IOWA MEDICAID P&T COMMITTEE THERAPEUTIC CLASS REVIEW AUGUST 10, 2012 ANTIPSYCHOTICS CLASS REVIEW [Literature Review search through July 16, 2012] [Last Review Update: August 9, 2012] Property of IME and may not be reproduced without permission. Requests for permission to use this material should be addressed to: [email protected]. Property of IME and may not be reproduced without permission. Antipsychotics‐2 SYNOPSIS Antipsychotics are also known as neuroleptic drugs, which comes from the Greek meaning "taking hold of one’s nerves". Antipsychotics are used to treat numerous psychiatric diagnoses including schizophrenia, bipolar disorder, aggression and irritability associated with autism and as augmentation agents for patients with major depressive disorder who fail to respond to antidepressant monotherapy. The first generation antipsychotics (FGAs), or the typical antipsychotics, have been in existence since the 1950s, while second generation antipsychotics, also known as the atypical antipsychotics (AAPs), have been available since the 1990s. The atypical antipsychotics are now considered 1st line treatment for schizophrenia and are one of the most widely prescribed drug classes. Schizophrenia affects approximately 1.1% of the U.S. adult population. Schizophrenia is a severe, progressive, chronic brain disorder, with symptoms falling into one of three categories. The categories include: (1) positive symptoms, which are unusual thoughts or perceptions (delusions and hallucinations respectively); (2) negative symptoms, which are a loss or decrease in the ability to initiate plans, speak or find pleasure in everyday life; and (3) cognitive deficits.30 Bipolar disorder, also known as manic‐depressive illness, is also a chronic brain disorder that's characterized as a mood disorder with periods of depression and mania. Bipolar disorder can cause a dramatic shift in mood, energy, and a person’s ability to function in numerous domains. These severe symptoms can lead to difficulties in leading a productive life if not properly treated and managed. There are currently 5.7 millions adults in the U. S. that are diagnosed with bipolar disorder, which is approximately 2.6% of the population. Individuals with bipolar disorder have increased rates of substance abuse, divorce, unemployment, and arrest rates. Bipolar disorder typically develops in late adolescence or early adulthood.29 Major depressive disorder has a lifetime prevalence of 16 % in the United States. First line antidepressant treatment is often ineffective at relieving symptoms. Augmentation of antidepressants is a commonly employed strategy and certain atypical antipsychotics have been demonstrated to be efficacious. Clozapine was first discovered in the 1950's, but was not used in clinical practice in the United States until 1990. Clozapine was found to be most effective for treatment resistant schizophrenia; however, associated adverse events limited its use. This led to the advent of newer atypicals with more tolerable side effect profiles compared with clozapine. Risperidone (Risperdal®) was the first of the newer atypicals, followed by olanzapine (Zyprexa®) and then quetiapine (Seroquel®) that were developed in the 1990's. Ziprasidone (Geodon®) and aripiprazole (Abilify®) became available in the early 2000’s. Paliperidone (Invega®) became available in 2006, while iloperidone (Fanapt®) and asenapine (Saphris®) became available in 2009. Most recently, the newest product that has been approved by the FDA is lurasidone (Latuda®). The frequency and severity of adverse events and drug‐drug interactions helps to differentiate the products from the earlier first generation antipsychotics such as haloperidol or perphenazine, with the atypicals. The oral atypical antipsychotics included in this therapeutic class review include: aripiprazole (Abilify®), asenapine (Saphris®), clozapine (Clozaril®, Fazaclo®), iloperidone (Fanapt®), lurasidone (Latuda®), olanzapine (Zyprexa®), olanzapine/fluoxetine (Symbyax®), paliperidone (Invega®), quetiapine (Seroquel®), quetiapine XR (Seroquel XR®), risperidone (Risperdal®), and ziprasidone (Geodon®). Property of IME and may not be reproduced without permission. Antipsychotics‐3 The injectable atypicals included in this therapeutic class review include: aripiprazole (Abilify®), olanzapine (Zyprexa® IntraMuscular, Zyprexa® Relprevv), paliperidone (Invega® Sustenna), risperidone (Risperdal® Consta), and ziprasidone (Geodon®). The oral typical antipsychotics included in this therapeutic class review include: chlorpromazine, fluphenazine, haloperidol (Haldol®), loxapine (Loxitane®), perphenazine, perphenazine/amitriptyline, pimozide (Orap®), thioridazine, thiothixene (Navane®), and trifluoperazine. Molindone (Moban®) is a typical antipsychotic used for schizophrenia. While there is no CMS term date, the manufacturer has recently discontinued this product and thus it will not be included in the review. The injectable typical antipsychotics included in this therapeutic class review include: chlorpromazine, fluphenazine decanoate, haloperidol (Haldol®), and haloperidol decanoate (Haldol® decanoate). Property of IME and may not be reproduced without permission. Antipsychotics‐4 ATYPICAL ANTIPSYCHOTICS FDA APPROVED INDICATIONS 1‐9, 32‐34, 67, 95‐99 Please note that the indications listed in the table below are for adults aged 18 years of age or older. Adult Indications ARI ASE CLO ILO LUR OLA OLA/FLU PAL QUE QUE XR RIS ZIP Bipolar I: Acute Mania, X X X X X X X Monotherapy Bipolar I: Acute Mania, Adjunct X X X X X X to valproate or lithium Bipolar I: Depression X X X Bipolar II: Depression X X Bipolar I: Mixed, Monotherapy X X X X X X Bipolar I: Mixed, Adjunct Therapy X X X X X to valproate or lithium Bipolar Maintenance: X X Monotherapy Bipolar Maintenance: Adjunct X X X X MDD Adjunct Therapy X X Schizoaffective Disorder: X Monotherapy & Adjunct Schizophrenia X X X X X X X X X X Treatment‐resistant Depression X Treatment‐resistant Schizophrenia X Recurrent suicidal behavior X w/Schizophrenia ARI‐aripiprazole (Abilify®); ASE‐ asenapine (Saphris®); CLO‐clozapine (Clozaril®, Fazaclo®); ILO‐iloperidone (Fanapt®); LUR‐lurasidone (Latuda®); OLA‐olanzapine (Zyprexa®); OLA/FLU‐ olanzapine/fluoxetine (Symbyax®); paliperidone (Invega®); QUE‐quetiapine (Seroquel®); QUE SR‐quetiapine SR (Seroquel® XR); RIS‐ risperidone (Risperdal®); ZIP‐ziprasidone (Geodon®). The following table illustrates the current FDA approved indications for the injectables. Property of IME and may not be reproduced without permission. Antipsychotics‐5 Agitation with Drug Schizophrenia Bipolar I: Monotherapy Bipolar I: Adjunct schizophrenia/bipolar aripiprazole * X2 (Abilify®) olanzapine * X1, 3 (Zyprexa® IntraMuscular) olanzapine ** X (Zyprexa® Relprevv) paliperidone ** X (Invega® Sustenna) risperidone ** X X X (Risperdal® Consta) ziprasidone* X3 (Geodon®) 1 Bipolar I Mania 2Bipolar disorder, Manic or Mixed 3Schizophrenia *Short‐acting injectables (SAI); **Long‐acting injectables (LAI) The following table illustrates the current FDA approved indications in the pediatric population. Drug Schizophrenia Bipolar I: Acute Mania1 Bipolar I: Mixed1 Irritability associated with autism aripiprazole 13‐17 yrs 10‐17 yrs 10‐17 yrs 6‐17 yrs (Abilify®) olanzapine 13‐17 yrs 13‐17 yrs 13‐17 yrs ‐ (Zyprexa®) paliperidone 12‐17 yrs ‐ ‐ ‐ (Invega®) quetiapine 13‐17 yrs 10‐17 yrs ‐ ‐ (Seroquel®) risperidone 13‐17 yrs 10‐17 yrs 10‐17 yrs 5‐16 yrs (Risperdal®) 1 Monotherapy DOSAGE FORMS, DOSE, MANUFACTURER1‐9, 32‐34, 67, 95‐99 Currently, the only generic versions available in this therapeutic class include clozapine (Clozaril®) and risperidone (Risperdal®). Daily doses may vary within the provided dose range based upon age and indication. Property of IME and may not be reproduced without permission. Antipsychotics‐6 Drug Dosage Forms Dose Manufacturer Tablets: 2mg, 5mg, 10mg, 15mg, aripiprazole 20mg, 30mg (Abilify®) Orally Disintegrating Tablet: 10‐30mg QD Bristol‐Myers Squibb (Abilify® Disc) 10mg, 15mg Oral Solution: 1mg/ml asenapine Sublingual Tablets: 5‐10mg BID Schering‐Plough (Saphris®) 5mg, 10mg Tablets1: clozapine 25mg, 50mg, 100mg, 200mg Various generic manufacturers (Clozaril®) Orally Disintegrating Tablet: 100‐900mg divided as TID (Novartis) (Fazaclo®) 12.5mg, 25mg, 100mg, (Azur Pharma) 150mg, 200mg Tablets: iloperidone Initial dose of 1mg BID, 1mg, 2mg, 4mg, 6mg, 8mg, Vanda Pharmaceuticals (Fanapt®) target of 6‐12mg BID 10mg, 12mg lurasidone Tablets: 40‐160mg QD with food Sunovion Pharmaceuticals (Latuda®) 20mg, 40mg, 80mg (at least 350 calories) Tablets: olanzapine 2.5mg, 5mg, 7.5mg, 10mg, Various generic manufacturers (Zyprexa®) 15mg, 20mg 5‐20mg QD (Lilly) (Zyprexa® Zydis) Orally Disintegrating Tablet: 5mg, 10mg, 15mg, 20mg Capsules: olanzapine/fluoxetine 3/25mg, 6/25mg, 6/50mg, QPM dosing, max: 18/75mg Lilly (Symbyax®) 12/25mg, 12/50mg paliperidone Extended‐Release Tablets: 3‐6mg QD, max:12mg Janssen (Invega®) 1.5mg, 3mg, 6mg, 9mg Tablets: quetiapine QD to BID dosing, Various generic manufacturers 25mg, 50mg, 100mg, 200mg, (Seroquel®) max:800mg (AstraZeneca) 300mg, 400mg Extended‐Release Tablets: quetiapine XR 50mg, 150mg, 200mg, 300‐800mg QPM AstraZeneca (Seroquel® XR) 300mg, 400mg Tablets/M‐Tabs (ODT): risperidone 0.25mg, 0.5mg, 1mg, 2mg, QD to BID dosing, with Various generic manufacturers (Risperdal®) 3mg, 4mg effective dose range 4‐16mg2 ( Janssen) (Risperdal® M tab) Oral Solution: 1mg/ml Property of IME and may not be reproduced without permission. Antipsychotics‐7 Drug Dosage