Study 1 was a randomized, placebo-controlled, double-blind, multicenter, 4-week phase 3 study 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 (esketamine) (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 (esketamine) could be titrated up to 84 mg starting with the second dose based on investigator discretion. 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. Spravato (esketamine) 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. The mean difference in the MADRS score between the 2 treatment groups is 4 (95 CI -7.3 -; -0.6 p = 0.020).

Study 2 was a long-term randomized, double-blind, parallel-group multicenter maintenance-of-effect study of adults 18 to less than 65 years old who were known remitters and responders of Spravato (esketamine). Stable remission was defined as a MADRS total score of at no more than 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction of at least 50% for at least 3 of the last 4 weeks and not in remission. After at least 16 initial weeks of treatment with Spravato (esketamine) and an oral AD, stable remitters and stable responders were randomized separately to continue intranasal treatment with Spravato (esketamine) or switch to placebo nasal spray while continuing their oral AD. The primary endpoint was time to relapse in the stable remitter (defined as a MADRS total score of at least 22 for 2 consecutive weeks or hospitalization for worsening depression or any other clinically relevant event indicative of relapse). Patients in stable remission who continued treatment with Spravato (esketamine) plus oral AD experienced a statistically significant longer time to relapse of depressive symptoms than did patients on placebo nasal spray plus an oral AD (median time to relapse: Spravato (esketamine) + AD = not estimable, placebo + AD = 273 days; P = 0.003). The same was seen in stable responders who continued treatment with Spravato (esketamine) plus oral AD (median time to relapse: Spravato (esketamine) + AD = 635 days, placebo + AD = 88 days, p < 0.001). Treatment with Spravato (esketamine) + AD decreased the risk of relapse by 51% among stable remitters (HR 0.49 95% CI 0.29 – 0.84) and by 70% among stable responders (HR 0.30 CI 0.16 – 0.55).

The most commonly observed adverse reactions in adult patients with TRD treated with Spravato (esketamine) were dizziness, nausea, sedation, vomiting, and feeling drunk.

On August 3, 2020, Janssen announced that the FDA approved Spravato (esketamine) nasal spray to be taken with an oral antidepressant for the treatment of major depressive disorder (MDD) with acute suicidal ideation or behavior. Spravato (esketamine) was evaluated in two identical Phase 3 short-term (4-week) randomized, double-blind, multicenter, placebo-controlled studies, ASPIRE I (NCT03039192) and ASPIRE II (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 (esketamine) 84 mg or placebo nasal spray twice weekly for 4 weeks. After the first dose, a one-time dose reduction to Spravato (esketamine) 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, study follow-up continued through Day 90. 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). Spravato (esketamine) plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care. Spravato plus standard of care was shown to reduce depressive symptoms within 24 hours in patients as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). Patients in the treatment arm of the two studies recorded a 15.9 and 16.0 point decrease in the severity of symptoms, compared with reductions of 12.0 and 12.2 points, respectively, in the placebo plus standard of care groups. Spravato has a different mechanism of action than other approved treatments for MDD as a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. It is a Class III substance and is only available through the Spravato Risk Evaluation and Mitigation Strategy (REMS) program.

As per the FDA approved package insert, Spravato (esketamine) carries the following boxed warnings:

● Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration.
● Potential for abuse and misuse. Consider the risks and benefits of prescribing Spravato (esketamine) prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse.
● Spravato is only available through a restricted program called the Spravato (esketamine) REMS due to serious risk of sedation, dissociation, and abuse/misuse
● Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors.

1. Spravato (esketamine) is considered medically necessary for the treatment of treatment-resistant depression (TRD) when ALL of the following are met:
a. Member is at least 18 years old
b. Member must meet the DSM-5 diagnostic criteria for
i. single-episode major depressive disorder (MDD) with the duration of greater than or equal to 2 years; OR
ii. recurrent MDD without psychotic features
c. Member must have had an inadequate response to at least 2 oral antidepressant treatments taken at adequate dosage and for adequate duration which is defined as the following:
i. The trial length was at least 6 weeks at generally accepted doses; AND
ii. The patient was ≥80% adherent to the agent during the trial;
d. Member must have depression symptom severity of at least 28 on the MADRS rating scale
e. Member must be taking Spravato (esketamine) in conjunction with an oral antidepressant. Spravato (esketamine) is not to be used as monotherapy.
f. Member must not have any contraindications to Spravato (esketamine) (i.e. aneurysmal vascular disease or intracerebral hemorrhage)
g. Member is not at risk for abuse and/or misuse
h. Spravato is to be administered under direct supervision of a healthcare professional only in setting with adequate patient monitoring facilities
i. Provider, patient, and facility must be enrolled in the Spravato (esketamine) REMS program
j. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. psychiatrist) or has consulted with a specialist in the area of the patient’s diagnosis

- Members with psychotic disorder or MDD with psychosis, bipolar or related disorders, obsessive compulsive disorder, and intellectual disability or with a history of moderate or severe substance /alcohol use disorder were excluded from clinical trials.
- Spravato (esketamine) may cause fetal harm. Consider pregnancy planning and prevention in females of reproductive potential.
- Spravato has the potential to be abused and misused. Consider the risks and benefits of prescribing Spravato (esketamine)prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse.
- Because of the risks of serious adverse outcomes resulting from sedation, dissociation, and abuse and misuse, Spravato (esketamine) is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Spravato (esketamine) REMS

The MADRS (Montgomery-asberg Depression Rating Scale) is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.
o Apparent sadness
§ 0 = No sadness.
§ 2 = Looks dispirited but does brighten up without difficulty.
§ 4 = Appears sad and unhappy most of the time.
§ 6 = Looks miserable all the time. Extremely despondent
o Reported sadness
§ 0 = Occasional sadness in keeping with the circumstances.
§ 2 = Sad or low but brightens up without difficulty.
§ 4 = Pervasive feelings of sadness or gloominess. The mood is still influenced by external circumstances.
§ 6 = Continuous or unvarying sadness, misery or despondency.
o Inner tension
§ 0 = Placid. Only fleeting inner tension.
§ 2 = Occasional feelings of edginess and ill-defined discomfort.
§ 4 = Continuous feelings of inner tension or intermittent panic which the patient can only master with some difficulty.
§ 6 = Unrelenting dread or anguish. Overwhelming panic.
o Reduced sleep
§ 0 = Sleeps as normal.
§ 2 = Slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep.
§ 4 = Moderate stiffness and resistance
§ 6 = Sleep reduced or broken by at least 2 hours.
o Reduced appetite
§ 0 = Normal or increased appetite.
§ 2 = Slightly reduced appetite.
§ 4 = No appetite. Food is tasteless.
§ 6 = Needs persuasion to eat at all.
o Concentration difficulties
§ 0 = No difficulties in concentrating.
§ 2 = Occasional difficulties in collecting one's thoughts.
§ 4 = Difficulties in concentrating and sustaining thought which reduced ability to read or hold a conversation.
§ 6 = Unable to read or converse without great difficulty.
o Lassitude
§ 0 = Hardly any difficulty in getting started. No sluggishness.
§ 2 = Difficulties in starting activities.
§ 4 = Difficulties in starting simple routine activities which are carried out with effort.
§ 6 = Complete lassitude. Unable to do anything without help.
o Inability to feel
§ 0 = Normal interest in the surroundings and in other people.
§ 2 = Reduced ability to enjoy usual interests.
§ 4 = Loss of interest in the surroundings. Loss of feelings for friends and acquaintances.
§ 6 = The experience of being emotionally paralyzed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends.)
o Pessimistic thoughts
§ 0 = No pessimistic thoughts.
§ 2 = Fluctuating ideas of failure, self-reproach or self- depreciation.
§ 4 = Persistent self-accusations, or definite but still rational ideas of guilt or sin. Increasingly pessimistic about the future.
§ 6 = Delusions of ruin, remorse or irredeemable sin. Self- accusations which are absurd and unshakable.
o Suicidal thoughts
§ 0 = Enjoys life or takes it as it comes.
§ 2 = Weary of life. Only fleeting suicidal thoughts.
§ 4 = Probably better off dead. Suicidal thoughts are common, and suicide is considered as a possible solution, but without specific plans or intention.
§ 6 = Explicit plans for suicide when there is an opportunity. Active preparations for suicide]

2. Spravato (esketamine) is considered medically necessary for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with active suicidal ideation or behavior when ALL of the following are met:
a. Member is at least 18 years old
b. Member must meet the DSM-5 diagnostic criteria for major depressive disorder (MDD) without psychotic features
c. Member must have current suicidal disease with intent
d. Member must have depression symptom severity of at least 28 on the MADRS rating scale
e. Member must be taking Spravato (esketamine) in conjunction with an oral antidepressant. Spravato (esketamine) is not to be used as monotherapy.
f. Member must not have any contraindications to Spravato (esketamine) (i.e. aneurysmal vascular disease or intracerebral hemorrhage)
g. Spravato is to be administered under direct supervision of a healthcare professional only in setting with adequate patient monitoring facilities
h. Provider, patient, and facility must be enrolled in the Spravato (esketamine) REMS program
i. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. psychiatrist) or has consulted with a specialist in the area of the patient’s diagnosis

3. When medically necessary, Spravato (esketamine) will be approved at the following FDA-approved doses:
• Treatment-resistant depression (TRD) - for 12 weeks
  a. Induction phase: administer intranasally twice per week for 4 weeks
  i. Day 1 starting dose: 56 mg
  ii. Subsequent doses: 56 mg or 84 mg
  b. Maintenance phase:
  i. Administer 56 or 84 mg intranasally once per week from Week 5 through Week 8.
  ii. Administer 56 or 84 mg intranasally once a week or once every 2 weeks from Week 9 on.
• Depressive symptoms in major depressive disorder (MDD) with acute suicidal ideation or behavior - for 4 weeks
  a. 84 mg twice per week for 4 weeks, dosage may be reduced to 56 mg twice per week based on tolerability
  b. After 4 weeks, evidence of therapeutic benefit should be evaluated to determine the need for continued treatment

- The nasal spray delivers 28 mg per device. Use 2 devices for a 56 mg dose or 3 devices for an 84 mg dose, with a 5-minute rest between use of each device. Note that initial dose on Day 1 of Week 1 is 56 mg, doses could be titrated up to 84 mg for subsequent doses
- Spravato (esketamine) carries a boxed warning of sedation and dissociation after administration. Members should be monitored for 2 hours after each dose. Spravato (esketamine) has a REMS program because of risk of severe sedation
- Per the FDA approved package insert, therapeutic benefit needs to be assessed at the end of initial induction phase to determine the need for continued treatment.]

4. When medically necessary, Spravato (esketamine) may be considered for renewal when ALL of the following criteria are met:
a. Member continues to meet initial criteria for each respective indication
b. Member has shown a positive clinical response to therapy which is defined by at least a 50% reduction of total MADRS score from baseline
c. Absence of any unacceptable toxicity (dissociation, cognitive impairment, suicidal thoughts, etc.)
d. Absence of any signs and symptoms of abuse and misuse
e. For the indication of treatment resistant depression, Spravato (esketamine) will be approved annually
f. For the indication of depressive symptoms in major depressive disorder with active suicidal ideation or behavior, Spravato will be approved for 4 weeks

[INFORMATIONAL NOTE: As per the FDA labeled package insert, the use of Spravator (esketamine), in conjunction with an oral antidepressant, beyond 4 weeks has not been systemically evaluated in the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior. After 4 weeks of treatment, evidence of therapeutic benefit should be evaluated to determine the need for continued treatment]

5. Other uses of Spravato (esketamine) are considered investigational.

There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL specifically for Esketamine (Spravato). Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Medicare covers drugs that are furnished “incident to” a physician’s service provided that the drugs are medically reasonable and necessary, approved by the Food and Drug Administration (FDA) and are not usually administered by the patients who take them. Therefore, Medicare Advantage Products will cover when the Horizon policy criteria is met AND the drug is furnished and administered by a licensed medical provider as part of a physician service.

Local Coverage Article: Self-Administered Drug Exclusion List (A53127). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Esketamine (Spravato)
Spravato (Esketamine)

References:
1. Spravato [package insert]. Janssen Pharmaceuticals. Beerse, Belgium. July 2020.

2. ClinicalTrials.gov. A Study to Evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression (TRANSFORM 2). Available at https://clinicaltrials.gov/ct2/show/NCT02418585. Accessed 03/20/2020.

3. ClinicalTrials.gov. A study of intranasal esketamine plus an oral antidepressant for relapse prevention in adult participants with treatment-resistant depression (SUSTAIN-1). Available at https://clinicaltrials.gov/ct2/show/NCT02493868. Accessed 03/20/2020.

4. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Participants Assessed to be at Imminent Risk for Suicide (Aspire II). NCT03097133. Available at: https://clinicaltrials.gov/ct2/show/NCT03097133. Accessed 8/27/2020.

5. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Participants Assessed to be at Imminent Risk for Suicide (Aspire I). NCT03039192. Available at: https://clinicaltrials.gov/ct2/show/NCT03039192, Accessed 8/27/2020.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*