian, and 4% Black. Patients in stable remission who continued treatment with SPRAVATO™ plus oral AD experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on placebo nasal spray plus an oral AD. Time to relapse was also significantly delayed in the stable responder population.
 
These patients experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus oral AD. In Study 2, based on depressive symptomatology, the majority of stable remitters (69%) received every-other-week dosing for the majority of time during the maintenance phase; 23% of stable remitters received weekly dosing. Among stable responders, 34% received every-other-week dosing and 55% received weekly dosing the majority of time during the maintenance phase. Of the patients randomized to SPRAVATO™, 39% received the 56 mg dose and 61% received the 84 mg dose.
 
November 2020 Update
SPRAVATO was evaluated in two identical Phase 3 short-term (4-week) randomized, double-blind, multicenter, placebo-controlled studies, Study 3 (NCT03039192) and Study 4 (NCT03097133), in adults with moderate-to-severe MDD (MADRS total score >28) who had active suicidal ideation and intent. In these studies, patients received treatment with SPRAVATO 84 mg or placebo nasal spray twice weekly for 4 weeks. After the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (AD) (AD monotherapy or AD plus augmentation therapy) as determined by the investigator. After completion of the 4-week treatment period with SPRAVATO/placebo, study follow-up continued through Day 90.
 
The baseline demographic and disease characteristics of patients in Study 3 and Study 4 were similar between the SPRAVATO plus standard of care or placebo nasal spray plus standard of care treatment groups. The median patient age was 40 years (range 18 to 64 years), 61% were female; 73% Caucasian and 6% Black; and 63% of patients had at least one prior suicide attempt. Prior to entering the study, 92% of the patients were receiving antidepressant therapy. During the study, as part of standard of care treatment, 40% of patients received AD monotherapy, 54% of patients received AD plus augmentation therapy, and 6% received both AD monotherapy/AD plus augmentation therapy.
 
The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after first dose (Day 2). In Study 3 and Study 4, SPRAVATO plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care. The secondary efficacy measure was the change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) score at 24 hours after first dose (Day 2). The CGI-SS-r is a one-item, clinician-rated assessment used to rate the current severity of a patient’s suicidal ideation and behavior. Scores on the CGI-SS-r range from 0 to 6, with higher scores indicating more severe suicidal ideation and behavior. In Study 3 and Study 4, SPRAVATO plus standard of care did not demonstrate superiority compared to placebo nasal spray plus standard of care in improving CGI-SS-r.
 
In both Study 3 and Study 4, SPRAVATO’s treatment difference compared to placebo was observed starting at 4 hours. Between 4 hours and Day 25, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 25. (SPRAVATO, 2020)
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures.
 
Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments.
 
In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Reif A, Bitter I, Buyze J, et.al., 2023)

CPT/HCPCS:
S0013Esketamine, nasal spray, 1 mg

References: • “Esketamine for Treatment-Resistant Major Depressive Disorder. Effectiveness and Value. Draft Background and Scope.” ICER, 2018. Accessed March 2019. Available at: https://icer-review.org/wpcontent/uploads/2018/10/TRD-Draft-Scope-FOR-PUBLICATION-10.31.pdf

• Canuso CM, Singh JB, Fedgchin M, et al(2018) Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018;175:620-630.

• Fu DJ, Ionescu DF, Li X, et al.(2020) 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). AM J Psychiatry 2020;81:3

• National Institute of Mental Health. Major Depression-Data Sources. 2017; • National Institute of Mental Health. Major Depression-Data Sources. 2017;

Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu DJ, Ito T, Kambarov Y, Llorca PM, Oliveira-Maia AJ, Messer T, Mulhern-Haughey S, Rive B, von Holt C, Young AH, Godinov Y; ESCAPE-TRD Investigators.(2023) Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med. 2023 Oct 5;389(14):1298-1309. doi: 10.1056/NEJMoa2304145. PMID: 37792613.


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