ZULRESSO, Brexanolone Form

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 Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Zulresso is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Postpartum Depression (must meet all):

1. Diagnosis of a major depressive episode that began no earlier than the third trimester and no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical Interview for DSM-5;
2. Prescribed by or in consultation with psychiatrist;
   3. Age ≥ 15 years;
   4. Member meets one of the following (a, b, c, d, or e): a. HAMD score is ≥ 24 (severe depression) (see Appendix D); b. MADRS score is ≥ 35 (severe depression) (see Appendix D); c. PHQ-9 score is ≥ 20 (severe depression) (see Appendix D); d. If member does not have severe depression as demonstrated by at least one of the depression scores above (a, b, or c), documentation of severe depression as evidenced by a psychiarist clinical interview; e. Failure of an 4-week trial of one of the following oral antidepressants at up to maximally indicated dose but no less than the commonly recognized minimum therapeutic dose, unless clinically significant adverse effects are experienced or all are contraindicated: selective serotonin reuptake inhibitor (SSRI), serotonin- norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), bupropion, mirtazapine (see Appendix B);

3. No more than 6 months have passed since member has given birth; Page 1 of 8

   CLINICAL POLICY Brexanolone

4. Member has not received prior treatment with Zulresso or Zurzuvae™ for the current pregnancy;
5. Dose does not exceed 90 mcg/kg per hour over 60 hours (2.5 days) as follows: 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):
6. 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) 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, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) 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, and CP.PMN.16 for Medicaid; or
7. 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, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Postpartum Depression
8. 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):

9. 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) 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, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) 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, and CP.PMN.16 for Medicaid; or Page 2 of 8

   CLINICAL POLICY Brexanolone

10. 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, 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 documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key 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®) escitalopram (Lexapro®) fluoxetine (Prozac®, Prozac Weekly®) paroxetine (Paxil®, Paxil CR®, Pexeva®) sertraline (Zoloft®) 20 mg PO QD; may increase to 40 mg PO QD after one week 10 mg PO QD; may increase to 20 mg PO QD after 1 week
    Prozac: 20 mg PO QD; may increase by 10-20 mg after several weeks
    Prozac Weekly: 90 mg PO q week beginning 7 days after the last daily dose Paxil, Pexeva: 20 mg PO QD; may increase by 10 mg every week as needed 40 mg/day (≤ 60 years) 20 mg/day (> 60 years) 20 mg/day Prozac: 80 mg/day Prozac Weekly: 90 mg/week
    Paxil, Pexeva: 50 mg/day Paxil CR: 62.5 mg/day Paxil CR: 25 mg PO QD; may increase by 12.5 mg every week as needed 50 mg PO QD; may increase every week as needed 200 mg/day Page 3 of 8

    CLINICAL POLICY Brexanolone Drug Name Dosing Regimen SNRIs duloxetine (Cymbalta®) venlafaxine (Effexor®, Effexor XR®) 20 mg PO BID or 30 mg PO BID or 60 mg PO QD Effexor: 75 mg/day PO in 2-3 divided doses; may increase by 75 mg every 4 days as needed Dose Limit/ Maximum Dose 120 mg/day Effexor: 225 mg/day (outpatient) or 375 mg/day (inpatient)
    Effexor XR: 75 mg PO QD; may increase by 75 mg every 4 days as needed 50 mg PO QD Effexor XR: 225 mg/day 400 mg/day 20 mg PO QD for 2 days, then 40 mg PO QD; may increase by 40 mg every 2 days 120 mg/day 25 to 50 mg/day PO QD or divided doses 150 mg/day desvenlafaxine (Pristiq®, Khedezla®) Fetzima® (levomilnacipran) TCAs amitriptyline (Elavil®) amoxapine clomipramine* (Anafranil®) desipramine (Norpramin®) doxepin (Sinequan®) imipramine HCl (Tofranil®)
    imipramine pamoate (Tofranil PM®) nortriptyline (Pamelor®) protriptyline (Vivactil®) trimipramine (Surmontil®) Other Antidepressants bupropion (Aplenzin®, Budeprion SR® , Budeprion XL®, Forfivo XL®, Wellbutrin®, 25 to 300 mg/day PO in divided doses 12.5 to 150 mg/day PO QD 25 to 300 mg/day PO QD 25 to 300 mg/day PO QD 25 to 150 mg/day PO QD 10 to 60 mg/day PO in divided doses 25 to 200 mg/day PO QD Varies Page 4 of 8 400 mg/day (300 mg/day if geriatric) 250 mg/day (200 mg/day if pediatric) 300 mg/day (100 mg/day if pediatric) 300 mg/day if geriatric or pediatric) if geriatric or pediatric) 150 mg/day 60 mg/day (30 mg/day if geriatric or pediatric) 200 mg/day (100 mg/day if geriatric or pediatric) Immediate-release: 450 mg/day (300 mg/day if pediatric) Sustained-release: 400 mg/day Extended-release (HCl): 450 mg/day 25 to 200 mg/day PO QD or divided doses 200 mg/day (150 mg/day 25 to 200 mg/day PO QD or divided doses 200 mg/day (100 mg/day

    CLINICAL POLICY Brexanolone Drug Name Dosing Regimen Wellbutrin SR®, Wellbutrin XL®) mirtazapine (Remeron®) 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. 15 to 15 mg PO QD Dose Limit/ Maximum Dose Extended-release (HBr): 522 mg/day 45 mg/day 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 0 – 7 8 – 16 17 – 23

    23 Depression Rating Normal, absence or remission of depression Mild depression Moderate depression Severe depression • MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. MADRS Score 0 – 6 7 – 19 20 – 34 34 Depression Rating Normal/symptom absent Mild depression Moderate depression 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 5 – 9 Depression Severity Minimal symptoms Minor depression Major depression, mild Major depression, moderately severe Major depression, severe 10 – 14 15 – 19 19 V. Dosage and Administration
    Indication PPD Dosing Regimen Administered as a continuous intravenous infusion over 60 hours (2.5 days) as follows: • 0 to 4 hours: Initiate with a dosage of 30 mcg/kg per hour Maximum Dose 90 mcg/kg per hour Page 5 of 8

    CLINICAL POLICY Brexanolone Indication Dosing Regimen • 4 to 24 hours: Increase dosage to 60 mcg/kg Maximum Dose per hour • 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)
    • 52 to 56 hours: Decrease dosage to 60 mcg/kg per hour
    • 56 to 60 hours: Decrease dosage to 30 mcg/kg per hour VI. Product Availability
    Vial for injection, single-dose: 100 mg/20 mL (5 mg/mL)
    VII.