Cariprazine (Vraylar) Form

Cariprazine (Vraylar®) is an atypical antipsychotic. FDA Approved Indication(s) Vraylar is indicated for: • Treatment of schizophrenia in adults • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults • Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults • Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults 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 Vraylar is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Bipolar Disorder and Schizophrenia (must meet all):

1. Diagnosis of bipolar disorder or schizophrenia;
2. Age ≥ 18 years;

3. Member meets one of the following (a or b):
   a. Request is for the treatment of a member in a State with limitations on step therapy in certain mental health settings (see Appendix D); b. Failure of two preferred atypical antipsychotics (e.g., aripiprazole, ziprasidone, quetiapine, risperidone, olanzapine) at up to maximally indicated doses, each used for ≥ 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated;

   4. Dose does not exceed any of the following (a or b): a. Schizophrenia or manic or mixed episodes of bipolar I disorder (i and ii):
      i. 6 mg per day; ii. 1 capsule per day; b. Depressive episodes of bipolar I disorder (i and ii):
      i. 3 mg per day; ii. 1 capsule per day. Page 1 of 11

   CLINICAL POLICY Cariprazine Approval duration: Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less B. Major Depressive Disorder (must meet all):

   1. Diagnosis of MDD;
4. Age ≥ 18 years;
5. Member meets one of the following (a or b):
   a. Request is for the treatment of a member in a State with limitations on step therapy in certain mental health settings (see Appendix D); b. Failure of THREE antidepressants from at least TWO different classes (e.g., selective serotonin reuptake inhibitor [SSRI], serotonin-norepinephrine reuptake inhibitor [SNRI], tricyclic antidepressant [TCA], bupropion, mirtazapine) at up to maximally indicated doses, each used for ≥ 4 weeks, unless member is unable to satisfy this requirement due to clinically significant adverse effects experienced, member’s age ≥ 65 years, or contraindication(s) to multiple antidepressants;
   4. Member meets one of the following (a or b): a. Request is for the treatment of a member in a State with limitations on step therapy in certain mental health settings (see Appendix D); b. Failure of a ≥ 4-week trial of aripiprazole at up to maximally indicated doses, used concurrently with an antidepressant, unless contraindicated or clinically significant adverse effects are experienced;
   5. Vraylar is prescribed concurrently with an antidepressant;

6. Dose does not exceed both of the following (a and b): a. 3 mg per day; b. 1 capsule per day.
   Approval duration: Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less C. 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) 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
   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 Page 2 of 11

   CLINICAL POLICY Cariprazine of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. All Indications in Section I (must meet all):

   1. Member meets one of the following (a, b, or c):
      a. Currently receiving medication via Centene benefit, or member has previously met initial approval criteria;
      b. Documentation supports that member is currently receiving Vraylar for bipolar disorder or schizophrenia and has received this medication for at least 30 days; c. 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);
7. Member is responding positively to therapy;

8. If request is for a dose increase, new dose does not exceed any of the following (a or b): a. Schizophrenia or manic or mixed episodes of bipolar I disorder (I and ii):
   i. 6 mg per day; ii. 1 capsule per day; b. Depressive episodes of bipolar I disorder or MDD (i and ii):
   i. 3 mg per day; ii. 1 capsule per day. Approval duration:
   Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less 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) 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
   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, and CP.PMN.53 for Medicaid.
      Page 3 of 11

   CLINICAL POLICY Cariprazine 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;
   B. Dementia-related psychosis.
   IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration MDD: major depressive disorder 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 Antipsychotics aripiprazole (Abilify®) olanzapine (Zyprexa®) Bipolar Disorder and Schizophrenia Adults: 10 to 15 mg PO QD Schizophrenia Initial: 5 to 10 mg PO QD; target: 10 mg PO QD 30 mg/day 20 mg/day quetiapine (Seroquel®) risperidone (Risperdal®) ziprasidone (Geodon®) Bipolar Disorder Monotherapy: 10 to 15 mg PO QD; adjunct to lithium or valproate: 10 mg PO QD
   Schizophrenia Initial: 25 mg PO BID; target: 400 to 800 mg/day Bipolar Disorder Initial: 50 mg PO BID; target: 400 to 800 mg/day Schizophrenia Initial: 1 mg PO BID or 2 mg PO QD; target: 4 to 8 mg PO QD Bipolar Disorder 2 to 3 mg PO QD Schizophrenia 20 mg PO BID Page 4 of 11 800 mg/day Schizophrenia: 16 mg/day Bipolar Disorder: 6 mg/day 160 mg/day

   CLINICAL POLICY Cariprazine Drug Name Dosing Regimen Dose Limit/ Maximum Dose Bipolar Disorder Initial: 40 mg PO BID; target: 40 to 80 mg PO BID Selective Serotonin Reuptake Inhibitors (SSRIs) citalopram (Celexa®) escitalopram (Lexapro®) fluoxetine (Prozac®) fluvoxamine
   (immediate-release) (Luvox®) paroxetine (Paxil®, Paxil CR®, Pexeva®) Major Depressive Disorder Refer to prescribing information sertraline (Zoloft®) Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) desvenlafaxine (Pristiq®) duloxetine (Cymbalta®) Fetzima® (levomilnacipran)
   venlafaxine (Effexor®, Effexor XR®) Tricyclic Antidepressant (TCAs) amitriptyline (Elavil®) amoxapine Major Depressive Disorder Refer to prescribing information clomipramine (Anafranil®) Major Depressive Disorder Refer to prescribing information 40 mg/day 20 mg/day Immediate-release: 80 mg/day (20 mg/day if pediatric) Delayed-release:
   90 mg/week 150 mg/day Immediate-release: 50 mg/day (40 mg/day if geriatric) Extended-release: 62.5 mg/day (50 mg/day if geriatric) 200 mg/day (20 mg/day if age 6-11 years) 400 mg/day 120 mg/day 120 mg/day Extended-release: 225 mg/day 150 mg/day 400 mg/day (300 mg/day if geriatric) 250 mg/day (200 mg/day if pediatric) Page 5 of 11

   CLINICAL POLICY Cariprazine Drug Name Dosing Regimen desipramine (Norpramin®) doxepin (Sinequan®) imipramine HCl (Tofranil®) imipramine pamoate (Tofranil PM®) nortriptyline (Pamelor®) protriptyline (Vivactil®) trimipramine (Surmontil®) Major Depressive Disorder Refer to prescribing information Monoamine Oxidase Inhibitors isocarboxazid (Marplan®) phenelzine (Nardil®) selegiline (EMSAM® transdermal; Eldepryl®, Zelapar®, Carbex®) tranylcypromine (Parnate®) Other Antidepressants bupropion (Aplenzin®, Budeprion SR® , Budeprion XL®, Forfivo XL®, Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®) mirtazapine (Remeron®) perphenazine/ amitriptyline (Triavil®) maprotiline (Ludiomil®) nefazodone (Serzone®) Major Depressive Disorder Refer to prescribing information Page 6 of 11 Dose Limit/ Maximum Dose 300 mg/day (100 mg/day if pediatric) 300 mg/day 200 mg/day (150 mg/day if geriatric or pediatric) 200 mg/day (100 mg/day 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) 60 mg/day 90 mg/day Transdermal:
   12 mg/24 hr Oral: 30 mg/day 60 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 45 mg/day 16 mg/day perphenazine and 200 mg/day amitriptyline 150 mg/day 600 mg/day

   CLINICAL POLICY Cariprazine Drug Name Dosing Regimen trazodone (Desyrel®, Oleptro®) Dose Limit/ Maximum Dose Immediate-release: 400 mg/day Extended-release: 375 mg/day 20 mg/day 40 mg/day vortioxetine (Trintellix®) vilazodone (Viibryd®) 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. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): known hypersensitivity to Vraylar • Boxed warning(s): Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Vraylar is not approved for the treatment of patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Safety and effectiveness of Vraylar have not been established in pediatric patients.
   Appendix D: States with Limitations against Redirections in Certain Mental Health Settings State Step Therapy Prohibited? Yes Notes AR NV No Applies to HIM requests only For the treatment of psychosis and serious mental illness through antipsychotic prescription drugs, no step therapies allowed. Applies to Medicaid requests only • MDD: Failure of aripiprazole or an antidepressant (e.g., selective serotonin reuptake inhibitor [SSRI], serotonin- norepinephrine reuptake inhibitor [SNRI], tricyclic antidepressant [TCA], bupropion, mirtazapine) at up to maximally indicated doses, used for ≥ 4 weeks, unless member is unable to satisfy this requirement due to clinically significant adverse effects experienced, member’s age ≥ 65 years, or contraindication(s) to multiple antidepressants. • Bipolar Disorder and Schizophrenia: Failure of ONE preferred atypical antipsychotic (e.g., aripiprazole, ziprasidone, quetiapine, risperidone, olanzapine) at up to maximally indicated doses, each used for ≥ 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated. TX No Applies to HIM requests only • MDD: Failure of aripiprazole or an antidepressant (e.g., selective serotonin reuptake inhibitor [SSRI], serotonin- norepinephrine reuptake inhibitor [SNRI], tricyclic antidepressant [TCA], bupropion, mirtazapine) at up to maximally indicated doses, used for ≥ 4 weeks, unless Page 7 of 11

   CLINICAL POLICY Cariprazine State Step Therapy Prohibited? Notes member is unable to satisfy this requirement due to clinically significant adverse effects experienced, member’s age ≥ 65 years, or contraindication(s) to multiple antidepressants. • Bipolar Disorder and Schizophrenia: Failure of ONE preferred atypical antipsychotic (e.g., aripiprazole, ziprasidone, quetiapine, risperidone, olanzapine) at up to maximally indicated doses, each used for ≥ 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated. V. Dosage and Administration
   Indication Schizophrenia Bipolar I disorder Manic or mixed episodes: 3 mg to 6 Dosing Regimen 1.5 mg to 6 mg PO QD MDD mg PO QD Depressive episodes: 1.5 mg or 3 mg PO QD As adjunct to antidepressants: 1.5 mg to 3 mg PO QD Maximum Dose 6 mg/day Manic or mixed episodes: 6 mg/day Depressive episodes: 3 mg/day 3 mg/day VI. Product Availability
   Capsules: 1.5 mg, 3 mg, 4.5 mg, 6 mg VII.