Esketamine (Spravato) Nasal Spray Coverage Criteria
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Defines medical necessity, initial and continuation coverage criteria, dosing limits, administration and REMS requirements for esketamine nasal spray for Blue Cross NC members age 18+.
Added requirement that the requested product be administered to the individual patient for whom it has been specifically prescribed and ordered, and within 14 days after receipt by the REMS-certified treatment facility.
Minor adjustments made to dosing table and coding description for clarity according to FDA label.
Coverage Criteria for Esketamine (Spravato)
Dosing and Maximum Units
FDA-labeled dosing and programmatic maximums
See HCPCS mapping for billing
Esketamine nasal spray must not be administered in combination with ketamine of any formulation or route for the same indication. Requests that propose concurrent use of esketamine and ketamine for the same clinical indication are excluded from coverage and are at risk for denial.
For initial medical necessity, the patient must have baseline depression severity of ≥ 28 on the MADRS or a comparable standardized rating scale that reliably measures depressive symptoms. Treatment initiation when baseline severity is below this threshold does not meet initial medical necessity criteria.
Billing Codes and Code-related Criteria
Prior Authorization, Documentation, and Billing Requirements
Prior Authorization & Coding
Prior authorization is required for esketamine (Spravato) therapy. Submit requests using the combined G-codes when the drug is supplied and administered at the same site: G2082 (up to 56 mg, includes 2-hour post‑administration observation) or G2083 (greater than 56 mg, includes 2-hour post‑administration observation). If the drug is dispensed by a different site (e.g., specialty pharmacy) than the administration site, submit S0013 for the drug and the appropriate E/M CPT code for the administration/monitoring visit. Ensure the REMS-certified facility administers the dose within 14 days of receipt and that dosing/quantity requested is within FDA‑labeled limits.
- Use combined G-codes (G2082/G2083) when drug is supplied/dispensed AND administered with monitoring at the same site.
- If supply and administration occur at separate sites, bill S0013 for the drug and the appropriate E/M CPT code for the service.
- Ensure REMS-certified facility administers within 14 days of receipt.
Prior Antidepressant Trials Required
Document that the patient has an inadequate response to at least two antidepressants from two different classes (different mechanisms of action) during the current depressive episode — each trial should be of adequate dose and duration (typically ~6 weeks) and demonstrate ≤ 25% improvement. Include medication names, doses, start/stop dates, durations, and reason for discontinuation.
- At least two adequate antidepressant trials from two different classes (e.g., SSRI, SNRI, TCA, bupropion, mirtazapine).
- Record dose, duration (typically ≥ 6 weeks), and clinical response for each trial.
Required Documentation for Authorization
Include the following baseline and ongoing documentation with the prior authorization request: patient age (≥18), diagnosis (TRD or MDD with suicidal ideation/behavior), confirmation of MDD subtype where applicable, baseline depression severity score (MADRS ≥28 or comparable scale), details of prior antidepressant history (names, classes, doses, durations, responses), planned concomitant oral antidepressant, REMS facility documentation, contraindications check (e.g., aneurysmal vascular disease, intracerebral hemorrhage), and proposed dosing schedule within FDA labelling. For continuation requests, include baseline and on‑therapy standardized rating scale scores showing ≥50% reduction in symptoms compared to baseline.
- Patient age ≥ 18 documented.
- Diagnosis: TRD (with MDD confirmation) or MDD with imminent suicidal ideation/behavior.
- Baseline MADRS ≥ 28 (or comparable scale) at initiation; for continuation, ≥50% reduction from baseline.
- Detailed prior antidepressant history with at least two adequate trials from two classes.
- Confirmation patient will continue an oral antidepressant while receiving esketamine.
- Evidence REMS‑certified facility involvement and supervised administration.
- Documentation that requested dose and quantity are within FDA‑labeled dosing and maximum units.
Common Denial Triggers
Common denial triggers include patients under 18 years of age, baseline MADRS (or comparable scale) less than 28 at initiation, missing or insufficient documentation of prior adequate antidepressant trials (fewer than two trials or from the same class), absence of REMS‑certified facility documentation or supervised administration, requests exceeding FDA‑labeled dosing/maximum units, and concurrent use of ketamine for the same indication.
- Patient age < 18 — not eligible.
- Baseline MADRS < 28 (or comparable) at initiation — may be denied.
- Insufficient prior trial documentation (fewer than two adequate trials from different classes).
- Lack of REMS‑certified facility confirmation or supervised administration documentation.
- Requests that exceed FDA‑labeled dosing or maximum units.
- Concurrent ketamine administration for the same indication.
Clinical Background
Esketamine nasal spray (Spravato®) is FDA-approved for adults with treatment-resistant depression and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior when used with an oral antidepressant as specified. Administration must occur under direct supervision at a treatment facility certified through the Spravato REMS program, with observation per the REMS requirements and programmatic dosing schedules. For TRD, the FDA-labeled dosing includes an induction phase (Weeks 1–4) of twice-weekly administration starting at 56 mg with optional increase to 84 mg, followed by maintenance dosing (Weeks 5–8) once weekly (56 mg or 84 mg) and thereafter every 2 weeks or once weekly individualized to the least frequent dosing that maintains response. Evidence of therapeutic benefit should be assessed at the end of the 4‑week induction phase. Billing and supply are reflected by HCPCS codes S0013, G2082, and G2083.
Key Definitions
Level of Care / Setting
Outpatient
Treatment Modalities
Esketamine nasal spray (Spravato)
Supervised Administration and Visit Billing
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