Comparison of Atypical Antipsychotics

PL Detail-Document #281006−This PL Detail-Document gives subscribersadditional insight related to the Recommendations published in−PHARMACIST’S LETTER / PRESCRIBER’S LETTEROctober 2012Comparison of Atypical AntipsychoticsSecond-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 QTprolongation, 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 sideeffects seem lowest with iloperidone and quetiapine (Seroquel), and higher with risperidone and paliperidone. 22-25 Hyperprolactinemia, associatedwith sexual dysfunction, gynecomastia, and irregular periods, seems most common with risperidone and paliperidone. 26 Side effects, cost, and dosingfrequency, 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 oforal aripiprazole, lurasidone, olanzapine, paliperidone, quetiapine XR, and risperidone are approved for once-daily administration. Divideasenapine, iloperidone, and ziprasidone twice daily.Generic(Brand)/Cost bAripiprazole(Abilify) c,k,L10 mg$574.47Asenapine(Saphris) m20 mg$627.55FDA-Approved Indications for Adultsand Usual or Target Adult DailyDosage Range (mg/day)* ,aSchizophrenia: 10-15 mgBipolar disorder (acute manic or mixedepisodes; maintenance): 15 mgDepression (adjunct): 5-10 mgSchizophrenia: 10 mg (acute), 20 mg(maintenance)Bipolar disorder (acute manic or mixedepisodes): 10-20 mg• For sublingual use. Avoid food ordrink for 10 min. after administration.Metabolic Adverse Effects 1,14-17,21,24,a QTWeight Diabetes Dyslipidemia Prolonging a,n,18Gain RiskLow to None None Yes Yes LownoneLow tononeLow tononeCopyright © 2012 by Therapeutic Research CenterP.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.comCYP3A4 Sedation a,19Metabolism aLow to none Yes d Yes (minor) Low toModerateMore. . .

(PL Detail-Document #281006: Page 2 of 6)Generic(Brand)/Cost bClozapine(Clozaril,generics)300 mg$148.50Iloperidone(Fanapt)12 mg$634.10Lurasidone(Latuda)40 mg$503.10Olanzapine(Zyprexa,generics) f,k10 mg$15.75Paliperidone(Invega) g6 mg$523.45FDA-Approved Indications for Adultsand Usual or Target Adult DailyDosage Range (mg/day) a, *Schizophrenia (treatment-resistant):300-900 mgRecurrent suicidal behavior risk reductionin schizophrenia & schizoaffectivedisorder: 12.5-900 mgSchizophrenia: 12-24 mgSchizophrenia: 40-80 mg• Take with food.Schizophrenia: 10-15 mgBipolar disorder(acute manic or mixed episodes;maintenance): 5-20 mgDepression (associated with bipolardisorder), with fluoxetine: 5-12.5 mgDepression (treatment-resistant), withfluoxetine: 5-20 mgSchizophrenia: 3-12 mgSchizoaffective disorder (acute): 3-12 mgSedation a,19Metabolic Adverse Effects 1,14-17,21,24,a QT CYP3A4Weight Diabetes Dyslipidemia Prolonging a,n,18 Metabolism aGain RiskHigh High High Yes Yes HighModerateLow Low Yes e Yes LowLow Low Low or none No Yes ModerateHigh High High Yes No ModerateLow Low None Yes d Yes (minor) LowCopyright © 2012 by Therapeutic Research CenterP.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.comMore. . .

(PL Detail-Document #281006: Page 3 of 6)Generic(Brand)/Cost bQuetiapine(Seroquel,generics)400 mg$32.46FDA-Approved Indications for Adultsand Usual or Target Adult DailyDosage Range (mg/day) a, *Schizophrenia: 150-750 mgBipolar disorder (acute depression):300 mgBipolar disorder (acute mania,maintenance [adjunct]): 400-800 mgMetabolic Adverse Effects 1,14-17,21,24,aWeightGainModerateDiabetesRiskDyslipidemiaQTProlonging a,n,18CYP3A4Metabolism a Sedation a,19Moderate Moderate Yes d Yes ModerateQuetiapine(SeroquelXR)400 mg$517.49Schizophrenia: 400-800 mgBipolar disorder (acute depression):300 mgBipolar disorder (manic or mixedepisodes; maintenance [adjunct]):400-800 mgMajor depressive disorder [adjunct]:150-300 mg• Take without food or with a lightmeal (about 300 kcal).Risperidone(Risperdal,generics) h,k,L4 mg$11.22Schizophrenia: 4-8 mgBipolar disorder (acute manic or mixedepisodes): 1-6 mgModerateModerate Low Yes No LowCopyright © 2012 by Therapeutic Research CenterP.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.comMore. . .

(PL Detail-Document #281006: Page 4 of 6)Generic(Brand)/Cost bZiprasidone(Geodon,generics) i80 mg$248.99FDA-Approved Indications for Adultsand Usual or Target Adult DailyDosage Range (mg/day) a, *Schizophrenia: 40-160 mgBipolar disorder(acute manic or mixed episodes;maintenance [adjunct]):80-160 mg• Take with food.Metabolic Adverse Effects 1,14-17,21,24,aWeightgainLow ornoneDiabetesRiskDyslipidemiaQTProlonging a,n,18CYP3A4Metabolism a Sedation a,19None None Yes j Yes Lowa. 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, QTprolongation has been reported in patients taking the medication, regardless of causality. Some of these medications have contraindications orrecommendations 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). 2d. Avoid use with medications that prolong the QT interval and in patients with risk factors for QT prolongation. 3,7-10e. Consider as second-line antipsychotic due to capacity to prolong QT interval. Avoid use with medications that prolong QT interval, and use caution andconsider dose reduction with drugs that inhibit its metabolism. Monitor potassium and magnesium in patients at risk of electrolyte disturbances. 5f. Olanzapine is available as a short-acting IM formulation (Zyprexa IntraMuscular) and a long-acting IM formulation (Zyprexa Relprevv). 6,27 ZyprexaIntraMuscular 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 andmaintenance treatment of schizophrenia in patients with established tolerability to oral olanzapine. Give the first dose in a facility equipped to handlemedical emergencies. Monitor for sedation and delirium. During the first eight weeks of therapy, the usual dose is 210 mg every two weeks or 405 mgevery 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 oncedaily). Start with 150 mg every four weeks for elderly or debilitated patients, or patients who may have slower olanzapine metabolism or extra sensitivityto 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). 27g. Paliperidone is available as an extended-release IM formulation (Invega Sustenna) for acute and maintenance treatment of schizophrenia in patients withestablished tolerability to paliperidone or risperidone. Initial dose is 234 mg, then 156 mg one week later, then 39 mg to 234 mg monthly. 8h. Risperidone is available as a long-acting IM formulation (Risperdal Consta) for schizophrenia and bipolar disorder (25 mg/dose every two weeks; 50 mgmaximum dose every two weeks). 12i. 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). 13j. 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 electrolytesat baseline and periodically in patients at risk for electrolyte disturbances. Ensure normal potassium and magnesium levels. 13Copyright © 2012 by Therapeutic Research CenterP.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.comMore. . .

(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 literaturereview. 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 makingclinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and nationalorganizations. Information and internet links in this article were current as of the date of publication.Copyright © 2012 by Therapeutic Research CenterP.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.comMore. . .

(PL Detail-Document #281006: Page 6 of 6)Project Leader in preparation of this PL Detail-Document: Melanie Cupp, Pharm.D., BCPSReferences1. American Diabetes Association; AmericanPsychiatric Association; American Association ofClinical Endocrinologists; North AmericanAssociation for the Study of Obesity. ConsensusDevelopment Conference on antipsychotic drugs andobesity and diabetes. Diabetes Care 2004;27:596-601.2. Product information for Abilify. Bristol-Myers SquibbCompany. Princeton, NJ 08543. February 2012.3. Product information for Saphris. Schering-PloughCorporation. Kenilworth, NJ 07033. October 2011.4. Product information for Clozaril. NovartisPharmaceuticals Corporation. East Hanover, NJ07936. October 2011.5. Product information for Fanapt. VandaPharmaceuticals Inc. Rockville, MD 20850. January2012.6. Product information for Zyprexa. Eli Lilly andCompany. Indianapolis, IN 46285. June 2011.7. Product information for Invega. Ortho-McNeilJanssen Pharmaceuticals, Inc. Titusville, NJ 08560.June 2011.8. Product information for Invega Sustenna. Ortho-McNeil Janssen Pharmaceuticals, Inc. Titusville, NJ08560. August 2012.9. Product information for Seroquel. AstraZenecaPharmaceuticals LP. Wilmington, DE 19850.November 2011.10. Product information for Seroquel XR. AstraZenecaPharmaceuticals LP. Wilmington, DE 19850.November 2011.11. Product information for Risperdal. Ortho-McNeilJanssen Pharmaceuticals, Inc. Titusville, NJ 08560.August 2012.12. Product information for Risperdal Consta. Ortho-McNeil Janssen Pharmaceuticals, Inc. Titusville, NJ08560. June 2012.13. Product information for Geodon. Pfizer Inc. NY, NY10017. December 2010.14. Bishara D, Taylor D. Upcoming agents for thetreatment of schizophrenia: mechanism of action,efficacy and tolerability. Drugs 2008;68:2269-92.15. Potkin SG, Cohen M, Panagides J. Efficacy andtolerability of asenapine in acute schizophrenia: aplacebo- and risperidone-controlled trial. J ClinPsychiatry 2007;68:1492-500.16. Kane JM, Lauriello J, Laska E, et al. Long-termefficacy and safety of iloperidone: results from 3clinical trials for the treatment of schizophrenia. JClin Psychopharmacol 2008;28 (2 Suppl 1):S29-S35.17. Fowler JA, Bettinger TL, Argo TR. Paliperidoneextended-release tablets for the acute andmaintenance treatment of schizophrenia. Clin Ther2008;30:231-48.18. PL Detail-Document, Drug-induced Long QT Interval.Pharmacist’s Letter/Prescriber’s Letter. January2012.19. Miller DD. Atypical antipsychotics: sleep, sedation,and efficacy. Prim Care Companion J ClinPsychiatry 2004;6(Suppl 2):3-7.20. Product information for Latuda. SunovionPharmaceuticals Inc. Marlborough, MA 01752. May2012.21. Lieberman JA, Stroup TS, McEvoy JP, et al.Effectiveness of antipsychotic drugs in patients withchronic schizophrenia. N Engl J Med2005;353:1209-23.22. Rummel-Kluge C, Komossa K, Schwarz S, et al.Second-generation antipsychotic drugs andextrapyramidal side effects: a systematic review andmeta-analysis of head-to-head comparisons.Schizophr Bull 2012;38:167-77.23. Caccia S, Pasina L, Nobili A. New atypicalantipsychotics for schizophrenia: iloperidone. DrugDes Devel Ther 2010;4:33-48.24. McDonagh MS, Peterson K, Carson S, et al. Drugclass review: atypical antipsychotic drugs: finalreport update 2 [Internet]. Portland, (OR): OregonHealth & Science University, 2008 Jun.http://www.ncbi.nlm.nih.gov/books/NBK10401/pdf/TOC.pdf. (Accessed January 7, 2011).25. Chwieduk CM, Keating GM. Paliperidone extendedrelease; a review of its use in the management ofschizophrenia. Drugs 2010;70:1295-317.26. Correll CU. Antipsychotic use in children andadolescents: minimizing adverse effects to maximizeoutcomes. J Am Acad Child Adolesc Psychiatry2008;47:9-20.27. Product information for Zyprexa Relprevv. Eli Lillyand Company. Indianapolis, IN 46285. August2012.Cite this document as follows: PL Detail-Document, Comparison of Atypical Antipsychotics. Pharmacist’sLetter/Prescriber’s Letter. October 2012.Evidence and Recommendations You Can Trust…3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249Copyright © 2012 by Therapeutic Research CenterSubscribers 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