8/22/19

Long-Acting Injectable Antipsychotics: The Benefits and Barriers

Danielle Moses, PharmD, BCPP Psychiatric Clinical Pharmacist SSM Health DePaul Hospital Adjunct Clinical Professor St. Louis College of Pharmacy

Disclosure and Conflict of Interest Pharmacist Objectives

At the conclusion of this program, the pharmacist will be able to: Danielle Moses has no personal or financial conflicts of interest to 1. Recognize the appropriateness of long-acting injectable disclose. antipsychotic (LAIA) therapy and select the most appropriate LAIA for a specific patient. 2. Describe the benefits of using LAIA therapy for schizophrenia, schizoaffective disorder, and bipolar disorder. 3. Identify barriers to access and use of LAIA therapy and potential strategies to overcome these barriers.

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FDA approvals Bipolar I D/O Schizoaffective D/O Schizophrenia

Aripiprazole extended release (Abilify Maintena®) X X Aripiprazole lauroxil (Aristada®) X Fluphenazine decanoate (Prolixin D®) X Haloperidol decanoate (Haldol Decanoate®) X Olanzapine pamoate (Zyprexa Relprevv®) X

Paliperidone palmitate (Invega Sustenna®, Invega X1 X Trinza®) Risperidone (Risperdal Consta®, Perseris®) X2 X

1Invega Sustenna only 2Risperdal Consta only

Current Practice Progression

• USA: 13-38% § Austria, UK, East Asia, Turkey, and Portugal: 30-50% • Typical LAIA patient § Severely and persistently ill § Multiple hospitalizations § History of severe aggression

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Guidelines Early Intervention

Canadian Risk of relapse after first episode schizophrenia: Recommendations AFPBN • APA 2004 PORT 2009 WFSBP 2012 2013 2013 § AP discontinuation: 77% 1 year post d/c and >90% by year 2 First episode Oral SGA Oral SGA or FGA Oral SGA > § AP continuation: 3% schizophrenia (except Oral FGA LAI LAI SGA olanzapine or • Better treatment response clozapine) • Increased social and occupational success Maintenance/ non-adherence LAI LAI LAI LAI LAI SGA or • Decreased hospitalizations FGA • Decreased cost burden on patient and healthcare system

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Assessment Question #1

KEY TAKEAWAY: What is a potential benefit of starting LAIA therapy at the point of diagnosis?

A. Increased compliance, which has not proven to have a LAIAs may be used at any point and should significant effect on the risk of relapse 1 year post-first episode. be offered to any patient in which B. Increased compliance, which has the potential to decrease the risk of relapse 1 year post-first episode from 77% to maintenance AP therapy is required 3%. C. Ease of rapid dose adjustments to control emerging symptoms. D. Larger amount of AP options to choose from to treat the patient.

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Dosing

AP Initial Dose Maintenance Dose Injection Site

Aripiprazole ER 400 mg IM q month + 14 days PO 400 mg IM q month; Deltoid or gluteal dose May be adjusted from 160 – 300 mg for tolerability or CYP interactions

Aripiprazole lauroxil 10 mg = 441 mg q month 441-882 mg IM q month 441 mg, Aristada Initio® 675 15 mg = 662 mg q month, 882 mg q 6 OR 882 mg IM q 6 weeks mg = deltoid or gluteal weeks, or 1064 mg q 2 months OR 1064 mg q 2 months >20 mg = 882 q month 662-1064 mg = gluteal + 21 days PO dose OR + Aristada Initio® 675 mg IM X 1 + aripiprazole 30 mg PO X 1

Dosing Dosing

AP Initial Dose Maintenance Dose Injection Site AP Initial Dose Maintenance Dose Injection Site

Fluphenazine decanoate 6.25-25 mg IM q 2 weeks 10 mg = 12.5 mg IM q 3 Gluteal Olanzapine pamoate 10 mg = 210 mg IM q2 weeks X 4 10 mg = 150 mg IM q2 weeks or Gluteal OR weeks *Deltoid has been successfully doses or 405 mg q4 weeks X 2 doses 300 mg q4 weeks 10 mg = 12.5 mg IM q 3 weeks Max = 100 mg IM studied 15 mg = 300 mg IM q2 weeks X 4 15 mg = 210 mg IM q2 weeks or + 50% PO dose until 2nd injection, doses 405 mg q4 weeks then consider d/c 20 mg = 300 mg IM q2 weeks 20 mg = 300 mg IM q2 weeks

Haloperidol decanoate 10-20 x PO dose 10-15 X PO dose IM q 4 Gluteal Paliperidone palmitate 234 mg IM day 1 then 156 mg IM day 3 mg = 39-78 mg IM q4 weeks Deltoid or gluteal weeks *Deltoid has been successfully 1M 8 (+/- 4 days) 6 mg = 117 mg IM q4 weeks Initial dose must not exceed 100 mg studied 9 mg = 156 mg IM q4 weeks IM; if dose conversion requires > 100 CrCl 50-79 mL/min: 12 mg = 234 mg IM q4 weeks mg, divide dose in 2 injections 156 mg IM day 1 then 117 mg IM day separated by 3-7 days 8 (+/- 4 days)

+ PO haloperidol; taper and d/c following 2-3 injections

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Dosing Adverse Effect Profiles AP Initial Dose Maintenance Dose Injection Site

Paliperidone palmitate 78 mg = 273 mg IM 273-819 mg IM q 3 months Deltoid or gluteal 3M 117 mg = 410 mg IM First Generation Antipsychotics 156 mg = 546 mg IM 234 mg = 819 mg IM

Risperidone 25 mg IM q2 weeks + 21 days PO 25-50 mg IM q2 weeks Deltoid or gluteal Sedation Anticholinergic EPS Hypotension QTc microspheres dose

Risperidone ER 3 mg = 90 mg SQ 90-120 mg SQ q4 weeks Abdomen fluphenazine Low Low Very High Low Low 4 mg = 120 mg SQ

haloperidol Very Low Very Low Very High Very Low High

Adverse Effect Profiles Assessment Question #2

Second Generation Antipsychotics A 29 year old female with a history of schizophrenia presents to your clinic with symptoms of pseudoparkinsonism after several months of haloperidol decanoate therapy. She wishes to switch LAIAs but is fearful of the Sedation EPS Hypotension QTc Metabolic potential for weight gain associated with newer antipsychotics. Which LAIA is the most appropriate option? aripiprazole Low Low Low Very Low Very Low

® olanzapine Moderate Low Low Low High A. Olanzapine pamoate (Zyprexa Relprevv ) B. Paliperidone palmitate (Invega Trinza ®) paliperidone Low Mod-High Moderate Low-Mod Moderate C. Aripiprazole lauroxil (Aristada ®) risperidone Low Moderate Moderate Low-Mod Moderate D. Risperidone ER (Perseris ®)

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Additional Considerations Additional Considerations

• Aripiprazole ER • Olanzapine pamoate No oral overlap required • Requires 14 day oral overlap • • Patients stabilized on olanzapine 20 mg PO daily require q2 week • Aripiprazole lauroxil administration • Requires 21 day oral overlap OR administration with Aristada Initio ® IM X • REMS for post-injection delirium/sedation syndrome (PDSS) 1 + aripiprazole 30 mg PO X 1 • Paliperidone palmitate 1M • Fluphenazine decanoate • No oral overlap required • Requires at least 1 month of oral overlap • Must receive 2 loading dose injections during week 1 • Haloperidol decanoate • Can transition to Invega Trinza after stabilization for 4 months on Invega Sustenna Pharmacokinetics highly variable; oral overlap based on symptoms • • Paliperidone palmitate 3M • Dosing frequency every 3 months

Additional Considerations Assessment Question #3

• Risperidone microspheres • Requires 3 weeks oral overlap Which LAIA requires no oral overlap, making it an ideal choice for a patient who is very unreliable with taking oral medications? • Dosing frequency every 2 weeks • Must be refrigerated A. Fluphenazine decanoate (Prolixin D ®) • Risperidone ER B. Paliperidone palmitate (Invega Sustenna ®) • No oral overlap required • First subcutaneous option C. Aripiprazole ER (Abilify Maintena ®) • Patients must be stabilized on risperidone 3 or 4 mg PO daily D. Haloperidol decanoate (Haldol Decanoate ®)

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Potential Advantages

• Compliance • Easy identification of non-compliance • Clearer understanding of cause of relapse • Reduced risk of intentional or accidental OD • Reduced concentration-dependent AEs • Lower total daily dose compared to oral APs • Consistent contact with healthcare team • Decreased relapses/hospitalizations and better long-term outcomes

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Potential Advantages Potential Disadvantages

Risperidone LAI vs oral, 2015 LAI PO p-value • Slow dose titration/ less flexibility for dosage adjustments Psych relapse 5% 33% <0.001 • Prolonged AEs after discontinuation Mean days to relapse 298.5 d 218.6 d <0.004 Psych hospitalization 5% 18.6% 0.05 • Injection site pain D/c due to AEs 10% 21% 0.14 • Stigma “Excellent level of 95% 33% <0.001 adherence” on scale 1-5 • Decreased AP options

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Potential Barriers Overcoming Barriers • Cost • Cost § Coupons • Transportation § Assistance programs • Limited access § Correct billing (e.g., completing prior authorizations, billing medical vs. prescription benefit) • Convenience (e.g., hours of operation for injection Utilization of hospital free trial programs administration sites) § • Transportation • Prescriber/ patient perceptions § Expand locations (e.g., retail pharmacies) § Incorporate complementary transportation into business model

Overcoming Barriers Attitudes Toward LAIAs

• Limited access/ convenience • Patients have more negative perceptions than § Expand locations psychiatrists and relatives • Prominent patient fears: coercion and pain § Incorporate LAIA administration into more professions 67% of patients did not receive information about LAIAs Prescriber/ patient perceptions • • from their psychiatrist § Education • <10% of psychiatrists offer LAIAs after first psychotic • Expanding the pharmacist’s role episode

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Attitudes Toward LAIAs Attitudes Toward LAIAs

Psychiatrists Patients Relatives I agree with… Pts w LAIA experience Pts w/out LAIA experience Depot APs have more advantages than 2.99 3.23 2.69 disadvantages I knew about the possibility to 90% 63% receive APs as a depot injection Depot APs have more advantages than 3.51 3.51 2.72 oral formulations My psychiatrists informed me 70% 21% about the option of depot AP trx Depot APs provide more security to the 2.89 3.51 2.47 patient than do oral APs My psychiatrist recommended 60% 9% me to change to depot APs With oral medication it is more likely to 2.86 3.58 2.68 relapse I obtained information about 40% 22% depot APs from other sources With depot medication patients are not 2.49 2.9 2.17 reminded of their disorder each day I feel sufficiently informed about 76% 61% different formulations of APs With oral medication, it is more likely 2.42 3.3 2.16 that patients will forget to take their tablets 1 (fully agree) to 5 (fully disagree)

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Overcoming Attitudes

• Always educate and assess patient willingness to try an LAIA • Educate and discuss options with any patient requiring long term AP therapy • Attempt multiple times • Identify and mitigate misconceptions carried by psychiatrist, families, and patients • Educate and promote LAIAs as an multidisciplinary team

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Expanding the Pharmacist's Role Expanding the Pharmacist's Role • Inpatient setting: § Identify patients eligible for LAIA use § Educate patients on the benefits of LAIAs § Assess patient willingness to try LAIAs § Collaborative practice agreements • Dose LAIAs • Modify oral counterpart • Discharge prescriptions

Expanding the Pharmacist's Role Expanding the Pharmacist's Role • Retail setting: • Ambulatory setting: § Identify patients eligible for LAIA use § Identify patients eligible for LAIA use § Educate patients on the benefits of LAIAs § Educate patients on the benefits of LAIAs § Assess patient willingness to try LAIAs § Assess patient willingness to try LAIAs § Pharmacist administration of LAIAs § Collaborative practice agreements Easy access • • Initiate and modify LAIAs and corresponding oral • Convenient hours counterparts • Decreased stigma • Initiate and modify medications used • Reminder alerts to treat AEs

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Assessment Question #4 Ambulatory Model

• Interdisciplinary team: In Missouri, pharmacists can work to overcome patient barriers to access § Psychiatrist: Assess patient for indication of LAI treatment (full scope of of LAIA administration by administering LAIAs in retail pharmacies. practice including oral medications for various psychiatric conditions if needed) A. True § Pharmacist: Assess medication regimen, initiate LAI or authorize LAI refills, and titrate doses with collaborative practice agreement B. False § Nurse: Complete nursing assessment and administers medication § Benefits specialist: Ensure coverage via prior authorizations with insurance, patient assistance programs, etc. § Therapist: Group therapy and 1:1 counseling

Ambulatory Model Results

• Prescriptions filled via retail pharmacy • Patients have experienced a 68% decrease in hospital admissions • Profit used to provide complementary: • 75% of patients experienced 0 hospitalizations § Transportation • 25 patients have attained jobs § Meals § Therapy

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Summary Resources 1. Brissos S, Veguilla M, Taylor D, Balanza-Martinez V. The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. • AP non-compliance is often not recognized, leading to Therapeutic Advances in Psychopharmacology. 2014;4(5):198-219 2. CPNP. 2018-2019 Psychiatric Pharmacotherapy Review. [VitalSource]. Retrieved from https://online.vitalsource.com/#/books/9780985181888/ unnecessary dosage increases and medication changes 3. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; March 2005. Accessed June, 2019. 4. Groves E and Hart J. Early Intervention Programs and Their Role in Recovery. National Alliance on Mental Health website. • LAIAs offer advantages to patients at the point of diagnosis https://www.nami.org/About-NAMI/NAMI-News/2014/Early-Intervention-Programs-and-Their-Role-in-Reco. Updated June 2014. Accessed May, 2019. and should not be reserved for the chronically ill 5. Guzman F. Long-Acting Injectable Antipsychotics: A Practical Guide for Prescribers. Psychopharmacology Institute website. https://psychopharmacologyinstitute.com/antipsychotics/long-acting-injectable-antipsychotics-a-practical-guide-for-prescribers/. Updated February Barriers to use and access of LAIAs exist but can be overcome 2018. Accessed May 2019. • 6. Jaeger M and Rossler W. Attitudes towards long-acting depot antipsychotics: A survey of patients, relatives, and psychiatrists. Psychiatry Research. 2010;175:58-62 • Guidelines are beginning to incorporate use of LAIAs in first 7. Kreyenbuhl J, Buchanan R, Dickerson F, Dixon L. The Schizophrenia Patient Outcomes Research Team (PORT): Updated Treatment episode schizophrenia Recommendations 2009. Schizophr Bull. 2010 Jan; 36(1): 94–103. (PORT 2009) 8. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50(11):884-897 • Choosing specific LAIAs should be based on patient specific 9. Llorca P, Abbar M, Courtet P, et al. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC factors and should involve shared decision making with patient Psychiatry. 2013;13:340 10. Malla A, Tibbo P, Chue P, et al. Long-acting injectable antipsychotics: recommendations for clinicians. Can J Psychiatry. 2013;58:30S-35S 11. Subotnik KL, Casaus LR, Ventura J, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a • Expanding the role of the pharmacist in the utilization of LAIAs recent first episode of schizophrenia. A randomized clinical trial. JAMA Psychiatry. 2015;72:822–829 can drastically improve access and patient 12. Zipursky RB, Menezes NM, and Streiner DL. Risk of symptom recurrence with medication discontinuation in first-episode psychosis: A systematic outcomes review. Schizophrenia Research. 2014;152:408-414

Speaker Contact Information

email: [email protected] office: 314.447.5714

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