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UnitedHealthcare® Community Plan Medical Benefit Drug Policy Injectable Atypical Agents (for Kentucky Only)

Policy Number: CSKYD0242.01 Effective Date: September 1, 2021  Instructions for Use

Table of Contents Page Related Policies Application ...... 1 None Coverage Rationale ...... 1 Applicable Codes ...... 4 Clinical Evidence ...... 6 U.S. Food and Drug Administration ...... 9 References ...... 9 Policy History/Revision Information ...... 10 Instructions for Use ...... 10

Applicable States

This Medical Benefit Drug Policy only applies to the state of Kentucky.

Coverage Rationale

This policy refers to the following injectable atypical antipsychotic agents: Aristada Initio® ( lauroxil injection, suspension, extended release Aristada® ( injection, suspension, extended release Zyprexa® Relprevv™ ( pamoate) Invega Sustenna® () Risperdal Consta® () Perseris® (risperidone) Geodon® ( mesylate)

Aristada Initio and Aristada are proven and medically necessary when all of the following are met: Submission of medical records documenting the diagnosis of ; and Dose is administered in combination with oral aripiprazole; and One of the following: o Both of the following: . Submission of medical records demonstrating treatment failure after at least a two-week trial of one of the following preferred antipsychotic : Abilify Maintena (aripiprazole) decanoate Geodon (ziprasidone mesylate) injection decanoate haloperidol lactate Invega Sustenna (paliperidone) Invega Trinza (paliperidone) Risperdal Consta (risperidone) Zyprexa (olanzapine) injection

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and . Physician attests that in their clinical opinion, the clinical response would be expected to be superior with Aristada Initio or Aristada than experienced with the other products or o Both of the following: . History of intolerance, contraindication, or severe adverse event, to one of the following preferred antipsychotic therapies: Abilify Maintena (aripiprazole) fluphenazine decanoate Geodon (ziprasidone mesylate) injection haloperidol lactate Invega Sustenna (paliperidone) Invega Trinza (paliperidone) Risperdal Consta (risperidone) Zyprexa (olanzapine) injection and . Physician attests that in their clinical opinion, the same intolerance, contraindication, or severe adverse event would not be expected to occur with Aristada Initio or Aistada than experienced with the other products and Dosing is in accordance with the U.S. FDA approved labeling; and Prescribed by or in consultation with a psychiatrist; and Authorization will be for no longer than 12 months

Zyprexa Relprevv is proven and medically necessary when all of the following are met: Submission of medical records documenting the diagnosis of schizophrenia; and One of the following: o Both of the following: . Submission of medical records demonstrating treatment failure after at least a two-week trial of one of the following preferred antipsychotic therapies: Abilify Maintena (aripiprazole) fluphenazine decanoate Geodon (ziprasidone mesylate) injection haloperidol decanoate haloperidol lactate Invega Sustenna (paliperidone) Invega Trinza (paliperidone) Risperdal Consta (risperidone) Zyprexa (olanzapine) injection and . Physician attests that in their clinical opinion, the clinical response would be expected to be superior with Zyprexa Relprevv than experienced with the other products or o Both of the following: . History of intolerance, contraindication, or severe adverse event, to one of the following preferred antipsychotic therapies: Abilify Maintena (aripiprazole) fluphenazine decanoate Geodon (ziprasidone mesylate) injection haloperidol decanoate haloperidol lactate Invega Sustenna (paliperidone) Invega Trinza (paliperidone) Risperdal Consta (risperidone) Zyprexa (olanzapine) injection

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and . Physician attests that in their clinical opinion, the same intolerance, contraindication, or severe adverse event would not be expected to occur with Zyprexa Relprevv than experienced with the other products and Dosing is in accordance with the U.S. FDA approved labeling; and Prescribed by or in consultation with a psychiatrist; and Authorization will be for no longer than 12 months

Invega Sustenna is proven and medically necessary when all of the following are met: Submission of medical records documenting one of the following diagnoses: o Diagnosis of schizophrenia in adults o Diagnosis of in adults and One of the following: o Used as monotherapy; or o Used as an adjunct to mood stabilizers or and One of the following: o Patient has tried and failed risperidone; or o Patient has hepatic impairment evident by one of the following: . Elevated liver enzymes; or . Diagnosis suggestive of hepatic impairment and Dosing is in accordance with the U.S. FDA approved labeling; and Prescribed by or in consultation with a psychiatrist; and Authorization will be for no longer than 12 months

Risperdal Consta is proven and medically necessary when all of the following are met: Submission of medical records documenting one of the following diagnoses: o Treatment of schizophrenia; or o Maintenance treatment of and one of the following: . Used as monotherapy; or . Used as adjunctive to or and Patient has established tolerability with oral risperidone prior to initiating treatment; and Dosing is in accordance with the U.S. FDA approved labeling; and Prescribed by or in consultation with a psychiatrist; and Authorization will be for no longer than 12 months

Perseris is proven and medically necessary when all of the following are met: Submission of medical records documenting the diagnosis of schizophrenia; and Patient has established tolerability with oral risperidone prior to initiating treatment; and One of the following: o Both of the following: . Submission of medical records demonstrating treatment failure after at least a two-week trial of one of the following preferred antipsychotic therapies: Abilify Maintena (aripiprazole) fluphenazine decanoate Geodon (ziprasidone mesylate) injection haloperidol decanoate haloperidol lactate Invega Sustenna (paliperidone) Invega Trinza (paliperidone) Risperdal Consta (risperidone) Zyprexa (olanzapine) injection

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and . Physician attests that in their clinical opinion, the clinical response would be expected to be superior with Perseris than experienced with the other products or o Both of the following: . History of intolerance, contraindication, or severe adverse event, to one of the following preferred antipsychotic therapies: Abilify Maintena (aripiprazole) fluphenazine decanoate Geodon (ziprasidone mesylate) injection haloperidol decanoate haloperidol lactate Invega Sustenna (paliperidone) Invega Trinza (paliperidone) Risperdal Consta (risperidone) Zyprexa (olanzapine) injection and . Physician attests that in their clinical opinion, the same intolerance, contraindication, or severe adverse event would not be expected to occur with Perseris than experienced with the other products and Dosing is in accordance with the U.S. FDA approved labeling; and Prescribed by or in consultation with a psychiatrist; and Authorization will be for no longer than 12 months

Geodon is proven and medically necessary when all of the following are met: Submission of medical records documenting a diagnosis of schizoprenia; and Both of the following: o Patient has symptoms of acute agitation; and o Intramuscular antipsychotic medication is required for rapid control of agitation and Dosing is in accordance with the U.S. FDA approved labeling; and Prescribed by or in consultation with a psychiatrist; and Authorization will be for no longer than 12 months

Applicable Codes

The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this policy does not imply that the service described by the code is a covered or non-covered health service. Benefit coverage for health services is determined by the member specific benefit plan document and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Guidelines may apply.

HCPCS Code Description J1943 Injection, aripiprazole lauroxil, (aristada initio), 1 mg J1944 Injection, aripiprazole lauroxil, (aristada), 1 mg J2358 Injection, olanzapine, long-acting, 1 mg J2426 Injection, paliperidone palmitate extended release, 1 mg J2794 Injection, risperidone (risperdal consta), 0.5 mg J2798 Injection, risperidone, (perseris), 0.5 mg J3486 Injection, ziprasidone mesylate, 10 mg

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Diagnosis Code Description F20.0 Paranoid schizophrenia F20.1 Disorganized schizophrenia F20.2 Catatonic schizophrenia F20.3 Undifferentiated schizophrenia F20.5 Residual schizophrenia F20.81 Schizophreniform disorder F20.89 Other schizophrenia F20.9 Schizophrenia, unspecified F21 Schizotypal disorder F25.0 Schizoaffective disorder, bipolar type F25.1 Schizoaffective disorder, depressive type F25.8 Other schizoaffective disorders F25.9 Schizoaffective disorder, unspecified F31.0 , current episode hypomanic F31.10 Bipolar disorder, current episode manic without psychotic features, unspecified F31.11 Bipolar disorder, current episode manic without psychotic features, mild F31.12 Bipolar disorder, current episode manic without psychotic features, moderate F31.13 Bipolar disorder, current episode manic without psychotic features, severe F31.2 Bipolar disorder, current episode manic severe with psychotic features F31.30 Bipolar disorder, current episode depressed, mild or moderate severity, unspecified F31.31 Bipolar disorder, current episode depressed, mild F31.32 Bipolar disorder, current episode depressed, moderate F31.4 Bipolar disorder, current episode depressed, severe, without psychotic features F31.5 Bipolar disorder, current episode depressed, severe, with psychotic features F31.60 Bipolar disorder, current episode mixed, unspecified F31.61 Bipolar disorder, current episode mixed, mild F31.62 Bipolar disorder, current episode mixed, moderate F31.63 Bipolar disorder, current episode mixed, severe, without psychotic features F31.64 Bipolar disorder, current episode mixed, severe, with psychotic features F31.70 Bipolar disorder, currently in remission, most recent episode unspecified F31.71 Bipolar disorder, in partial remission, most recent episode hypomanic F31.72 Bipolar disorder, in full remission, most recent episode hypomanic F31.73 Bipolar disorder, in partial remission, most recent episode manic F31.74 Bipolar disorder, in full remission, most recent episode manic F31.75 Bipolar disorder, in partial remission, most recent episode depressed F31.76 Bipolar disorder, in full remission, most recent episode depressed F31.77 Bipolar disorder, in partial remission, most recent episode mixed F31.78 Bipolar disorder, in full remission, most recent episode mixed F31.9 Bipolar disorder, unspecified R45.1 Restlessness and agitation

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Clinical Evidence

The effectiveness of ARISTADA INITIO, in combination with oral aripiprazole, for initiation of ARISTADA when used for the treatment of schizophrenia in adults was established by adequate and well-controlled studies of oral aripiprazole and ARISTADA in adult patients with schizophrenia. The safety of ARISTADA INITIO, in combination with oral aripiprazole, for the initiation of ARISTADA when used for the treatment of schizophrenia in adults has been established and is based on clinical trials of ARISTADA (aripiprazole lauroxil) including 1019 adult patients with schizophrenia.

The efficacy of ARISTADA in the treatment of patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of ARISTADA was established in a 12-week, randomized, double-blind, placebo-controlled, fixed dose study in adult patients with schizophrenia meeting DSM-IV TR criteria [Study 1, n = 622; 207 (ARISTADA 441 mg monthly), 208 (ARISTADA 882 mg monthly), and 207 (placebo)]. After establishing tolerability to oral aripiprazole, patients received oral aripiprazole or placebo daily for the first 3 weeks. The intramuscular (IM) injections were administered on Days 1, 29 and 57. Efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I): The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210. The CGI-I rates improvement in mental illness on a scale of 1 (very much improved) to 7 (very much worse) based on the change from baseline in clinical condition. Eligible patients were 18 to 70 years of age with PANSS total score of 70 to 120 and a score of ≥4 for at least 2 of the selected Positive Scale items. Patients were also required to have a CGI-S score of ≥4. The primary efficacy variable was the change from baseline to endpoint (Day 85) in PANSS total score. Statistically significant separation from placebo on PANSS total score change was observed in each ARISTADA dose group.

The efficacy of ARISTADA 662 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months in the treatment of adults with schizophrenia was established by pharmacokinetic bridging which demonstrated that these dosing regimens resulted in plasma aripiprazole concentrations that are within the range provided by doses of 441 mg monthly and 882 mg monthly. As depicted in Figure 6, the doses of 441 mg monthly and 882 mg monthly showed clinical responses similar to each other in the ARISTADA placebo-controlled trial.

The short-term effectiveness of ZYPREXA RELPREVV was established in an 8-week, placebo-controlled trial in adult patients (n=404) who were experiencing psychotic symptoms and met DSM-IV or DSM-IV-TR criteria for schizophrenia. Patients were randomized to receive injections of ZYPREXA RELPREVV 210 mg every 2 weeks, ZYPREXA RELPREVV 405 mg every 4 weeks, ZYPREXA RELPREVV 300 mg every 2 weeks, or placebo every 2 weeks. Patients were discontinued from their previous and underwent a 2-7 day washout period. No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was change from baseline to endpoint in total Positive and Negative Syndrome Scale (PANSS) score (mean baseline total PANSS score 101). Total PANSS scores showed statistically significant improvement from baseline to endpoint with each dose of ZYPREXA RELPREVV (210 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks) as compared to placebo. The effectiveness of ZYPREXA RELPREVV in the treatment of schizophrenia is further supported by the established effectiveness of the oral formulation of olanzapine.

A longer-term trial enrolled patients with schizophrenia (n=1065) who had remained stable for 4 to 8 weeks on open-label treatment with oral olanzapine (mean baseline total PANSS score 56) and were then randomized to continue their current oral olanzapine dose (10, 15, or 20 mg/day); or to ZYPREXA RELPREVV 150 mg every 2 weeks (405 mg every 4 weeks, 300 mg every 2 weeks, or 45 mg every 4 weeks). No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was time to exacerbation of symptoms of schizophrenia defined in terms of increases in Brief Psychiatric Rating Scale (BPRS) positive symptoms or hospitalization. ZYPREXA RELPREVV doses of 150 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks were each statistically significantly superior to low dose ZYPREXA RELPREVV (45 mg every 4 weeks).

The efficacy of INVEGA SUSTENNA in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of INVEGA SUSTENNA in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies, i.e., at a weekly interval for the initial two doses and then every 4 weeks for maintenance. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative

Injectable Atypical Antipsychotic Agents (for Kentucky Only) Page 6 of 10 UnitedHealthcare Community Plan Medical Benefit Drug Policy Effective 09/01/2021 Proprietary Information of UnitedHealthcare. Copyright 2021 United HealthCare Services, Inc. symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of INVEGA SUSTENNA (initial deltoid injection of 234 mg followed by 3 gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA were superior to placebo in improving the PANSS total score. In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses of INVEGA SUSTENNA (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of INVEGA SUSTENNA was superior to placebo in improving the PANSS total score. In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses of INVEGA SUSTENNA (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA were superior to placebo in improving the PANSS total score. In Study 4 (SCH-201), the 9- week study (n=197) comparing two fixed doses of INVEGA SUSTENNA (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of INVEGA SUSTENNA were superior to placebo in improving PANSS total score.

The efficacy of INVEGA SUSTENNA in maintaining symptomatic control in schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included a minimum 12-week, fixed dose stabilization phase, and a randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of INVEGA SUSTENNA they received during the stabilization phase, i.e., 39 mg, 78 mg, or 156 mg administered every 4 weeks, or to placebo. A total of 410 stabilized patients were randomized to either INVEGA SUSTENNA or to placebo until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization, ≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was ≤ 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of ≥ 5 (if the maximum baseline score was ≤ 3) or ≥ 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with INVEGA SUSTENNA compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the INVEGA SUSTENNA group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of INVEGA SUSTENNA . A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 3. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the INVEGA SUSTENNA group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race. The efficacy of INVEGA SUSTENNA in delaying time to treatment failure compared with selected oral antipsychotic medications was established in a long-term, randomized, flexible-dose study in subjects with schizophrenia and a history of incarceration. Subjects were screened for up to 14 days followed by a 15-month treatment phase during which they were observed for treatment failure. The primary endpoint was time to first treatment failure. Treatment failure was defined as one of the following: arrest and/or incarceration; psychiatric hospitalization; discontinuation of antipsychotic treatment because of safety or tolerability; treatment supplementation with another antipsychotic because of inadequate efficacy; need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment because of inadequate efficacy; or suicide. Treatment failure was determined by an Event Monitoring Board (EMB) that was blinded to treatment assignment. A total of 444 subjects were randomly assigned to either INVEGA SUSTENNA (N = 226; median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly prescribed oral antipsychotic medications (N = 218; aripiprazole, haloperidol, olanzapine, paliperidone, , , or risperidone). The selection of the oral antipsychotic medication was determined to be appropriate for the patient by the investigator. A statistically significantly longer time to first treatment failure was seen for INVEGA SUSTENNA compared with oral antipsychotic medications. The median time to treatment failure was 416 days and 226 days for INVEGA SUSTENNA and antipsychotic medications, respectively.

The effectiveness of RISPERDAL CONSTA in the treatment of schizophrenia was established, in part, on the basis of extrapolation from the established effectiveness of the oral formulation of risperidone. In addition, the effectiveness of RISPERDAL CONSTA in the treatment of schizophrenia was established in a 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia. Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of 25 mg, 50 mg, or 75 mg RISPERDAL CONSTA or placebo every 2 weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral RISPERDAL . Patients who received RISPERDAL CONSTA were given doses of oral RISPERDAL (2 mg for patients in the 25-mg group, 4 mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for the 3 weeks after the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets. Efficacy was evaluated using the Positive and

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Negative Syndrome Scale (PANSS), a validated, multiitem inventory, composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and /depression. The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study was 81.5. Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic patients treated with each dose of RISPERDAL CONSTA (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no statistically significant differences between the treatment effects for the three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose group.

The effectiveness of RISPERDAL CONSTA for the maintenance treatment of Bipolar I Disorder was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on medications or experiencing an acute manic or mixed episode. A total of 501 patients were treated during a 26-week open-label period with RISPERDAL CONSTA (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were judged to be stable and were randomized to double-blind treatment with either the same dose of RISPERDAL CONSTA or placebo and monitored for relapse. The primary endpoint was time to relapse to any mood episode (depression, , , or mixed). Time to relapse was delayed in patients receiving RISPERDAL CONSTA monotherapy as compared to placebo. The majority of relapses were due to manic rather than depressive symptoms. Based on their bipolar disorder history, subjects entering this study had had, on average, more manic episodes than depressive episodes.

The effectiveness of RISPERDAL CONSTA as an adjunct to treatment with lithium or valproate for the maintenance treatment of Bipolar Disorder was established in a multi-center, randomized, doubleblind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at least 4 episodes of requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study. A total of 240 patients were treated during a 16-week open-label period with RISPERDAL CONSTA (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg), as adjunctive therapy in addition to continuing their treatment as usual for their bipolar disorder, which consisted of mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first three weeks of the initial RISPERDAL CONSTA injection. In the open-label phase, 124 (51.7%) were judged to be stable for at least the last 4 weeks and were randomized to double-blind treatment with either the same dose of RISPERDAL CONSTA or placebo in addition to continuing their treatment as usual and monitored for relapse during a 52-week period. The primary endpoint was time to relapse to any new mood episode (depression, mania, hypomania, or mixed). Time to relapse was delayed in patients receiving adjunctive therapy with RISPERDAL CONSTA as compared to placebo. The relapse types were about half depressive and half manic or mixed episodes.

Efficacy for PERSERIS was demonstrated in an 8-week, randomized, double-blind, placebo-controlled study (Study 1, NCT #02109562). The study evaluated the efficacy, safety and tolerability of PERSERIS (90 and 120 mg subcutaneous every 4- weeks) compared with placebo in adults (age 18- to 55-years, inclusive) experiencing acute exacerbations of schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score of 80- to 120-inclusive (moderate to severely ill) at the screening visit, occurring 3- to 8-days before the start of double-blind treatment, without an improvement in the PANSS total score of ≥ 20% between screening and the first dosing day. At the screening visit, all patients received two doses of 0.25 mg oral risperidone 24-hours apart to establish tolerability. Patients were then placed in an inpatient setting, if not already hospitalized, and tapered off their current oral antipsychotic medication (if they were taking one) over a period of 3- to 8-days. Patients were randomized to receive 2 doses of subcutaneous PERSERIS (90 mg or 120 mg) or placebo 28-days apart (on Day 1 and Day 29). No supplemental oral risperidone was permitted during the study. The primary endpoint was the change in PANSS total score from baseline to end of study (Day 57). Both PERSERIS 90 and 120 mg doses demonstrated a statistically significant improvement compared with placebo based on the primary endpoint. Characteristics of the patient population were balanced across the treatment groups. The mean baseline PANSS total score ranged from 94 to 96 across the groups. Most patients were male (74 to 83% per group), and the mean ages were 40 to 43 in each group. Most patients in this study were black or African American (71 to 75% per group). Of the 354 subjects randomized to treatment, 337 were included in the intent- to-treat (ITT) population, and 259 (73%) completed the study. The secondary efficacy endpoint was defined as the CGI-S score at Day 57. Both PERSERIS treatment groups demonstrated statistically significantly better CGI-S scores versus placebo.

The efficacy of intramuscular ziprasidone in the management of agitated schizophrenic patients was established in two short- term, double-blind trials of schizophrenic subjects who were considered by the investigators to be "acutely agitated" and in

Injectable Atypical Antipsychotic Agents (for Kentucky Only) Page 8 of 10 UnitedHealthcare Community Plan Medical Benefit Drug Policy Effective 09/01/2021 Proprietary Information of UnitedHealthcare. Copyright 2021 United HealthCare Services, Inc. need of IM antipsychotic medication. In addition, patients were required to have a score of 3 or more on at least 3 of the following items of the PANSS: anxiety, tension, hostility and excitement. Efficacy was evaluated by analysis of the area under the curve (AUC) of the Behavioural Activity Rating Scale (BARS) and Clinical Global Impression (CGI) severity rating.

The BARS is a seven point scale with scores ranging from 1 (difficult or unable to rouse) to 7 (violent, requires restraint). Patients' scores on the BARS at baseline were mostly 5 (signs of overt activity [physical or verbal], calms down with instructions) and as determined by investigators, exhibited a degree of agitation that warranted intramuscular therapy. There were few patients with a rating higher than 5 on the BARS, as the most severely agitated patients were generally unable to provide informed consent for participation in premarketing clinical trials. Both studies compared higher doses of ziprasidone intramuscular with a 2 mg control dose. In one study, the higher dose was 20 mg, which could be given up to 4 times in the 24 hours of the study, at interdose intervals of no less than 4 hours. In the other study, the higher dose was 10 mg, which could be given up to 4 times in the 24 hours of the study, at interdose intervals of no less than 2 hours. The results of the intramuscular ziprasidone trials follow: In a one-day, double-blind, randomized trial (n=79) involving doses of ziprasidone intramuscular of 20 mg or 2 mg, up to QID, ziprasidone intramuscular 20 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 4 hours, and by CGI severity at 4 hours and study endpoint. In another one-day, double-blind, randomized trial (n=117) involving doses of ziprasidone intramuscular of 10 mg or 2 mg, up to QID, ziprasidone intramuscular 10 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 2 hours, but not by CGI severity.

U.S. Food and Drug Administration (FDA)

This section is to be used for informational purposes only. FDA approval alone is not a basis for coverage.

Aristada Initio®, in combination with oral aripiprazole, is indicated for the initiation of Aristada® when used for the treatment of schizophrenia in adults.

Aristada® is indicated for the treatment of schizophrenia in adults.

Zyprexa® Relprevv™ is indicated for the treatment of schizophrenia.

Invega Sustenna® (paliperidone palmitate) is indicated for the treatment of: Schizophrenia in adults and Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants

Risperdal Consta® is indicated for the treatment of schizophrenia and as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder

Perseris® is indicated for the treatment of schizophrenia in adults

Geodon® intramuscular is indicated for the treatment of acute agitation in schizophrenic adult patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of agitation.

References

1. Aristada Initio® [prescribing information]. Waltham, MA: , Inc.; October 2020. 2. Aristada® [prescribing information] . Waltham, MA: Alkermes, Inc.; October 2020. 3. Zyprexa® Relprevv™ [prescribing information]. Indianapolis, IN: ; April 2020. 4. Invega Sustenna® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; July 2018. 5. Risperdal Consta® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; July 2020. 6. Perseris™ [prescribing information]. Greenville, NC: Patheon Manufacturing Services; December 2019. 7. Geodon [prescribing information]. New York, NY: Pfizer Inc.; October 2020.

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8. Ziprasidone mesylate [prescribing information]. Princeton, NJ: Dr.Reddy’s Laboratories Inc.; January 2020.

Policy History/Revision Information

Date Summary of Changes 09/01/2021 • New Medical Benefit Drug Policy

Instructions for Use

This Medical Benefit Drug Policy provides assistance in interpreting UnitedHealthcare standard benefit plans. When deciding coverage, the federal, state, or contractual requirements for benefit plan coverage must be referenced as the terms of the federal, state, or contractual requirements for benefit plan coverage may differ from the standard benefit plan. In the event of a conflict, the federal, state, or contractual requirements for benefit plan coverage govern. Before using this policy, please check the federal, state, or contractual requirements for benefit plan coverage. UnitedHealthcare reserves the right to modify its Policies and Guidelines as necessary. This Medical Benefit Drug Policy is provided for informational purposes. It does not constitute medical advice.

UnitedHealthcare uses InterQual® for the primary medical/surgical criteria, and the American Society of Addiction Medicine (ASAM) for substance use, in administering health benefits. If InterQual® does not have applicable criteria, UnitedHealthcare may also use UnitedHealthcare Medical Benefit Drug Policies. The UnitedHealthcare Medical Benefit Drug Policies are intended to be used in connection with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice.

Injectable Atypical Antipsychotic Agents (for Kentucky Only) Page 10 of 10 UnitedHealthcare Community Plan Medical Benefit Drug Policy Effective 09/01/2021 Proprietary Information of UnitedHealthcare. Copyright 2021 United HealthCare Services, Inc.