CurrentPremera BluecrossPolicy 5.01.609

PHARMACY MEDICAL POLICY 5.01.609 Spravato (esketamine) Nasal Spray

Defines medical necessity, investigational uses, dosing limits, authorization durations, documentation and coding requirements for Spravato (esketamine) nasal spray for treatment of major depressive disorder (including treatment-resistant depression and MDD with acute suicidal ideation/behavior) in adults.

Policy Summary

PayerPremera Bluecross

PolicyPHARMACY MEDICAL POLICY 5.01.609 Spravato (esketamine) Nasal Spray

Policy CodePolicy 5.01.609

Change TypeCriteria consolidated; dosing, substance-use, and authorization updates

Effective DateJul 1, 2025

Next Review Date

Key ActionObtain prior authorization and document DSM-5 MDD criteria, named oral antidepressant, induction/maintenance dosing, failed medication trials, and substance use/remission status per policy to support approvals up to 12 months.

POLICY UPDATE CHANGES

Removed separate coverage criteria for Spravato for MDD with acute suicidal ideation or behavior; criteria for MDD now apply to individuals with or without acute suicidal ideation or behavior (2025 update).

Clarified DSM-5 documentation requirement: MDD without psychotic features (unipolar, not bipolar) and required no current substance use disorder unless in remission with a 3-month abstinence period or confinement.

Added dosing limits consistent with FDA prescribing information: induction and maintenance dose limits.

Added requirement that Spravato must be used in conjunction with an oral antidepressant and that the oral antidepressant must be specifically named in documentation.

Added HCPCS codes G2082 and G2083 (06/01/20).

Removed HCPCS code J3490 and added HCPCS code S0013 (01/01/21).

Added coverage for treatment of MDD with acute suicidal ideation or behavior when criteria are met (01/01/22).

Updated required failed-antidepressant trial definition to three antidepressants from at least two different classes or two antidepressants from two different classes plus an augmenting agent (11/01/22 interim).

Added requirement that no concurrent use of mind-altering or mood-altering substances that could interfere with Spravato (including alcohol, marijuana, stimulants, hallucinogens/psychedelics) is allowed; substance use disorder must be in remission (defined) or individual confined where access is not possible (06/01/22 and updates).

Added induction dosing option: initial 56 mg on first day then no more than 84 mg twice per week for first 4 weeks (11/01/24).

Clarified that medications listed in this policy are subject to the product's FDA dosage and administration prescribing information (04/01/25).

Increased initial authorization period for Spravato to 12 months and aligned re-authorization period to 12 months regardless of formulary status (06/01/25).

Updated documentation requirement to include induction dose and maintenance dose frequency and time period specified (08/01/25).

84 mgMax induction dose

84 mgMax maintenance dose

12 monthsMax approval duration

3 monthsSubstance remission required

G2082/G2083/S0013Relevant codes (history)

Coverage Summary & Scope

Coverage summary: Spravato (esketamine) nasal spray is addressed for adults with major depressive disorder (MDD), including treatment-resistant depression (TRD) and MDD with or without acute suicidal ideation or behavior. The policy applies to individuals aged 18 years or older, requires DSM-5 documentation of MDD without psychotic features, and specifies dosing, monitoring, and documentation requirements. The coverage stance is mixed, with defined situations where use is medically necessary and other situations considered investigational or not medically necessary.

Medical Necessity - Treatment of Depression (including TRD and MDD with/without acute suicidal ideation or behavior)

Spravato (esketamine) may be considered medically necessary when ALL of the following are met:

ALL of the following

Eligibility: Individual is aged 18 years or older
Diagnosis: Has medical record documentation of DSM-5 diagnostic criteria for major depressive disorder without psychotic features (unipolar, not bipolar)
Severity: Current episode of depression is moderate to severe as demonstrated by documentation of individual's symptoms and their severity or by one or more standardized depression rating scales
Psychosis exclusion: No current or past psychosis
Substance use requirement
- Remission option: No current substance use disorder unless in remission (complete abstinence for at least three months or verification that none of the DSM diagnostic criteria for a substance use disorder have been met for at least 3 months)Complete abstinence for at least 3 months
  Remission defined in policy thresholds
- Confinement exception: Confined 24/7 in a hospital or residential treatment facility or similar facility where access to alcohol or non-prescribed drugs is not possible and the individual has agreed to not use alcohol or non-prescribed drugs after discharge while continuing treatment with Spravato
Concurrent substance exclusions: No concurrent use of any hallucinogens/psychedelics; no concurrent use of any illicit drugs; no concurrent use of any illicit or non-prescribed stimulants; no concurrent use of any prescribed stimulants in excess of prescribed doses; no concurrent use of any prescribed controlled medications that were not prescribed for the individual
Alcohol or marijuana use agreement: If the individual uses alcohol or marijuana, the individual agrees to either cease use while being treated with Spravato OR to not use within 24 hours before and 24 hours after each Spravato treatment24 hours before and after treatment
Prior antidepressant therapy trials
- Option A: Tried and failed three antidepressants from at least two different classesEach failed medication trial documented ≥30 continuous days unless stopped sooner for intolerable adverse effects
  Failed trial defined as not effective, partially but inadequately effective, initially effective then lost effectiveness, or intolerable side effects
- Option B: Tried and failed two antidepressants from two different classes plus an augmenting agentEach failed medication trial documented ≥30 continuous days unless stopped sooner for intolerable adverse effects
Induction dosing: Induction dose (weeks 1 to 4) limited to 84 mg twice per week, or 56 mg on first day followed by no more than 84 mg twice per week for 4 weeksInduction dosing limit (weeks 1-4): 84 mg twice per week or initial 56 mg then up to 84 mg twice weekly
Policy threshold
Maintenance dosing: Maintenance dose (week 5 and after) limited to 84 mg once weeklyMaintenance dosing limit: 84 mg once weekly
Policy threshold

Initial Therapy Criteria (Induction)

Medical Necessity - New Course (re-initiation) of Spravato

A new course of Spravato starting with an induction dose may be considered medically necessary when ALL of the following are met:

ALL of the following

Prior course and response: The individual previously met criteria for coverage for Spravato and had a prior course of treatment
Prior positive response: Had a positive response to the previous course of treatment with Spravato
Time-since-last-treatment: Previous course of treatment with Spravato was terminated, and the time since the last Spravato treatment is greater than (time truncated in source)
NOTE: time-since-last-treatment text truncated in source; populate exact threshold from source when available

Authorization Duration & Re-authorization Criteria

Authorization Duration and Re-authorization Criteria

Authorization may be granted when criteria met:

ALL of the following

Initial authorization duration: Initial authorization (first course or repeat course) may be approved up to 12 months for the treatment of depressionInitial / Re-authorization period: 12 months
Policy specifies 12 months for initial authorization
Re-authorization improvement: Re-authorization may be approved up to 12 months when chart notes document improvement in signs and symptoms of MDD
Chart notes must document improvement
Substance use for re-authorization:

Investigational and Not Medically Necessary Uses

Investigational / Not Medically Necessary

Spravato is considered investigational or not medically necessary in the following situations:

ALL of the following

Other uses investigational: All other uses of Spravato for conditions not outlined in this policy are investigational (including treatment for chronic pain and bipolar depression)
Neuromodulation combination investigational: Use in conjunction with any modality of neuromodulation (e.g., TMS, ECT, VNS) is investigational
Other formulations investigational: Use in conjunction with other formulation of ketamine or with any psychedelic drug is investigational; formulations other than Spravato nasal spray (IV, IM, subcutaneous, oral, etc.) are considered investigational for treatment of the conditions addressed

Provider Actions — Authorization, Documentation & Billing

Prior Authorization

Prior authorization required

Prior authorization is required for Spravato (esketamine) Nasal Spray. Requests must include clinical documentation that supports medical necessity per policy criteria.

Affected codes: G2082, G2083, S0013

Documentation Required

Diagnosis and symptom severity documentation

Medical records must document DSM-5 diagnostic criteria for major depressive disorder (unipolar, without psychotic features) and evidence that the current episode is moderate to severe. Severity must be demonstrated by documentation of symptoms and their severity in clinical notes or by one or more standardized depression rating scales (e.g., PHQ-9, MADRS). A diagnosis code alone (including severity numeral or descriptor) is not sufficient to establish severity.

Applicable Codes

HCPCS codes for supervised administration and drugHCPCS

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.
S0013	Esketamine; nasal spray (Spravato), mg

HCPCS / Drug Codes referenced in historyHCPCS

G2082	HCPCS code added 06/01/20
G2083	HCPCS code added 06/01/20
S0013	HCPCS code added 01/01/21
J3490	HCPCS code removed 01/01/21

HCPCS codes for supervised administration and drugHCPCS

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.
S0013	Esketamine; nasal spray (Spravato), mg

HCPCS / Drug Codes referenced in historyHCPCS

G2082	HCPCS code added 06/01/20
G2083	HCPCS code added 06/01/20
S0013	HCPCS code added 01/01/21
J3490	HCPCS code removed 01/01/21

Clinical Evidence & Key Trials

MultipleKey trials: TRANSFORM-1/2/3, SUSTAIN-1/2/3, ASPIRE/ASPIRE II, ASPIRE I; Janssen PI (Jan 2025)

JAMA/PsychNotable publications cited (e.g., JAMA Psychiatry 2018; TRANSFORM; SUSTAIN-3; ASPIRE I)

Evidence summary: Randomized Phase 3 trials (TRANSFORM series and SUSTAIN) and the ASPIRE studies showed mixed efficacy — TRANSFORM-2 showed a significant MADRS improvement at 4 weeks while TRANSFORM-1 and TRANSFORM-3 did not meet significance, and SUSTAIN-1 showed reduced relapse risk (HR 0.49). Trials of MDD with acute suicidal ideation (ASPIRE) showed early MADRS improvement but inconsistent effects on suicidal severity measures. Safety concerns include sedation and dissociation (common and often peaking around 40 minutes), abuse/misuse potential similar to IV ketamine in abuse-potential studies, and multiple boxed warnings leading to a REMS program requiring 2-hour post-dose observation.

Background & Definitions

Background: The FDA-approved indications include treatment-resistant major depressive disorder in adults and, in 2020, an indication for MDD with acute suicidal ideation or behavior. Because of serious risks (sedation, dissociation, abuse/misuse, increased suicidal ideation in younger individuals) esketamine is available only through a REMS program and must be administered under direct supervision with 2-hour monitoring after each treatment. Dosing limits in the policy follow FDA prescribing information with induction up to 84 mg twice weekly (with an option of 56 mg on day 1 then up to 84 mg twice weekly for 4 weeks) and maintenance up to 84 mg once weekly. Other formulations of esketamine/ketamine (IV, IM, oral, etc.) are considered investigational.

Term	Definition
Failed trial	Not effective, partially but inadequately effective, initially effective then lost effectiveness, or intolerable side effects.
Remission of substance use disorder	Complete abstinence for at least three months or verification that DSM criteria have not been met for at least 3 months.
Substance use disorder in remission	Complete abstinence for at least three months or verification that none of the current DSM diagnostic criteria for a substance use disorder have been met for at least 3 months.

Revision History

2019-07-01policy_approved

Policy approved (initial policy for Spravato coverage criteria).

2020-06-01coding_added

HCPCS codes G2082 and G2083 added for supervised administration and observation (effective 06/01/20).

2020-07-01regulatory_indication

FDA added indication for MDD with acute suicidal ideation or behavior (noted in policy updates).

Policy Summary

PayerPremera Bluecross

PolicyPHARMACY MEDICAL POLICY 5.01.609 Spravato (esketamine) Nasal Spray

Policy CodePolicy 5.01.609

Change TypeCriteria consolidated; dosing, substance-use, and authorization updates

Effective DateJul 1, 2025

Next Review Date

On This Page

Severity: Current episode of depression is moderate to severe as demonstrated by documentation of symptoms or standardized rating scales

Psychosis exclusion: No current or past psychosis

Substance use requirement (repeat)

Remission option: No current substance use disorder unless in remission (complete abstinence for at least 3 months or verification that none of DSM diagnostic criteria have been met for at least 3 months)Complete abstinence for at least 3 months
Confinement exception: Confined 24/7 in a hospital or residential treatment facility where access to alcohol/non-prescribed drugs is not possible and individual agreed to not use after discharge while continuing Spravato

Concurrent substance exclusions: No concurrent use of hallucinogens/psychedelics, illicit drugs, illicit/non-prescribed stimulants, prescribed stimulants in excess of prescribed doses, or prescribed controlled medications not prescribed for the individual

Alcohol or marijuana use agreement (repeat): If the individual uses alcohol or marijuana, the individual agrees to either cease use while being treated with Spravato or to not use within 24 hours before and 24 hours after each Spravato treatment24 hours before and after treatment

Induction thresholds

TitleInduction thresholds

Induction dosing limit (weeks 1-4)84 mg twice per week, or initial 56 mg on first day then no more than 84 mg twice weekly for first 4 weeks

Induction dosing option (first day)56 mg on day 1 allowed as an alternate to starting at 84 mg

Prior antidepressant trial durationAt least 30 continuous days per failed medication (unless stopped sooner for intolerable adverse effects)

Documentation requiredRecords must document induction dosing frequency and time period specified

No current substance use disorder unless in remission (complete abstinence for at least three months) OR confined 24/7 in an appropriate facility as specified

Substance use remission timeframe: complete abstinence for at least 3 months

Concurrent substance exclusions for re-authorization: No concurrent use of hallucinogens/psychedelics, illicit drugs, illicit/non-prescribed stimulants, prescribed stimulants in excess, or prescribed controlled meds not prescribed for the individual

Alcohol or marijuana use agreement for re-authorization: If the individual uses alcohol or marijuana, agrees to cease or not use within 24 hours before and after each treatment24 hours before and after treatment

Clinical status: Improvement is being maintained (is not wearing-off) and the individual is not experiencing serious or dangerous side-effects

Maintenance dosing limit: Maintenance dose prescribed (week 5 and after) limited to 84 mg once weeklyMaintenance dosing limit: 84 mg once weekly

TitleMaintenance thresholds & authorization period

Maintenance dosing limit (week 5 and after)84 mg once weekly

Initial / Re-authorization periodInitial authorization up to 12 months; re-authorization up to 12 months when clinical benefit documented

Max approval duration12 months

Documentation requiredRecords must document maintenance dosing frequency and a time period consistent with a 12-month authorization

Age/diagnosis not met: Use that does not meet the age or diagnosis requirements within the Medical Necessity section is investigational

Not meeting medical necessity: Use that meets age and diagnosis but does not meet other Medical Necessity criteria is considered not medically necessary

Concurrent providers not allowed: Spravato with more than one provider/group/clinic at the same time is not medically necessary

Documentation Required

Document failed medication trials

The medical record must document all prior antidepressant medication trials used to treat the current episode. For each failed medication trial, list the specific medication, dose, duration (at least 30 continuous days unless stopped earlier for intolerable adverse effects), and reason for failure (ineffective, inadequate response, loss of effect, or intolerable side effects). Trials of antidepressants commonly used for insomnia count only if given at antidepressant doses.

Documentation Required

Dosing documentation

The record must document induction and maintenance dosing consistent with policy limits. Induction (weeks 1–4): up to 84 mg twice weekly, or 56 mg on one day followed by up to 84 mg twice weekly for 4 weeks. Maintenance (week 5 and after): limited to 84 mg once weekly. Documentation should include prescribed dose, frequency, and dates corresponding to induction or maintenance phases.

Documentation Required

Concomitant oral antidepressant requirement (DSM-5 diagnosis & documentation)

Spravato must be used in conjunction with an oral antidepressant unless contraindicated. Documentation must indicate the concomitant oral antidepressant prescribed for the current episode and that the patient is taking it as directed.

Documentation Required

Confinement exception for substance use / remission documentation

If the member has active substance use, Spravato is not covered unless the substance use disorder has been in remission (complete abstinence for at least 3 months) OR the member is confined 24/7 in a hospital, residential treatment facility, or similar setting where access to alcohol or non-prescribed drugs is not possible and the member has agreed to abstain after discharge while continuing Spravato. Documentation must verify remission or confinement status and any agreement to abstain.

Billing Rule

Billing rules — supervised administration and observation; code guidance

Supervised administration and observation are required for each Spravato dose. Claims/billing should use HCPCS G2082 for administration/provision up to 56 mg and G2083 for administration/provision greater than 56 mg; both include a 2‑hour post-administration observation period. Use S0013 for esketamine drug coding as applicable per billing guidance.

Use HCPCS G2082 for up to 56 mg (includes 2-hour observation)
Use HCPCS G2083 for >56 mg (includes 2-hour observation)
Include S0013 per drug billing guidance
Document supervised administration and 2-hour observation in clinical notes for each treatment

Billing Rule

Billing rules — formulary / non‑formulary exception clarifications

Formulary and non‑formulary exception requests should reference medical necessity criteria and include the required documentation (diagnosis, severity, prior medication trials, dosing plan, concomitant antidepressant, and substance use status). Exception approvals depend on meeting the same clinical criteria required for prior authorization.

Denial Risk

Denial risk — substance use and concurrent medication restrictions

Spravato is contraindicated or may be denied when there is active substance use disorder (unless in documented remission or confinement exception applies), concurrent use of hallucinogens/psychedelics, illicit drugs, non‑prescribed stimulants, or prescribed stimulants above prescribed doses, or concurrent use of prescribed controlled medications not prescribed for the individual. Documentation must show absence of these risk factors.

2021-01-01coding_change

HCPCS code J3490 removed and S0013 (drug code for esketamine mg) added (effective 01/01/21).

2021dosing_limits_added

Policy updated to add dosing limits per FDA: induction and maintenance dose limits (induction up to 84 mg twice weekly; maintenance up to 84 mg once weekly).

2022-01-01coverage_added

Coverage criteria added for treatment of MDD with acute suicidal ideation or behavior when criteria are met (01/01/22).

2022-06-01substance_use_restrictions_added

Policy updated to prohibit concurrent use of mind-altering/mood-altering substances (including alcohol, marijuana, stimulants, hallucinogens/psychedelics) and to add confinement exception and substance use remission requirement (initially defined as 1 month in 06/01/22 updates).

2022-11-01prior_therapy_requirement_revised

Definition of required failed-antidepressant trials revised to three antidepressants from at least two different classes or two antidepressants from two classes plus an augmenting agent (interim review 11/01/22).

2023-05-01DSM_and_substance_clarification

Clarified requirement for DSM-5 documentation of MDD without psychotic features and clarified substance use requirement: remission defined as complete abstinence for three months or confinement 24/7 in a facility where access is not possible (effective 05/01/23 with subsequent 08/01/23 clarification).

2024-07-09prior_trial_definition_removed

Removed stipulation that adding a second antidepressant counts as an augmenting agent (07/09/24 interim review).

2024-11-01induction_option_added

Added induction dosing option: initial 56 mg on first day then up to 84 mg twice weekly for first 4 weeks; also specified formulations other than Spravato nasal spray considered investigational (11/01/24).

2025-04-01documentation_and_fda_clarification

Clarified that medications listed are subject to FDA prescribing information and updated documentation requirements to include induction and maintenance dose frequency and time period (effective 04/01/25).

2025-06-01substance_remission_definition_and_auth_period_increased

Clarified remission definition as complete abstinence for at least 3 months or verification no DSM criteria met for at least 3 months; increased initial authorization period to 12 months and aligned re-authorization to 12 months; deleted separate criteria for acute suicidal ideation/behavior (06/01/25).

2025-07-07policy_effectiveLatest

Policy effective/approved (07/07/25); criteria for MDD now apply to individuals with or without acute suicidal ideation or behavior following comprehensive review questioning suicidality indication (material change).

2025-08-01documentation_updateLatest

Updated documentation requirement to include induction dose and maintenance dose frequency and time period specified (08/01/25).