Clinical Policy: Brexanolone (Zulresso) Form

# Clinical Policy: Brexanolone (Zulresso)
Reference Number: CP.PHAR.417  
Effective Date: 06.01.19  
Last Review Date: 05.26  
Line of Business: Commercial, HIM/ICHRA, Medicaid  

Coding Implications  
Revision Log  

See Important Reminder at the end of this policy for important regulatory and legal information.  

## Description  
Brexanolone (Zulresso™) is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator.  

## FDA Approved Indication(s)  
Zulresso is indicated for the treatment of postpartum depression (PPD) in patients 15 years and older.  

## Policy/Criteria  
  
   a. 0 to 4 hours: Initiate with a dosage of 30 mcg/kg per hour;  
   b. 4 to 24 hours: Increase dosage to 60 mcg/kg per hour;  
   c. 24 to 52 hours: Increase dosage to 90 mcg/kg per hour (alternatively consider a dosage of 60 mcg/kg per hour for those who do not tolerate 90 mcg/kg per hour);  
   d. 52 to 56 hours: Decrease dosage to 60 mcg/kg per hour;  
   e. 56 to 60 hours: Decrease dosage to 30 mcg/kg per hour.  

Approval duration: 30 days (one time infusion per pregnancy)  

#### B. Other diagnoses/indications (must meet 1 or 2):  
1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b):  
   a. For drugs on the formulary (commercial, health insurance marketplace/ICHRA) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace/ICHRA, and CP.PMN.255 for Medicaid; or  
   b. For drugs NOT on the formulary (commercial, health insurance marketplace/ICHRA) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace/ICHRA, and CP.PMN.16 for Medicaid;  
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace/ICHRA, and CP.PMN.53 for Medicaid.  

### II. Continued Therapy  
#### A. Postpartum Depression  
1. Re-authorization is not permitted. Members must meet the initial approval criteria.  
Approval duration: Not applicable  

#### B. Other diagnoses/indications (must meet 1 or 2):  
1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b):  
   a. For drugs on the formulary (commercial, health insurance marketplace/ICHRA) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace/ICHRA, and CP.PMN.255 for Medicaid; or  
   b. For drugs NOT on the formulary (commercial, health insurance marketplace/ICHRA) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace/ICHRA, and CP.PMN.16 for Medicaid;  
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace/ICHRA, and CP.PMN.53 for Medicaid.  

### III. Diagnoses/Indications for which coverage is NOT authorized:  
#### A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documented evidence of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace/ICHRA, and CP.PMN.53 for Medicaid, or evidence of coverage documents.  

## IV. Appendices/General Information  
### Appendix A: Abbreviation/Acronym Key  
BDI: Beck Depression Inventory  
EPDS: Edinburgh Postnatal Depression Scale  
FDA: Food and Drug Administration  
HAM-D: Hamilton Rating Scale for Depression  
MADRS: Montgomery-Åsberg Depression Rating Scale  
PHQ-9: Patient Health Questionnaire  
PPD: postpartum depression  
SNRI: serotonin-norepinephrine reuptake inhibitor  
SSRI: selective serotonin reuptake inhibitor  
TCA: tricyclic antidepressant  

### Appendix B: Therapeutic Alternatives  
This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.  

| Drug Name | Dosing Regimen | Dose Limit/Maximum Dose |
|-----------|---------------|------------------------|
| **SSRIs** |               |                        |
| citalopram (Celexa®) | 20 mg PO QD; may increase to 40 mg PO QD after one week | 40 mg/day (≤ 60 years) 20 mg/day (> 60 years) |
| escitalopram (Lexapro®) | 10 mg PO QD; may increase to 20 mg PO QD after 1 week | 20 mg/day |
| fluoxetine (Prozac®) | Immediate release: 20 mg PO QD; may increase by 10-20 mg after several weeks<br>Delayed release: 90 mg PO q week beginning 7 days after the last daily dose | Immediate release: 80 mg/day<br>Delayed release: 90 mg/week |
| paroxetine (Paxil®, Paxil CR®) | Paxil: 20 mg PO QD; may increase by 10 mg every week as needed<br>Paxil CR: 25 mg PO QD; may increase by 12.5 mg every week as needed | Paxil: 50 mg/day<br>Paxil CR: 62.5 mg/day |

| Drug Name | Dosing Regimen | Dose Limit/Maximum Dose |
|-----------|---------------|------------------------|
| sertraline (Zoloft®) | 50 mg PO QD; may increase every week as needed | 200 mg/day |
| **SNRIs** |               |                        |
| duloxetine (Cymbalta®) | 20 mg PO BID or 30 mg PO BID or 60 mg PO QD | 120 mg/day |
| venlafaxine (Effexor®, Effexor XR®) | Effexor: 75 mg/day PO in 2-3 divided doses; may increase by 75 mg every 4 days as needed<br>Effexor XR: 75 mg PO QD; may increase by 75 mg every 4 days as needed | Effexor: 225 mg/day (outpatient) or 375 mg/day (inpatient)<br>Effexor XR: 225 mg/day |
| desvenlafaxine (Pristiq®) | 50 mg PO QD | 400 mg/day |
| Fetzima® (levomilnacipran) | 20 mg PO QD for 2 days, then 40 mg PO QD; may increase by 40 mg every 2 days | 120 mg/day |
| **TCAs** |               |                        |
| amitriptyline | 25 to 50 mg/day PO QD or divided doses | 150 mg/day |
| amoxapine | 25 to 300 mg/day PO in divided doses | 400 mg/day (300 mg/day if geriatric) |
| clomipramine† (Anafranil®) | 25 mg PO QD for 3 days, then 50 mg PO QD, and then 75 mg/day (25 mg in the morning and 50 mg in the evening) | 150 mg/day |
| desipramine (Norpramin®) | 25 to 200 mg/day PO QD or in divided doses | 300 mg/day (150 mg/day if geriatric or pediatric) |
| doxepin | Adults: 75 to 300 mg/day PO QD or in divided doses<br>Pediatric†: 25 to 100 mg/day PO QD | Adults: 300 mg/day<br>Pediatric†: 100 mg/day |
| imipramine HCl | 30 to 200 mg/day PO QD or divided doses | 200 mg/day (100 mg/day if geriatric or pediatric) |
| imipramine pamoate | 75 to 200 mg/day PO QD or divided doses | 200 mg/day (100 mg/day if geriatric or pediatric) |
| nortriptyline (Pamelor®) | 30 to 150 mg/day PO QD or in divided doses | 150 mg/day (50 mg/day if geriatric or pediatric) |
| protriptyline | 15 to 60 mg/day PO in divided doses | 60 mg/day (30 mg/day if geriatric or pediatric) |
| trimipramine | 50 to 200 mg/day PO QD | 200 mg/day (100 mg/day if geriatric or pediatric) |
| **Other Antidepressants** |               |                        |
| bupropion (Aplenzin®, Forfivo XL®, Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®) | Varies | Immediate-release: 450 mg/day (300 mg/day if pediatric)<br>Sustained-release: 400 mg/day |

*Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic.*  
†Off-label  

### Appendix C: Contraindications/Boxed Warnings  
- Boxed warning(s): Excessive sedation and sudden loss of consciousness during administration. Patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. Because of these risks, Zulresso is available only through a restricted program under a REMS program.  
- Contraindication(s): none reported  

### Appendix D: General Information  
- HAM-D scale is a 17-item depression assessment scale to assess severity of, and change in, depressive symptoms.  

| HAM-D Score | Depression Rating |
|-------------|-------------------|
| 0 – 7       | Normal, absence or remission of depression |
| 8 – 16      | Mild depression |
| 17 – 23     | Moderate depression |
| > 23        | Severe depression |

- MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders.  

| MADRS Score | Depression Rating |
|-------------|-------------------|
| 0 – 6       | Normal/symptom absent |
| 7 – 19      | Mild depression |
| 20 – 34     | Moderate depression |
| > 34        | Severe depression |

- PHQ-9 is a 9-item multiple choice questionnaire used for diagnosis, screening, monitoring, and measuring the severity of depression.  

| PHQ-9 Score | Depression Severity |
|-------------|---------------------|
| 5 – 9       | Minimal symptoms |
| 10 – 14     | Minor depression |
| 15 – 19     | Major depression, mild |
| > 19        | Major depression, severe |

- EPDS is a 10-item multiple choice questionnaire used to screen and assist in identifying possible symptoms of depression in the postnatal period.  

| EPDS Score | Depression Severity |
|------------|---------------------|
| 5 – 9      | Minimal symptomatology |
| 10 – 14    | Mild symptomatology |
| 15 – 19    | Moderate symptomatology |
| > 19       | Severe symptomatology |

- BDI is a 21-item, self-reported rating inventory that measures characteristic attitudes and symptoms of depression.  

| BDI Score | Depression Severity |
|-----------|---------------------|
| 0 – 13    | Minimal depression |
| 14 – 19   | Mild depression |
| 20 – 28   | Moderate depression |
| > 28      | Severe depression |

### V. Dosage and Administration  

| Indication | Dosing Regimen | Maximum Dose |
|------------|---------------|--------------|
| PPD        | Administered as a continuous intravenous infusion over 60 hours (2.5 days) as follows:<br>• 0 to 4 hours: Initiate with a dosage of 30 mcg/kg per hour<br>• 4 to 24 hours: Increase dosage to 60 mcg/kg per hour<br>• 24 to 52 hours: Increase dosage to 90 mcg/kg per hour (alternatively consider a dosage of 60 mcg/kg per hour for those who do not tolerate 90 mcg/kg per hour)<br>• 52 to 56 hours: Decrease dosage to 60 mcg/kg per hour<br>• 56 to 60 hours: Decrease dosage to 30 mcg/kg per hour | 90 mcg/kg per hour |

### VI. Product Availability  
Vial for injection, single-dose: 100 mg/20 mL (5 mg/mL)  

  

### Coding Implications  
Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.  

| HCPCS Codes | Description |
|-------------|-------------|
| J1632       | Injection, brexanolone, 1 mg |

### Reviews, Revisions, and Approvals  

| Reviews, Revisions, and Approvals | Date | P&T Approval Date |
|----------------------------------|------|-------------------|
| 2Q 2022 annual review: no significant changes; references reviewed and updated. | 02.06.22 | 05.22 |
| RT4: per updated prescribing information, updated indication and age requirements from adults (18 years) to 15 years of age or older. Template changes applied to other diagnoses/indications. | 07.18.22 |  |
| 2Q 2023 annual review: shortened the trial durations of antidepressant agent from 8 weeks to 4 weeks; references reviewed and updated. | 02.07.23 | 05.23 |
| Revised criterion for diagnosis of major depressive episode that began no later than the first 4 weeks following delivery per updated ACOG guidance; added requirement that member has not received prior treatment with Zulresso or Zurzuva for the current pregnancy; corrected MADRS score to ≥ 35 for severe depression; added additional approval pathway if member does not have severe | 08.25.23 | 11.23 |

| Reviews, Revisions, and Approvals | Date | P&T Approval Date |
|----------------------------------|------|-------------------|
| depression as demonstrated by at least one of the depression scores, documentation of severe depression as evidenced by a psychiatrist clinical interview. |  |  |
| 2Q 2024 annual review: Added obstetrician-gynecologist as an additional prescriber specialty and specialist that can perform a clinical interview to confirm severe depression; per competitor analysis, added BDI and EPDS scales as additional methods to identify severe depression. | 04.04.24 | 05.24 |
| 2Q 2025 annual review: in Appendix B per Clinical Pharmacology, updated dosing regimens and removed commercially unavailable branded therapeutic alternatives; references reviewed and updated. | 02.20.25 | 05.25 |
| 2Q 2026 annual review: no significant changes; references reviewed and updated. Added ICHRA line of business. | 03.31.26 | 05.26 |

### Important Reminder  
This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.  

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions, and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.  

This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.  

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions.  

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.  

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members, and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services.  

**Note:**  
For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.  

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