ModifiedHealth NetPolicy CP.PMN.68

Clinical Policy: Brexpiprazole (Rexulti)

Defines medical necessity, prior authorization, and coverage criteria for brexpiprazole (Rexulti) for Commercial, HIM, and Medicaid lines of business governed by Health Net/Centene; applies to providers requesting coverage for indicated diagnoses.

Policy Summary

PayerHealth Net

PolicyClinical Policy: Brexpiprazole (Rexulti)

Policy CodePolicy CP.PMN.68

Change TypeMaterial revisions (indication addedschizophrenia step requirement reducedcontinued therapy revised)

Effective DateDec 1, 2015

Next Review DateN/A

Key ActionSubmit prior authorization with indication-specific documentation including prior trial history, age, and dosing to support medical necessity.

SourceLink

POLICY UPDATE CHANGES

For Schizophrenia, changed to failure of one of the following generic atypical antipsychotics (previously failure of two) to align with other atypical antipsychotics.

New indication added for treatment of agitation associated with dementia due to Alzheimer's disease.

Revised continued therapy criteria to allow continuity of care for MDD.

3FDA indications

12 moApproval duration

≥13Min age (schizophrenia)

≥18Min age (MDD/AD agitation)

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3–4 mgAdult max dose

State rulesAppendix D

Coverage Criteria for Brexpiprazole (Rexulti)

Initial approval — Major Depressive Disorder (MDD)

Covered when ALL of the following are met

MDD Initial Criteria: 1) Diagnosis of major depressive disorder (MDD); 2) Age >= 18 years; 3) Member meets one of the following (a or b): (a) Request is for a member in a State with limitations on therapy in certain mental health settings (see Appendix D) [state exception]; OR (b) Failure of THREE antidepressants from at least TWO different classes (e.g., SSRI, SNRI, TCA, bupropion, mirtazapine) at up to maximally indicated doses, each used for >= 4 weeks, unless unable due to clinically significant adverse effects, age >= 65 years, or contraindication(s) to multiple antidepressants; 4) Rexulti is prescribed concurrently with an antidepressant; 5) Alternatively, failure of a >= 4-week trial of aripiprazole used concurrently with an antidepressant unless contraindicated or clinically significant adverse effects are experienced; 6) Dose does not exceed both: a) 3 mg per day; and b) 1 tablet per day.

For Illinois HIM requests, step therapy requirements do not apply as of 1/1/2026 per IL HB 5395.

Initial approval — Schizophrenia

Covered when ALL of the following are met

Schizophrenia Initial Criteria: 1) Diagnosis of schizophrenia; 2) Age >= 13 years; 3) Member meets one of the following (a, b, or c): (a) Request is for a member in a State with limitations on therapy in certain mental health settings (see Appendix D) [state exception]; (b) Member has diabetes mellitus or BMI > 30 kg/m^2; OR (c) Failure of ONE of the following generic atypical antipsychotics at up to maximally indicated doses, each used for >= 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated: risperidone, quetiapine, olanzapine, ziprasidone; 4) Alternatively, failure of a >= 4-week trial of aripiprazole at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced; 5) Dose does not exceed both: a) 4 mg per day; and b) 1 tablet per day.

3Q2024 revision: schizophrenia step requirement changed to failure of one generic atypical antipsychotic (previously two). For Illinois HIM requests, step therapy requirements do not apply as of 1/1/2026 per IL HB 5395.

Initial approval — Agitation associated with Alzheimer’s disease (AD)

Covered when ALL of the following are met

AD-related agitation Initial Criteria: 1) Diagnosis of agitation associated with dementia due to Alzheimer’s disease; 2) Age >= 18 years; 3) Rexulti is not prescribed as an as-needed (PRN) treatment; 4) Dose does not exceed both: a) 3 mg per day; and b) 1 tablet per day.

Rexulti is not indicated as PRN treatment for agitation associated with dementia due to AD; dementia-related psychosis without AD-related agitation is excluded (see Appendix C boxed warning).

Continued therapy

Covered when ALL of the following are met

Continued therapy criteria: 1) Member is currently receiving Rexulti via the Centene benefit or has previously met initial approval criteria; 2) Documentation supports that member is currently receiving Rexulti for schizophrenia or major depressive disorder and has received this medication for at least 30 days; 3) Member is responding positively to therapy; 4) If request is for a dose increase, the new dose does not exceed indicated maxima (MDD/AD agitation: 3 mg/day; schizophrenia: 4 mg/day and 1 tablet/day).

Approval duration: Medicaid/HIM 12 months; Commercial 12 months or duration of request, whichever is less. 3Q2024 revision allows continuity of care for MDD.

Initial and indication-specific coverage

Covered when the following indication-specific criteria are met (per document notes and state variations):

Adjunctive MDD: Member has major depressive disorder and brexpiprazole is prescribed as adjunctive therapy to an antidepressant; dosing per label (start 0.5 mg or 1 mg PO QD up to target 2 mg; maximum 3 mg/day). Prior failures may be required per state rules (e.g., failure of aripiprazole or an antidepressant used for >= 4 weeks at maximally indicated doses) unless contraindicated or clinically significant adverse effects occur.

See Appendix D for state-specific step therapy and redirection rules (e.g., NV, TX, AR); Illinois HIM exceptions effective 1/1/2026.

Schizophrenia (Adult and Pediatric 13-17): Member has a diagnosis of schizophrenia. Adult dosing per label (start 1 mg PO QD up to target 2-4 mg; maximum 4 mg/day). Pediatric patients aged 13-17 follow pediatric dosing (start 0.5 mg PO QD up to target 2-4 mg). Prior failure of ONE generic atypical antipsychotic for >= 4 weeks at up to maximally indicated doses is required unless contraindicated or clinically significant adverse effects occur (changed from two agents in 3Q2024).

State variations and redirection rules apply; see Appendix D.

Agitation associated with dementia due to AD:

Dementia-related psychosis is explicitly listed as a diagnosis for which coverage is not authorized. Requests for Rexulti for dementia-related psychosis should be denied as not covered per policy.

Rexulti is not indicated as an as‑needed (PRN) treatment for agitation associated with dementia due to Alzheimer’s disease; PRN use for this indication is not covered under this policy. Prescriptions for AD‑related agitation must be for scheduled dosing consistent with the dosing limits specified in the policy.

Use of Rexulti for dementia‑related psychosis in the absence of agitation associated with Alzheimer’s disease is not approved and carries an increased risk of death in elderly patients with dementia‑related psychosis per the boxed warning. This policy therefore does not authorize Rexulti for dementia‑related psychosis without AD‑associated agitation.

The policy states that use of Rexulti for dementia‑related psychosis is not medically necessary (NMN) and is not authorized for coverage under this document.

Safety and effectiveness of Rexulti have not been established in pediatric patients with major depressive disorder. Use of Rexulti for MDD in pediatric patients is unsupported by this policy and should be considered non‑covered or not medically necessary in that population.

Provider Requirements and Prior Authorization

Prior Authorization

Prior Authorization Required

Prior authorization is required. Requests must meet indication-specific criteria and include documentation that prior therapies and step therapy requirements (when applicable) have been tried per the criteria below. Failure to obtain prior authorization or to meet indication-specific criteria may result in denial or delay.

Policy Number: CP.PMN.68
Effective Date: 2015-12-01

Step Therapy

Prior Authorization — Step Therapy Documentation

Documentation of prior failures per indication is required. For Major Depressive Disorder (MDD), documentation must show failure of aripiprazole or failure of antidepressant trials as specified (e.g., ≥3 antidepressants from ≥2 classes or a 4-week trial of aripiprazole used concurrently with an antidepressant) unless contraindicated. For schizophrenia, documentation must show failure of one of the listed generic atypical antipsychotics or a trial of aripiprazole at up to maximally indicated doses for ≥4 weeks unless contraindicated.

Pharmacotherapy and Treatment Details

Pharmacotherapy (brexpiprazole)

Pharmacotherapy (brexpiprazole): Follow labeled dosing and administration for each indication: MDD adjunctive dosing (0.5 or 1 mg PO QD up to target 2 mg; max 3 mg/day); schizophrenia adult dosing (1 mg PO QD up to target 2-4 mg; max 4 mg/day) and pediatric (13-17 years) dosing (0.5 mg PO QD up to target 2-4 mg); agitation due to AD dosing (0.5 mg PO QD up to target 2 mg; max 3 mg/day). Adjust dose for CYP2D6 poor metabolizers (reduce usual dosage by half), and reduce maximum recommended dosage for moderate-severe hepatic impairment and for CrCl < 60 mL/min per label.

Modality covers oral pharmacotherapy with brexpiprazole; adherence to indication-specific maxima and metabolic/hepatic/renal adjustments required.

Definitions, Warnings, and Background

Major Depressive Disorder — key term mapping (MDD)

TermMajor Depressive Disorder (MDD)

AbbreviationMDD

Age requirement (policy)Age ≥ 18 years for MDD indication

Alzheimer's disease — key term mapping (AD)

TermAlzheimer's disease (AD)

AbbreviationAD

Context in policyUsed in criteria for agitation associated with dementia due to Alzheimer’s disease

Coding, Appendix, and State Redirection Notes

Appendix D contains state‑specific redirection and step therapy details and limitations. Providers should consult Appendix D for applicable state rules, redirection bypasses, and step‑therapy requirements when submitting prior authorization requests.

Policy Summary

PayerHealth Net

PolicyClinical Policy: Brexpiprazole (Rexulti)

Policy CodePolicy CP.PMN.68

Change TypeMaterial revisions (indication addedschizophrenia step requirement reducedcontinued therapy revised)

Effective DateDec 1, 2015

Next Review DateN/A

Key ActionSubmit prior authorization with indication-specific documentation including prior trial history, age, and dosing to support medical necessity.

SourceLink

On This Page

Member has agitation associated with dementia due to Alzheimer’s disease; dosing per label (start 0.5 mg PO QD up to target 2 mg; maximum 3 mg/day). Rexulti is not approved for dementia-related psychosis without agitation associated with AD and carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis.

New indication added in 3Q2023; PRN use is not indicated.

MDD: trials at up to maximally indicated doses, each used ≥4 weeks unless intolerant or contraindicated

Schizophrenia: failure of ONE generic atypical antipsychotic (risperidone, quetiapine, olanzapine, ziprasidone) at up to maximally indicated doses for ≥4 weeks unless intolerant or contraindicated

Documentation Required

Clinical Documentation Required

Providers must submit supporting clinical documentation with the prior authorization request. Acceptable documentation includes office chart notes, medication trial records, laboratory results, and other clinical information demonstrating that the member meets all applicable criteria.

Include dates, doses, durations, and reasons for discontinuation (e.g., lack of efficacy, adverse effects, contraindication) for prior therapies
Failure to submit required documentation may result in denial or delayed processing

Denial Risk

Step Therapy / Redirection Risks and State Rules

State-specific step therapy and redirection rules apply. Some states (see Appendix D) prohibit or limit step therapy/redirection in certain mental health settings (for example, Arkansas prohibits step therapy for HIM requests; Illinois: step therapy requirements do not apply for HIM requests as of 1/1/2026). Failure to account for these state rules or applicable redirection bypass provisions may lead to denial or redirection of the request.

Refer to Appendix D for state-specific rules and any redirection bypass provisions (e.g., AR, IL, NV, TX)
If member is in a state or setting with limitations, indicate this in the request to ensure applicable bypass/redirection rules are applied

Documentation Required

Required Dosing Documentation

Prescriptions must follow dosing and maximum dose guidance and include documentation of dose prescribed. Use indication-specific dosing, pediatric dosing, and adjustments for hepatic/renal impairment or CYP2D6 poor metabolizers as specified in the policy.

MDD: start 0.5 or 1 mg PO QD, target up to 2 mg QD; maximum 3 mg/day
Schizophrenia (Adults): start 1 mg PO QD, target 2–4 mg QD; maximum 4 mg/day; Pediatrics (13–17 y): 0.5 mg PO QD up to 2–4 mg QD
Agitation due to AD: start 0.5 mg PO QD, target up to 2 mg QD; maximum 3 mg/day
Adjustments: reduce usual dose by half for CYP2D6 poor metabolizers; lower maximums for moderate–severe hepatic impairment and CrCl <60 mL/min as specified

Contraindications/Boxed Warnings

Boxed warning — increased mortalityElderly patients with dementia-related psychosis treated with antipsychotics are at increased risk of death

ContraindicationKnown hypersensitivity to Rexulti (brexpiprazole) or any of its components

Approval limitationRexulti is not approved for treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease

Suicide risk warning

Suicide risk warning — scopeAntidepressants increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients

Monitoring guidanceClosely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors

Pediatric MDD statusSafety and effectiveness of Rexulti have not been established in pediatric patients with MDD

Brexpiprazole (Rexulti) is an atypical antipsychotic with FDA‑approved indications for: adjunctive treatment of major depressive disorder in adults; treatment of agitation associated with dementia due to Alzheimer’s disease in adults; and treatment of schizophrenia in adults and patients aged ≥13 years. Dosing and maximum daily limits are indication‑specific (for example, max 3 mg/day for MDD and AD agitation, and max 4 mg/day for schizophrenia), and the policy incorporates these indication and dosing details along with prior‑trial and state‑specific step‑therapy considerations.