Comparison of Atypical Antipsychotics

PL Detail-Document #281006 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2012 Comparison of Atypical Antipsychotics Second-generation or atypical antipsychotics have a lower propensity than the first generation agents to cause extrapyramidal side effects. Clozapine may be the most effective atypical for schizophrenia, but its use is limited due to the risk of agranulocytosis. 1,21 All carry black box warnings regarding mortality risk in dementia-related psychosis, and suicidality if indicated for depression. Atypicals pose varying risks of QT prolongation, drug interactions, and metabolic adverse effects. The newest agents are asenapine (Saphris), paliperidone (Invega, Invega Sustenna), iloperidone (Fanapt), and lurasidone (Latuda). Thus, their side effect profiles are not as well-characterized as the older agents. Extrapyramidal side effects seem lowest with iloperidone and quetiapine (Seroquel), and higher with risperidone and paliperidone. 22-25 Hyperprolactinemia, associated with sexual dysfunction, gynecomastia, and irregular periods, seems most common with risperidone and paliperidone. 26 Side effects, cost, and dosing frequency, are all considerations in choice of agent. The chart below compares atypicals in regard to indications, dosing, metabolic side effects, sedation, QT prolongation, CYP3A4 metabolism, and cost. FDA-approved pediatric indications/doses are available in our PL Detail-Document, Atypical Antipsychotics in Kids. NOTE: *Usual or target daily adult dosage range may not include initial and maximum doses. Use lowest effective dose. Maximum doses of oral aripiprazole, lurasidone, olanzapine, paliperidone, quetiapine XR, and risperidone are approved for once-daily administration. Divide asenapine, iloperidone, and ziprasidone twice daily. Aripiprazole (Abilify) c,k,l 10 mg $574.47 Asenapine (Saphris) m 20 mg $627.55 Dosage Range (mg/day)*,a Schizophrenia: 10-15 mg Bipolar disorder (acute manic or mixed episodes; maintenance): 15 mg Depression (adjunct): 5-10 mg Schizophrenia: 10 mg (acute), 20 mg (maintenance) Bipolar disorder (acute manic or mixed episodes): 10-20 mg For sublingual use. Avoid food or drink for 10 min. after administration. Metabolic Adverse Effects 1,14-17,21,24,a QT Weight Diabetes Dyslipidemia Prolonging a,n,18 Gain Risk Low to None None Yes Yes Low Low to Low to CYP3A4 Sedation a,19 Metabolism a Low to Yes d Yes (minor) Low to

(PL Detail-Document #281006: Page 2 of 6) Clozapine (Clozaril, generics) 300 mg $148.50 Iloperidone (Fanapt) 12 mg $634.10 Lurasidone (Latuda) 40 mg $503.10 Olanzapine (Zyprexa, generics) f,k 10 mg $15.75 Paliperidone (Invega) g 6 mg $523.45 Dosage Range (mg/day) a, * Schizophrenia (treatment-resistant): 300-900 mg Recurrent suicidal behavior risk reduction in schizophrenia & schizoaffective disorder: 12.5-900 mg Schizophrenia: 12-24 mg Schizophrenia: 40-80 mg Take with food. Schizophrenia: 10-15 mg Bipolar disorder (acute manic or mixed episodes; maintenance): 5-20 mg Depression (associated with bipolar disorder), with fluoxetine: 5-12.5 mg Depression (treatment-resistant), with fluoxetine: 5-20 mg Schizophrenia: 3-12 mg Schizoaffective disorder (acute): 3-12 mg Sedation a,19 Metabolic Adverse Effects 1,14-17,21,24,a QT CYP3A4 Weight Diabetes Dyslipidemia Prolonging a,n,18 Metabolism a Gain Risk High High High Yes Yes High Low Low Yes e Yes Low Low Low Low or No Yes High High High Yes No Low Low None Yes d Yes (minor) Low

(PL Detail-Document #281006: Page 3 of 6) Quetiapine (Seroquel, generics) 400 mg $32.46 Dosage Range (mg/day) a, * Schizophrenia: 150-750 mg Bipolar disorder (acute depression): 300 mg Bipolar disorder (acute mania, maintenance [adjunct]): 400-800 mg Metabolic Adverse Effects 1,14-17,21,24,a Weight Gain Diabetes Risk Dyslipidemia QT Prolonging a,n,18 CYP3A4 Metabolism a Sedation a,19 Yes d Yes Quetiapine (Seroquel XR) 400 mg $517.49 Schizophrenia: 400-800 mg Bipolar disorder (acute depression): 300 mg Bipolar disorder (manic or mixed episodes; maintenance [adjunct]): 400-800 mg Major depressive disorder [adjunct]: 150-300 mg Take without food or with a light meal (about 300 kcal). Risperidone (Risperdal, generics) h,k,l 4 mg $11.22 Schizophrenia: 4-8 mg Bipolar disorder (acute manic or mixed episodes): 1-6 mg Low Yes No Low

(PL Detail-Document #281006: Page 4 of 6) Ziprasidone (Geodon, generics) i 80 mg $248.99 Dosage Range (mg/day) a, * Schizophrenia: 40-160 mg Bipolar disorder (acute manic or mixed episodes; maintenance [adjunct]): 80-160 mg Take with food. Metabolic Adverse Effects 1,14-17,21,24,a Weight gain Low or Diabetes Risk Dyslipidemia QT Prolonging a,n,18 CYP3A4 Metabolism a Sedation a,19 None None Yes j Yes Low a. Per FDA-approved product labeling and our PL Chart, Drug-induced Long QT Interval. 2-7,9-11,13,20 A yes in the QT column means, at minimum, QT prolongation has been reported in patients taking the medication, regardless of causality. Some of these medications have contraindications or recommendations to avoid use related to QT prolongation (see footnotes). b. Wholesale Average Cost (WAC) of one-month supply of daily oral dose specified (lowest cost generic, when available). c. Aripiprazole is available as an IM formulation for agitation associated with schizophrenia or bipolar disorder (usual dose 9.75 mg [may consider 5.25 mg]; may re-dose after two hours if needed; 30 mg maximum daily dose). 2 d. Avoid use with medications that prolong the QT interval and in patients with risk factors for QT prolongation. 3,7-10 e. Consider as second-line antipsychotic due to capacity to prolong QT interval. Avoid use with medications that prolong QT interval, and use caution and consider dose reduction with drugs that inhibit its metabolism. Monitor potassium and magnesium in patients at risk of electrolyte disturbances. 5 f. Olanzapine is available as a short-acting IM formulation (Zyprexa IntraMuscular) and a long-acting IM formulation (Zyprexa Relprevv). 6,27 Zyprexa IntraMuscular is indicated for agitation associated with schizophrenia or bipolar I mania. Usual dose is 10 mg (lower dose [2.5, 5, 7.5 mg] may be given). Max daily dose 30 mg (i.e., 10 mg two hours after first dose, and 10 mg four hours after second dose). 6 Zyprexa Relprevv is indicated for acute and maintenance treatment of schizophrenia in patients with established tolerability to oral olanzapine. Give the first dose in a facility equipped to handle medical emergencies. Monitor for sedation and delirium. During the first eight weeks of therapy, the usual dose is 210 mg every two weeks or 405 mg every four weeks (corresponding to an oral dose of 10 mg once daily), or 300 mg every two weeks (corresponding to an oral dose of 15 to 20 mg once daily). Start with 150 mg every four weeks for elderly or debilitated patients, or patients who may have slower olanzapine metabolism or extra sensitivity to its effects, including hypotension. Maintenance doses of Zyprexa Relprevv are 150, 210, or 300 mg every two weeks (corresponding to oral doses of 10, 15, or 20 mg once daily, respectively) or 300 or 405 mg every four weeks (corresponding to oral doses of 10 or 15 mg once daily, respectively). 27 g. Paliperidone is available as an extended-release IM formulation (Invega Sustenna) for acute and maintenance treatment of schizophrenia in patients with established tolerability to paliperidone or risperidone. Initial dose is 234 mg, then 156 mg one week later, then 39 mg to 234 mg monthly. 8 h. Risperidone is available as a long-acting IM formulation (Risperdal Consta) for schizophrenia and bipolar disorder (25 mg/dose every two weeks; 50 mg maximum dose every two weeks). 12 i. Ziprasidone is available as IM formulation for acute agitation in schizophrenic patients (10-20 mg/dose; Doses of 10 mg may be given every two hours. Doses of 20 mg may be given every four hours. 40 mg maximum daily dose). 13 j. Consider as second-line antipsychotic due to capacity to prolong QT interval. Contraindicated in long QT syndrome, recent myocardial infarction, uncompensated heart failure, and with medications that prolong the QT interval. Avoid use in patients with bradycardia or arrhythmias. Check electrolytes at baseline and periodically in patients at risk for electrolyte disturbances. Ensure normal potassium and magnesium levels. 13

(PL Detail-Document #281006: Page 5 of 6) k. Also available as an orally disintegrating tablet. L. Also available as an oral solution. m. Sublingual formulation. n. Aripiprazole, olanzapine, and lurasidone (Latuda) may pose relatively lower torsades risk vs other antipsychotics based on product labeling and literature review. Risperidone may pose more moderate risk vs higher-risk atypical antipsychotics. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

(PL Detail-Document #281006: Page 6 of 6) Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus Development Conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601. 2. Product information for Abilify. Bristol-Myers Squibb Company. Princeton, NJ 08543. February 3. Product information for Saphris. Schering-Plough Corporation. Kenilworth, NJ 07033. October 2011. 4. Product information for Clozaril. Novartis Pharmaceuticals Corporation. East Hanover, NJ 07936. October 2011. 5. Product information for Fanapt. Vanda Pharmaceuticals Inc. Rockville, MD 20850. January 6. Product information for Zyprexa. Eli Lilly and Company. Indianapolis, IN 46285. June 2011. 7. Product information for Invega. Ortho-McNeil Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. June 2011. 8. Product information for Invega Sustenna. Ortho- McNeil Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. August 9. Product information for Seroquel. AstraZeneca Pharmaceuticals LP. Wilmington, DE 19850. November 2011. 10. Product information for Seroquel XR. AstraZeneca Pharmaceuticals LP. Wilmington, DE 19850. November 2011. 11. Product information for Risperdal. Ortho-McNeil Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. August 12. Product information for Risperdal Consta. Ortho- McNeil Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. June 13. Product information for Geodon. Pfizer Inc. NY, NY 10017. December 2010. 14. Bishara D, Taylor D. Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability. Drugs 2008;68:2269-92. 15. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry 2007;68:1492-500. 16. Kane JM, Lauriello J, Laska E, et al. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol 2008;28 (2 Suppl 1):S29-S35. 17. Fowler JA, Bettinger TL, Argo TR. Paliperidone extended-release tablets for the acute and maintenance treatment of schizophrenia. Clin Ther 2008;30:231-48. 18. PL Detail-Document, Drug-induced Long QT Interval. Pharmacist s Letter/Prescriber s Letter. January 19. Miller DD. Atypical antipsychotics: sleep, sedation, and efficacy. Prim Care Companion J Clin Psychiatry 2004;6(Suppl 2):3-7. 20. Product information for Latuda. Sunovion Pharmaceuticals Inc. Marlborough, MA 01752. May 21. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23. 22. Rummel-Kluge C, Komossa K, Schwarz S, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 2012;38:167-77. 23. Caccia S, Pasina L, Nobili A. New atypical antipsychotics for schizophrenia: iloperidone. Drug Des Devel Ther 2010;4:33-48. 24. McDonagh MS, Peterson K, Carson S, et al. Drug class review: atypical antipsychotic drugs: final report update 2 [Internet]. Portland, (OR): Oregon Health & Science University, 2008 Jun. http://www.ncbi.nlm.nih.gov/books/nbk10401/pdf/to C.pdf. (Accessed January 7, 2011). 25. Chwieduk CM, Keating GM. Paliperidone extended release; a review of its use in the management of schizophrenia. Drugs 2010;70:1295-317. 26. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry 2008;47:9-20. 27. Product information for Zyprexa Relprevv. Eli Lilly and Company. Indianapolis, IN 46285. August Cite this document as follows: PL Detail-Document, Comparison of Atypical Antipsychotics. Pharmacist s Letter/Prescriber s Letter. October Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com