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SUMMACARE PHARMACY & THERAPEUTICS COMMITTEE MONOGRAPH November, 2015 PREPARED BY MEDIMPACT HEALTHCARE SYSTEMS, INC Rexulti (brexpiprazole) GENERIC BRAND STRENGTH DOSAGE FORM ROUTE GPID (GCN) EXCEPTION/OTHER brexpiprazole Rexulti 0.25, 0.5, 1, 2, 3 and 4 mg tablet oral 38278, 38476, 38589, 38609, 38618, 38619 MANUFACTURER Otsuka Pharmaceutical Co. FDA APPROVED INDICATION(S) Rexulti is an atypical antipsychotic indicated for: Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) Treatment of schizophrenia DRUG CLASS BEHAVIORAL HEALTH OTHER; ANTIPSYCHOTICS, ATYP, D2 PARTIAL AGONIST/5HT MIXED PLACE IN THERAPY Rexulti is the newest addition to the second generation (atypical) antipsychotic class which currently contains Abilify (aripiprazole), Clozaril (clozapine), Fanapt (iloperidone), Geodon (ziprasidone), Invega (paliperidone), Latuda (lurasidone), Risperdal (risperidone), Saphris (asenapine), Seroquel (quetiapine) and Zyprexa (olanzapine). Of these agents, only Abilify, Clozaril, Zyprexa, Seroquel, Risperdal, and Geodon have generic therapeutic equivalents available. Rexulti is currently indicated for the treatment of schizophrenia and as an adjunct to antidepressants for the treatment of MDD. Currently, there are 2.4 million adults in the United States (U.S.) diagnosed with schizophrenia. Schizophrenia is a mental disorder in which patients lose touch with reality, unable to differentiate between what is real and what is not. Patients typically experience positive symptoms such as hallucinations and delusions, and some also experience negative symptoms such as loss in pleasure and the ability to engage in goal directed activities. Patients with schizophrenia can pose a danger to themselves and others. Therefore, it is important to manage their symptoms to mitigate potential harm. Antipsychotics are considered first line treatment for schizophrenia and have been shown to reduce the positive symptoms of hallucinations and delusions. Current practice deems all antipsychotics, with the exception of clozapine, equivalent in their efficacy for the treatment of schizophrenia. Clozapine has been shown to have a higher efficacy than other antipsychotics but due to its high side effect profile, clozapine is reserved only for refractory schizophrenia or those with suicidal ideation. Given the similar efficacies, the main determining factors in choosing an initial antipsychotic for schizophrenia are the side effect profile and the ease of administration. Although all antipsychotics are indicated for the treatment of schizophrenia, the evidence for its use in the treatment of Major Depressive Disorder (MDD) has grown in the last decade. Currently Abilify, Seroquel, and Zyprexa are FDA approved for augmenting antidepressants. MDD is a chronic and recurrent mood disorder that affects approximately 15 million people in the U.S. It is characterized by depressed mood or loss of interest in daily activities for at least a two week period. First line treatment for MDD is the use of an antidepressant such as a November 2015 Page 1

selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI). However, despite treatment, most patients do not achieve adequate response or remission with antidepressants alone. Augmentation therapy with a second generation antipsychotic has been shown to increase remission rates and yield early treatment effects on core depressive symptoms. Rexulti may offer an alternate treatment option for patients that do not respond adequately or are intolerant to other antipsychotics. Similar to Abilify, Rexulti has a mild side effect profile, with the main adverse effects being weight gain and akathisia (the need for constant movement). Rexulti is taken once daily and is available only as an oral tablet. No trials have been conducted directly comparing Rexulti with other antipsychotics. There are ongoing clinical trials for Rexulti in the treatment of agitation associated with dementia due to Alzheimer s disease which may expand the treatment population eligible for Rexulti. EFFICACY The efficacy of Rexulti in the treatment of schizophrenia was assessed in two 6 week, randomized, double blind, placebo controlled, fixed dose trials in 1,076 patients meeting the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM IV TR) criteria for schizophrenia. The first study (referred to as Study 3) consisted of 536 patients while the second study (Study 4) consisted of 540 patients. Patients in both studies were randomized in a 1:1:1 ratio to receive maintenance doses of either Rexulti 2 mg by mouth daily, Rexulti 4 mg daily or placebo. Patients in the Rexulti treatment groups were initiated on Rexulti 1 mg by mouth daily during days 1 to 4 and titrated to 2 mg daily on days 5 to 7. Patients in the 4 mg treatment group were then titrated up to 4 mg by mouth daily on day 8 and maintained at the 4 mg dose for the remaining 5 weeks of the trial. The primary efficacy outcome in both studies was the change in the Positive and Negative Syndrome Scale (PANSS) score at week 6 from baseline. PANSS is a 30 item scale that measures the positive and negative symptoms of schizophrenia as well as general psychopathology. PANSS scores range from 30 being the best to 210 being the worst. In both studies, patients on either dose of Rexulti had a greater decrease in PANSS score compared to placebo although the decrease in study 4 for the 2 mg dose of Rexulti was not statistically significant (see Table 1). Table 1. Summary of Efficacy Results for Studies in Schizophrenia (from Rexulti Prescribing Information) The efficacy of Rexulti in the treatment of MDD was assessed in two 6 week, double blind, placebo controlled, fixed dose trials in 980 patients meeting the DSM IV TR criteria for MDD (+/ anxiety symptoms) who had an inadequate response to prior antidepressant therapy (1 to 3 courses) and demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment before randomization. Study 1 consisted of 353 November 2015 Page 2

patients randomized in a 1:1 ratio to either receive Rexulti 2 mg by mouth daily or placebo with their current antidepressant therapy. Study 2 consisted of 627 patients randomized in a 1:1:1 ratio to either receive Rexulti 1 mg by mouth daily, Rexulti 3 mg daily or placebo with their current antidepressant therapy. Patients in the Rexulti treatment groups were initiated on Rexulti 0.5 mg by mouth daily for the first week, 1 mg by mouth daily for the second week and either maintained at 1 mg by mouth daily for the remainder of the 6 weeks or increased to either 2 or 3 mg by mouth daily during week 3 depending on their treatment arm. The primary outcome was the change in the Montgomery Asberg Depression Rating Scale (MADRS) score at week 6 from baseline. MADRS is a 10 item scale that assesses depressive symptomatology with 0 representing no symptoms and 60 representing the worst symptoms. Rexulti at all doses showed a greater decrease in MADRS score than placebo but only the 2 mg dose of Rexulti showed a statistically significant decrease (see Table 2). Table 2. Summary of Efficacy Results for Studies 1 and 2 for the Adjunctive Treatment of MDD (from Rexulti Prescribing Information) SAFETY Similar to other antipsychotics, Rexulti has a black box warning for increased risk of death in elderly patients with dementia related psychosis. Due to its additional indication for MDD, Rexulti also has a standard black box warning against antidepressants increasing the risk of suicidal thoughts and behaviors in patients of age 24 years and younger. In addition, Rexulti also has many warnings and precautions that are common among the antipsychotics. These include increased risk for: cerebrovascular adverse events in elderly patients with dementia, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia, hyperlipidemia, weight gain, neutropenia, leukopenia, agranulocytosis, orthostatic hypotension, and seizures. Common adverse effects seen while using Rexulti for MDD (reported as absolute treatment effect) include akathisia (7%), weight gain (5%), somnolence (4.5%) and restlessness (3%). Adverse reactions lead to the discontinuation of treatment in 3% of Rexulti treated patients compared to 1% in the placebo group. For schizophrenia, the most common adverse effects associated with Rexulti (reported as absolute treatment effect) were weight gain (2%), tremor (2%), and akathisia (1%). Although Rexulti has not been studied in pregnancy, use of antipsychotics during the third trimester of pregnancy increases the risk for extrapyramidal and withdrawal symptoms in the newborn. In animal reproduction studies, November 2015 Page 3

no teratogenicity was observed with oral administration of Rexulti to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of maximum recommended human dose (MRHD) of 4 mg/day on a mg/m 2 basis. However, when pregnant rats were administered Rexulti during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD. No lactation studies have been conducted with Rexulti but Rexulti is present in rat milk. Rexulti use has not been studied in pediatric and geriatric populations but based on a safety trial, the pharmacokinetics of Rexulti in elderly patients taking up to Rexulti 3 mg by mouth daily for 14 days were comparable to nonelderly populations. Dose adjustment of Rexulti is recommended in poor CYP2D6 metabolizers, patients with moderate to severe hepatic impairment (Child Pugh score 7) and patients with moderate, severe or end stage renal impairment (CrCl <60 ml/min). Rexulti is metabolized via CYP3A4 and CYP2D6. Therefore, dose reduction of Rexulti is recommended when used concomitantly with CYP3A4 and 2D6 inhibitors. However, no dose adjustment is required when using Rexulti with paroxetine and fluoxetine even though they are strong CYP2D6 inhibitors because their inhibition properties were already accounted for in the dosing recommendations. A dose increase of Rexulti is also recommended if used concomitantly with a CYP3A4 inducer. DOSAGE For schizophrenia, the recommended starting dose is 1 mg by mouth daily on days 1 to 4. Titrate to 2 mg daily on days 5 to 7 and then 4 mg daily on day 8 based on the patient s clinical response and tolerability. The maximum recommended daily dosage is 4 mg. For MDD, the recommended Rexulti starting dose is 0.5 to 1 mg by mouth daily. Titrate weekly to a target dose of 2 mg daily based on the patient s clinical response and tolerability. Rexulti can be taken with or without food. The patient should be reassessed periodically to determine appropriate dosage and continued need for treatment. In patients with moderate to severe hepatic impairment (Child Pugh score 7) or patients with moderate, severe or end stage renal impairment (CrCl <60 ml/min), the maximum recommended dose is 2 mg for MDD and 3 mg for schizophrenia. Dose adjustments as shown in Table 3 are also required in CYP2D6 poor metabolizers and patients taking CYP2D6 inhibitors or CYP3A4 inducers or inhibitors. Table 3. Dosage Adjustments of Rexulti for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP3A4 and CYP2D6 Inhibitors and/or CYP3A4 Inducers (from Rexulti Prescribing Information) November 2015 Page 4

COST DRUG REGIMEN COST/UNIT COST PER 30 DAYS Rexulti (brexpiprazole) 0.25, 0.5, 1, 2, 3 and 4 mg oral tablets MDD: 2mg daily Schizophrenia: 4 mg daily AWP= $34.62 (all strengths) $1039 Abilify (aripiprazole) 2, 5, 10, 15, 20 and 30 mg oral tablets Seroquel XR (quetiapine) 150, 200, 300, 400 mg tablet Zyprexa (olanzapine) 5mg, 10mg, 20mg Risperdal (risperidone) 1, 2, 3, 4 mg tablet Geodon (ziprasidone) 20, 40, 60, 80 mg capsule Invega (paliperidone) 3, 6, 9 mg tablet MDD: 2 15mg daily Schizophrenia: 15 30 mg daily MDD: 150 300mg daily Schizophrenia: 400 800mg daily MAC= $14.49 $435 to $660 (2, 5, 10, 15mg) MAC=$21.99 (20 & 30mg) AWP= $16.38 $27.78 $491 to $1,660 Schizophrenia:10 20mg daily MAC=$0 18 $0.45 $5 to $14 Treatment resistant depression:5 20mg daily Schizophrenia: 2 8mg daily MAC=$0.12 $0.25 $7 to $15 Schizophrenia: 20mg 80mg BID MAC=$1.68 $1.97 $101 to $118 Schizophrenia: 3 12mg daily AWP= $23.09 $33.99 $693 to $2039 FORMULARY PLACEMENT RECOMMENDATIONS Based on this initial assessment of available clinical and financial information, consider NOT ADDING Rexulti to the formulary pending complete review by the appropriate oversight committee for the plan. Commercial: Specialty with Step Therapy Trial of two atypical antipsychotics, SSRIs, or SNRIs and Quantity limit of 1 tablet daily HIEx: Specialty with Step Therapy Trial of two atypical antipsychotics, SSRIs, or SNRIs and Quantity limit of 1 tablet daily REFERENCES Rexulti [Prescribing Information]. Otsuka Pharmaceutical Co.: Tokyo, Japan July 2015. Otsuka Pharmaceutical Co. [Media Release]. U.S. FDA Approves Otsuka and Lundbeck s REXULTI (Brexpiprazole) as Adjunctive Treatment for Adults with Major Depressive Disorder and as a Treatment for Adults with Schizophrenia Available at: http://otsuka us.com/newsroom/pages/newsarticle.aspx?itemid=13 UpToDate, Inc. Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate [database online]. Waltham, MA. Available at: http://www.uptodate.com/home/index.html. US National Institutes of Health. Brexpiprazole. Clinical Trials. Available at: https://clinicaltrials.gov/ct2/results?term=brexpiprazole&search=search National Guideline Clearinghouse. Practice guideline for the treatment of patients with major depressive disorder, third edition. Available at: http://www.guideline.gov/content.aspx?id=24158#section420 Second generation Antipsychotics in the Treatment of Major Depressive Disorder. Expert Rev Neurother. 2013;13(7):851 870. Available at: http://www.medscape.com/viewarticle/810095_2 November 2015 Page 5