SPRAVATO, Esketamine HCl Form

Esketamine (Spravato™) is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist. FDA Approved Indication(s) Spravato, in conjunction with an oral antidepressant, is indicated for the treatment of: • Treatment-resistant depression (TRD) in adults. • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. Limitation(s) of use:
• Spravato is not approved as an anesthetic agent. The safety and effectiveness of Spravato as an anesthetic agent have not been established. • The effectiveness of Spravato in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of Spravato does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of Spravato. 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 Spravato is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Treatment-Resistant Depression (must meet all):

1. Diagnosis of TRD;
   2. Prescribed by or in consultation with a psychiatrist;
   3. Age ≥ 18 and < 65 years (see Appendix E);
   4. Member has a documented baseline Patient Health Questionnaire (PHQ-9) score ≥ 15, indicating moderately severe major depression, within the previous four weeks (see Appendix D);

2. Failure of two antidepressants from at least two different classes at up to maximally indicated doses but no less than the commonly recognized minimum therapeutic doses, each used for ≥ 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated (e.g., selective serotonin reuptake inhibitor Page 1 of 11

   CLINICAL POLICY Esketamine [SSRI], serotonin-norepinephrine reuptake inhibitor [SNRI], tricyclic antidepressant [TCA], bupropion, mirtazapine);

3. Failure of two of the following antidepressant augmentation therapies, each used for ≥ 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated: second-generation antipsychotic, lithium, thyroid hormone, buspirone;
4. Currently stabilized on an oral antidepressant for at least two weeks (must not be one of the aforementioned agents previously failed) and (a): a. Spravato will be used in combination with oral antidepressant;
5. Member meets one of the following (a or b): a. No prior history of treatment with Spravato; b. Documentation of a prior positive response to Spravato as documented by a history of ≥ 50% reduction in PHQ-9 score;
6. Dose does not exceed 168 mg per week during four week induction phase. Approval duration: 3 months (up to 23 nasal spray devices) B. Major Depressive Disorder with Suicidal Ideation or Behavior (must meet all):
7. Diagnosis of MDD;
   2. Prescribed by or in consultation with a psychiatrist;
   3. Age ≥ 18 years;
   4. Spravato is prescribed in combination with initiation or optimization of oral antidepressant therapy;
8. Member is recently (within the last 5 days) discharged from or currently in an acute or subacute inpatient care for suicidality;
   6. Member meets one of the following (a or b): a. No prior history of treatment with Spravato; b. Documentation of a prior positive response to Spravato (see Appendix E);
9. Member meets one of the following (a, b, or c): a. Montgomery-Åsberg Depression Rating Scale (MADRS) score is ≥ 20 (moderate depression) (see Appendix D); b. Hamilton Rating Scale for Depression (HAMD) score is ≥ 17 (moderate depression) (see Appendix D); c. PHQ-9 score is ≥ 15 (moderately severe depression) (see Appendix D);
10. Dose does not exceed 84 mg (3 nasal spray devices) twice weekly.
    Approval duration: 4 weeks (up to 23 nasal spray devices) C. Other diagnoses/indications (must meet 1 or 2):

11. 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: Page 2 of 11

    CLINICAL POLICY Esketamine CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

12. 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. Treatment-Resistant Depression (must meet all):
    
    1. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
13. Member is responding positively to therapy as evidenced by at least a 50% reduction in PHQ-9 score compared to baseline (see Appendix D);
14. Spravato is being used in combination with an oral antidepressant;
    4. If request is for a dose increase, new dose does not exceed 84 mg (3 nasal spray devices) per week. Approval duration: 6 months
       B. Major Depressive Disorder with Suicidal Ideation or Behavior
15. Re-authorization is not permitted. Members must meet the initial approval criteria.
    Approval duration: Not applicable C. Other diagnoses/indications (must meet 1 or 2):
16. 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

17. 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.
    Page 3 of 11

    CLINICAL POLICY Esketamine 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 MDD: major depressive disorder NMDA: non-competitive N-methyl D aspartate PHQ-9: Patient Health Questionnaire SNRI: serotonin norepinephrine reuptake inhibitor SSRI: selective serotonin reuptake inhibitor TCA: tricyclic antidepressant TRD: treatment-resistant depression 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.
    Dosing Regimen Drug Name Dose Limit/ Maximum Dose SSRI citalopram (Celexa®) escitalopram (Lexapro®) fluoxetine (Prozac®, Prozac Weekly®) paroxetine (Paxil®, Paxil CR®, Pexeva®) sertraline (Zoloft®) SNRIs duloxetine (Cymbalta®) venlafaxine (Effexor®, Effexor XR®) 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 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 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 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 200 mg/day 120 mg/day Effexor: 225 mg/day (outpatient) or 375 mg/day (inpatient)
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    CLINICAL POLICY Esketamine Drug Name Dosing Regimen Dose Limit/ Maximum Dose desvenlafaxine (Pristiq®, Khedezla®) Fetzima® (levomilnacipran) TCAs amitriptyline (Elavil®) amoxapine 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 50 to 100 mg/day PO QD or divided doses 150 mg/day 25 to 300 mg/day PO in divided doses 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 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) 15 mg/day 3 mg/day 4.5 mg/day 20 mg/day 400 mg/day 3 mg/day 10 to 60 mg/day PO in divided doses 25 to 150 mg/day PO QD 12.5 to 150 mg/day PO QD 25 to 300 mg/day PO QD 25 to 300 mg/day PO QD clomipramine (Anafranil®) desipramine (Norpramin®) doxepin (Sinequan®) imipramine HCl (Tofranil®)
    imipramine pamoate (Tofranil PM®) nortriptyline (Pamelor®) protriptyline (Vivactil®) trimipramine (Surmontil®) Second Generation Antipsychotics aripiprazole (Abilify®) Rexulti® (brexpiprazole) Vraylar® (cariprazine) olanzapine (Zyprexa®) quetiapine (Seroquel®) risperidone (Risperdal®)* 2 to 15 mg PO QD 0.5 to 3 mg PO QD 0.5 to 4.5 mg PO QD 5 to 20 mg PO QD 25 to 400 mg PO QD 0.25 to 3 mg PO QD 25 to 200 mg/day PO QD Page 5 of 11

    CLINICAL POLICY Esketamine Drug Name Dosing Regimen 20 to 80 mg PO BID Varies ziprasidone (Geodon®) Other Antidepressants bupropion (Aplenzin®, Budeprion SR® , Budeprion XL®, Forfivo XL®, Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®) Dose Limit/ Maximum Dose 160 mg/day Immediate-release: 450 mg/day (300 mg/day if pediatric) Sustained-release: 400 mg/day Extended-release (HCl): 450 mg/day Extended-release (HBr): 522 mg/day 60 mg/day 45 mg/day buspirone mirtazapine (Remeron®) lithium 15 to 20 mg/day PO in 2 divided doses 15 to 45 mg PO QD 300 mg PO QD or BID; up to 600 to 1,200 mg PO daily in divided doses 1,200 mg/day thyroid hormone 25 to 50 mcg/day PO 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 50 mcg/day Appendix C: Contraindications/Boxed Warnings • Spravato is not indicated for the treatment of bipolar depression.
    • Contraindication(s): o Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation. o History of intracerebral hemorrhage. o Hypersensitivity to esketamine, ketamine, or any of the excipients. • Boxed warning(s): o Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration.
    o Potential for abuse and misuse. Consider the risks and benefits of prescribing Spravato prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse. o Spravato is only available through a restricted program called the Spravato REMS.
    o 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. Spravato is not approved for use in pediatric patients. Spravato is available only through a restricted program under a REMS called the Spravato REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse. Page 6 of 11

    CLINICAL POLICY Esketamine • Healthcare settings must be certified in the REMS program and ensure that Spravato is: o Only dispensed in healthcare settings and administered to patients who are enrolled in the program. o Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of Spravato. o Pharmacies must be certified in the REMS and must only dispense Spravato to healthcare settings that are certified in the program. o Further information, including a list of certified pharmacies is available at www.Spravatorems.com or 1-855-382-6022. Appendix D: PHQ-9, MADRS, and HAM-D Rating Scales • The 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 10 – 14 Depression Severity Minimal symptoms Minor depression Major depression, mild Major depression, moderately severe Major depression, severe • The MADRS is a 10-item diagnostic questionnaire used to measure the severity of 15 – 19

    20 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 • The HAM-D17 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 24 Depression Rating Normal, absence or remission of depression Mild depression Moderate depression Severe depression Appendix E: General Information
    • Positive responses to therapy include but are not limited to:
    o Previous demonstrated improvement in depressive symptoms o Rapid reduction in depressive symptoms and thus rapid reduction in suicidality, either during hospitalization, or during a previous episode of suicidality. o Improvement from baseline in PHQ-9, MADRS, or HAM-D17 score. • The efficacy of Spravato for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study with patients receiving placebo or Spravato intranasally plus an oral antidepressant (TRANSFORM-3).
    o The trial included patients between the ages of 65 and 74 years old. Page 7 of 11

    CLINICAL POLICY Esketamine o At the end of four weeks, Spravato plus antidepressant did not achieve statistically significant difference when compared to those receiving placebo plus antidepressant on the primary efficacy endpoint of change from baseline to Week 4 on the MADRS.
    o During the double-blind phase, TEAEs occurred in 70.8% (51/72) of patients receiving antidepressant plus Spravato and 60.0% (39/65) receiving antidepressant plus placebo. Overall, safety results were consistent with those reported in previous esketamine studies in younger adults, including those in patients ≥ 75 years old. V. Dosage and Administration
    Indication TRD Dosing Regimen Administer in conjunction with an oral antidepressant. Maximum Dose 84 mg/dose Induction Phase
    Weeks 1 to 4: Administer nasally twice per week Day 1 starting dose: 56 mg Subsequent doses: 56 mg or 84 mg Maintenance Phase
    Weeks 5 to 8: Administer 56 mg or 84 mg nasally once weekly Week 9 and after: Administer 56 mg or 84 mg every 2 weeks or once weekly
    Administer in conjunction with an oral antidepressant. Administer 56 mg or 84 mg nasally twice weekly for 4 weeks.
    84 mg/dose Depressive symptoms with MDD with acute suicidal ideation or behavior VI. Product Availability
    Nasal spray: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg esketamine. VII.