Long-Acting Injectable Antipsychotic Medications in Schizophrenia Management

Sanika and Aparasu: Long-Acting Injectable Antipsychotic Medications in Schizophrenia Management 3507 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 9 Issue 6 November December 2016 Review Article MS ID: IJPSN-10-25-16-APARASU Long-Acting Injectable Antipsychotic Medications in Schizophrenia Management Sanika Rege and Rajender R. Aparasu Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Texas Medical Center, 1441 Moursund Street, Houston, Texas 77030, USA. Received October 25, 2016; accepted November 16, 2016 ABSTRACT Antipsychotic medications are indicated for the treatment of schizophrenia and other psychiatric disorders including bipolar disorder. However, oral antipsychotics are associated with a number of issues including poor treatment adherence. Long Acting Injectable (LAI) antipsychotics were designed to address these issues with oral antipsychotics. LAI antipsychotics offer several advantages including less frequent dose administration, better adherence and tolerability, and relapse prevention, which in turn help in improving patients quality of life. Recent development of atypical antipsychotics has the advantages over typical antipsychotics in terms of improved efficacy and tolerability. This review highlights the advantages and disadvantages of LAI antipsychotics, outlines the currently available LAIs and their indications, and real-world evidence for LAIs based on the observational studies. KEYWORDS: Antipsychotics; Injectables; efficacy; tolerability; quality of life. Introduction Long-acting injectable antipsychotics (LAIs) such as risperidone, paliperidone, aripiprazole, and risperidone are commonly used in the treatment of psychotic disorders, particularly schizophrenia (Jarema et al., 2015). The goals of schizophrenia treatment include improved function and recovery across lifespan, with symptom reduction and relapse prevention. LAIs were developed in order to overcome the drawbacks associated with oral antipsychotics such as poor medication adherence (Sacchetti et al., 2015). However, they are not solely used to improve patient s compliance, but also have other advantages including better tolerability, reduced frequency of administration, and maintenance of stable level of antipsychotics which assures better bioavailability. LAIs provide a persistent and effective blockade of dopaminergic D2 receptors in a range that is required to control psychotic symptoms, and also reduce the risk of abrupt treatment discontinuation (Jarema et al., 2015). Despite their widespread use, there are some concerns of LAIs due to slow dose titration, less flexibility of dose adjustment, longer time to achieve steady state levels, pain at injection site, and burden of frequent travel to outpatient clinics (Brissos et al., 2014). Historical Background of LAI Development The initial LAIs were based on first-generation antipsychotics or typical antipsychotics. Fluphenazine enanthate was developed as injectable in 1966 followed by development of fluphenazine decanoate, to address the issue of poor adherence to oral antipsychotics. Haloperidol decanoate became available in USA in 1986 (Brissos et al., 2014). The LAIs of second generation or atypical antipsychotics were recently developed to avail the advantages of both, improved efficacy and tolerability of atypical antipsychotics and increased compliance and better bioavailability of LAIs (Nahata and Saini, 2009; Offord et al., 2013; Brissos et al., 2014; Pesa 2015). Available LAI Products Currently, there are six LAI antipsychotics available for treatment of schizophrenia and other psychotic disorders. These include first-generation antipsychotics (Fluphenazine decanoate, and Haloperidol decanoate) and second-generation antipsychotics (Aripiprazole, Risperidone, Paliperidone and Olanzapine) (Jarema Brissos et al., 2014). Table 1 outlines the characteristics of various LAIs. Indications for LAI use Current guidelines recommend the use of LAI antipsychotics for the maintenance treatment of schizophrenia among other available treatment options and when there is a need to improve patient s medication adherence (Jaskelainen et al., 2013; Leucht et al., 2012; CG, 2005). Several guidelines recommend that LAI antipsychotics should be used only in patients with recurrent relapses related to partial or full nonadherence (Lehman et al., 2004; Lindenmayer, 2010; Mauri et al., 2014; LAIA, 2015; Marcus McEvan et al., 2016). 3507

3508 Int J Pharm Sci Nanotech Vol 9; Issue 6 November December 2016 Fluphenazine Fluphenazine mainly acts as a dopamine antagonist. Fluphenazine LAI is indicated in the management of patients requiring prolonged parenteral neuroleptic therapy (e.g., chronic schizophrenia). It is not intended for use in children under 12 years of age. Fluphenazine may be administered as a maintenance therapy in patients who have been stabilized on a fixed daily dosage of oral fluphenazine. Fluphenazine LAI is administered at a dose of 12.5-100 mg at 1-4 weeks interval (AAP, 2010). Haloperidol Haloperidol blocks the dopamine receptors; however, its exact mechanism of action is not known. Haloperidol LAI is indicated for treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy. Haloperidol is not indicated in patients with severe toxic central nervous system depression, comatose patients, and in individuals hypersensitive to this drug or having Parkinson s disease. Haloperidol LAI should be administered in patients who have been previously stabilized with an oral antipsychotic, preferably oral haloperidol. The maintenance dose of haloperidol LAI must be individualized with titration and the usual maintenance dose range is 10 to 15 times the previous daily oral dose. It is administered in the dose range of 50-400 mg every four weeks (LAIA, 2015). Risperidone Risperidone blocks the serotonin 5-HT 2A and 5-HT 7 receptors as well as dopamine D2 receptors. Risperidone LAI is indicated for the treatment of schizophrenia in patients presently treated with oral antipsychotics. It should be used with caution in patients with dementia and cerebrovascular disorders and is not indicated for patients below 18 years of age. Risperidone LAI should be administered to patients who have been treated with an antipsychotic, preferably oral risperidone. The period of oral risperidone treatment should be no shorter than 2 weeks. The maximum dosage of risperidone LAI is 50 mg every two weeks (JP, 2016; Mauri et al., 2014). Aripiprazole Aripiprazole is an antipsychotic agent that is sometimes referred to as the third-generation antipsychotic drug due to its unique mechanism of action; it is serotonergic 5-HT 2 antagonist as well as 5-HT 1A and D 2 partial agonist. Aripiprazole LAI is indicated for maintenance treatment of patients with schizophrenia who have been initially prescribed oral antipsychotics. It is not indicated in elderly patients with dementia and in patients under 18 years of age. It is associated with an increased risk of death, mainly due to cardiovascular causes. In patients who have been treated with oral aripiprazole, 400 mg of Aripiprazole LAI should be administered with simultaneous continuation of oral aripiprazole for 14 days in order to maintain stable serum aripiprazole levels. After 14 days, oral aripiprazole should be discontinued, and aripiprazole LAI should be given every four weeks (Jarema 2015; AW, 2014). Paliperidone Paliperidone blocks the monoamine activity with a strong affinity to serotonergic 5-HT 2A and dopaminergic D2 receptors. In addition, it also blocks the α-1, H1 and α-2 receptors, but does not bind to cholinergic receptors. Its central antagonistic action may be the reason for the lower incidence of extrapyramidal side-effects. Paliperidone LAI is indicated in adult schizophrenia patients after atleast one relapse or exacerbation of symptoms due to non-adherence to treatment; and should be used in patients who have been stabilized using risperidone or paliperidone treatment. If the patient is treated with another antipsychotic, they should first be switched to oral risperidone or paliperidone followed by paliperidone LAI. Paliperidone LAI is administered at a dose of 25-150 mg at every four weeks interval (Mauri et al., 2014; JP, 2016 (a)). TABLE 1 Characteristics of LAI antipsychotics Name Fluphenazine decanoate Haloperidol decanoate Risperidone long-acting Year of approval Formulation Dose range (mg) Administration interval (weeks) Injection Site 1967 Sesame oil solution 12.5-100 1-4 Gluteal 1986 Sesame oil solution 50-400 4 Gluteal 2001 Aqueous suspension, risperidone encapsulated into biodegradable microspheres 25-50 2 Gluteal or deltoid Half-life (days) (multiple dose) Time to reach peak plasma concentration (days) Monitoring post injection Reference 14 0.3-1.5 No (Sacchetti Curry et al., 1979) 21 3-9 No (Sacchetti Reyntijens et al., 1982; Kissling et al., 1991) 4-6 28 No (Sacchetti Agid et al., 2010; Gefvert et al., 2005; Thyssen et al., 2010) TABLE 1 Contd

Sanika and Aparasu: Long-Acting Injectable Antipsychotic Medications in Schizophrenia Management 3509 Name Paliperidone palmitate Olanzapine pamoate Aripiprazole long-acting Year of approval Formulation 2009 Aqueous suspension of nanoparticles 2009 Aqueous microcrystalline suspension 2009-10 Aqueous suspension microparticles Dose range (mg) Administration interval (weeks) Injection Site 25-150 4 Gluteal or deltoid 150-300 2-4 Gluteal 300-400 4 Gluteal Half-life (days) (multiple dose) Time to reach peak plasma concentration (days) Monitoring post injection Reference 25-49 13 No (Sacchetti Gilday and Nasrallah, 2012) 14-30 8-12 Yes (3 hours) (Sacchetti Agid et al., 2010; Rosaria and Alice, 2010) 29-46 5-7 No (Sacchetti Nahata and Saini, 2009) Olanzapine Olanzapine is an antipsychotic that has affinity towards multiple receptors including serotonergic 5-HT 2A and 5-HT 2C, 5-HT 3, 5-HT 6, dopaminergic D1-D5, muscarinic M1-M5, adrenergic α-1 and histaminergic H1 receptors. This multi-receptor affinity is probably associated with its antipsychotic effectiveness. Olanzapine LAI is indicated for maintenance treatment of adult schizophrenia patients who have been stabilized by oral olanzapine. They are not recommended for patients aged 65 years or older, or for children and adolescents. They are also not indicated for patients with renal and liver failure. Olanzapine LAI should be administered in patients already stabilized on oral olanzapine, usually 150-300 mg at four weeks interval (Jarema Lindenmayer, 2010). Real World Evidence of LAIs LAIs and Hospital Re-admission Rates In a retrospective cohort study conducted by McEvan et al., lower probability (adjusted OR = 0.60, 95% CI = 0.41-0.90) of re-hospitalization was observed for LAIs compared to oral antipsychotics for schizophrenia patients (McEvan et al., 2016). Similar results were observed in a study by Marcus et al. in adult schizophrenia patients with a recent history of nonadherence. Patients who were initiated LAIs, had lower odds (adjusted OR = 0.73, 95% CI = 0.54-0.99) of rehospitalization compared to those receiving oral antipsychotics (Marcus et al., 2015). Another study evaluated the risk of re-hospitalization among patients with schizophrenia and LAIs. In this study, the adjusted odds ratio for re-hospitalization risk was 0.80 (95% CI = 0.65-0.98), compared to the oral antipsychotics group (Ju 2014). Also, in a study evaluating the association between second generation antipsychotic medication half-life and hospitalization in adult schizophrenia, a significantly lower rate of hospitalization was evident for long half-life (0.74/patient-year) compared to short half-life (1.06/patient-year) antipsychotics (Broder et al., 2012). LAIs Cost and Resource Utilization Schizophrenia represents 1.5-3% of national healthcare expenditures, hence cost-effective treatment is essential to ensure reduction in disease burden and efficient resource utilization (Brissos et al., 2014). Many retrospective studies have been conducted to determine the cost and resource utilization in patients using LAI antipsychotics. A study by Pesa et al., found that schizophrenia patients who were prescribed paliperidone palmitate had higher per-month mental-health prescription costs, however they had lower inpatient and outpatient care costs. Use of paliperidone palmitate resulted in 0.44 times reduction in all-cause hospitalizations and 0.47 times reduction in the odds of mental-health-related hospitalizations, compared to oral atypical antipsychotics, over a twelve-month follow-up period (Pesa et al., 2015). Similar results were observed in a study conducted by Baser et al., where schizophrenia patients from Veterans Health Administration treated with paliperidone palmitate had lower inpatient costs ($18,560 vs. $31,505, p=0.002) and lower frequency of hospitalization (34% vs. 53%, p<0.001) compared to patients with oral atypical antipsychotics (Baser et al., 2015). Lin et al. observed that among schizophrenia patients, LAI users had lower schizophrenia-related hospital costs during the follow-up period compared to the pre-index period, but oral antipsychotic users had increased costs ($5,981 ± $16,554 vs. $758 ± $14,328, p<0.001) (Lin et al., 2013). Offord et al. observed that schizophrenia patients initiating LAI vs oral antipsychotics, showed significantly greater reduction in the average number of all-cause hospitalizations (-0.90 ± 1.77 vs. 0.02 ± 1.49, p < 0.001), length of stay (-10.3 ± 23.2 vs. 0.7 ± 16.7 days, p < 0.001) and schizophreniarelated hospitalizations (-0.60 ± 1.37 vs. 0.05 ± 0.99, p < 0.001) (Offord et al., 2013). Comparative Effectiveness of LAIs In a Medicaid claims database study, patients who switched from risperidone LAI to paliperidone palmitate had fewer events (schizophrenia-related hospitalization) (26 vs. 32), longer time to event (mean 70 vs. 47 days), and lower risk of relapse (HR= 0.54, 95% CI= 0.32-0.92)

3510 Int J Pharm Sci Nanotech Vol 9; Issue 6 November December 2016 compared to those who switched from risperidone LAI to oral antipsychotics (Voss et al., 2015). In another study comparing risperidone and paliperidone LAIs, significantly lower discontinuation rates (36.5% vs. 53.3%, p<0.001) and longer days of LAI coverage (233.6 vs. 131.7 days, p<0.001) were associated with paliperidone. Also, patients treated with paliperidone palmitate were 12.5 times (95% CI= 9.0-17.8) more likely to be adherent based on medication possession ratio and 11.7 times (95% CI= 8.0-17.4) more likely to be adherent based on proportion of days covered (Joshi et al., 2016). Conclusions Based on the findings of observational studies, compared to oral antipsychotics, LAIs were found to be associated with significantly lower re-hospitalizations, better medication adherence, and lower all-cause and schizophrenia-related costs of hospitalizations; thus ensuring effective resource utilization, reduced disease burden and pharmaceutical costs of schizophrenia (Reyntijens et al., 1982; Rosaria and Alice, 2010; Sacchetti Thyssen et al., 2010). LAI antipsychotics provide a valuable treatment option for individualized and personalized treatment of schizophrenia. LAIs have shown to be associated with reduced hospital readmissions, improved treatment adherence, and reducing the costs and burden of the disease. Although there has been recent emergence of LAI atypical antipsychotics, there is a need to evaluate comparative effectiveness and safety for patients with schizophrenia due to cost and quality of care concerns. Also, well-designed long-term studies are needed to evaluate its role in other psychiatric disorders. References Agid O, Foussias G, and Remington G (2010). Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention. Expert Opin Pharmacother 11: 2301-2317. APP Pharmaceuticals (2010). Fluphenazine decanoate Injection USP. Available at http://www.accessdata.fda.gov/ drugsatfda_ docs/label/2010/071413s019lbl.pdf. Accessed 3 rd November 2016. Avon and Wiltshire (2014). Mental Health Partnership NHS Trust, Aripiprazole long acting injection (Abilify Maintena), Guidance for prescribing and administration, Prescribing Guidelines V1.1 BLS. Baser O, Xie L, Pesa J, and Durkin M (2015). Healthcare utilization and costs of Veterans Health Administration patients with schizophrenia treated with paliperidone palmitate long-acting injection or oral atypical antipsychotics. J Med Econ 18: 357-365. Brissos S, Veguilla MR, Taylor D, and Martinez VB (2014). The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol 4:198-219. Broder MS et al (2012). Association between second-generation antipsychotic medication half-life and hospitalization in the community treatment of adult schizophrenia. J Med Econ 15: 105-111. CG (2005). Canadian guidelines. Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry 50: 7S-57S. Curry S, Whelpton R, de Schepper P, Vranckx S, and Schiff A (1979). Kinetics of fluphenazine after fluphenazine dihydrochloride, ethanthate and decanoate administration to man. Br J Clin Pharmacol 7: 325-331. Gefvert O, Eriksson B, Persson P, Helldin L, Bjorner A, and Mannaert E (2005). Pharmacokinetucs and D2 receptor occupancy of long-acting injectable risperisone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol 8: 27-36. Gilday E and Nasrallah H (2012). Clinical pharmacology of paiperidone palmitate a parenteral long-acting formulation for the treatment of schizophrenia. Rev Recent Clin Trials 7: 2-9. Jaaskelainen E, Juola P, and Hirvonen N (2013). A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull 39: 1296-1306. JP (2016a). Janssen Pharmaceuticals, Inc Invega Sustenna (paliperidone palmitate) extended-release injectable suspension, for intramuscular use, Highlights of prescribing information. 2009. Available at https://www.janssencns.com/shared/ product/invegasustenna/prescribing-information.pdf. Accessed 4 th November 2016. JP (2016b). Janssen Pharmaceuticals, Inc., Risperdral Consta (risperidone) long-acting injection, Highlights of prescribing information. 2007. Available atttp://www.janssencns.com/shared/ product/risperdalconsta/prescribing-information.pdf. Accessed 4 th November 2016. Jarema M (2015). Practical Guidelines for the use of long-acting injectable second-generation antipsychotics. Psychiatr Pol 49: 225-241. Joshi K, Pan X, Wang R, Yang E, and Benson C (2016). Healthcare resource utilization of second-generation long-acting injectable antipsychotics in schizophrenia: risperidone versus paliperidone palmitate. Curr Med Res Opin 32: 1873-1881. Ju PC (2014). Long-acting injectables for rehospitalization among patients with schizophrenia in the home care program in Taiwan. J Clin Psychopharmacol 34: 23-29. Kissling W, Moller H, Walter K, Wittmann B, Krueger R, and Trenk D (1991). Double-blind comparison of haloperidol decanoate and fluphenazine decanoate effectiveness, side-effects, dosage and serum levels during a six months treatment for relapse prevention. Pharmacopsychiatry 18: 240-245. Lehman A, Lieberman J, Dixon L, McGlashan T, Miller A, and Perkins D (2004). American Psychiatric Association; Steering Committee on Practice Guidelines, Practice Guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 161 (2 Suppl.): 1-56. Leucht S, Tardy M, and Komossa K (2012). Antipsychotic drugsversus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 379: 2063-2071. Lin J, Wong B, Offord S, and Mirski D (2013). Healthcare cost reductions associated with the use of LAI formulations of antipsychotic medications versus oral among patients with schizophrenia. J Behav Health Serv Res 40: 355-66. Lindenmayer JP (2010). Long-acting injectable antipsychotics: focus on olanzapine pamoate.neuropsychiatr Dis Treat 6: 261-267. LAIA (2015). Long-acting Injectable Antipsychotics: Haloperidol and fluphenazine decanoate, aripiprazole (Abilify Maintena), risperidone (Risperdal Consta), and paliperidone (Invega Sustenna), Criteria for use and evidence summary, VA Pharmacy Benefits Management Services 2015, Available at http://www.pbm.va.gov, accessed 29 th October 2016. Marcus (2015). Antipsychotic adherence and rehospitalization in schizophrenia patients receiving oral versus long-acting injectable antipsychotics following hospital discharge. J Mang Care Spec Pharm 21: 754-68. Mauri MC, Paletta S, Maffini M, Colasanti A, Dragogna F, Di Pace C, and Altamura AC (2014). Clinical pharmacology of atypical antipsychotics: an update. Excli J 13: 1163-1191. McEvan JP (2016). Hospital readmission rates among patients with schizophrenia treated with long-acting injectables or oral antipsychotics. Psychiatr Serv 67: 1183-1188. Nahata T and Saini T (2009). Formulation optimization of longacting depot injection of aripiprazole by using D-optimal mixture design. PDA J Pharm Sci Technol 63: 113-122.

Sanika and Aparasu: Long-Acting Injectable Antipsychotic Medications in Schizophrenia Management 3511 Offord S, Wong B, Mirski D, Baker RA, and LinJ (2013). Healthcare resource usage of schizophrenia patients initiating long-acting injectable antipsychotics vs oral. J Med Econ 16: 231-239. Pesa JA (2015). Costs and Resource Utilization among Medicaid patients with schizophrenia treated with paliperidone palmitate or oral atypical antipsychotics. Drugs Real World Outcomes 2: 377-385. Reyntijens A, Heykants J, Woestenborghs R, Gelders Y and Aerts T (1982). Pharmacokinetics of haloperidol decanoate. Int Pharmacopsychiatry 17: 238-246. Rosaria D and Alice B (2010). Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia. Neuropsychiatr Dis Treat 6: 573-581. Sacchetti E (2015). Long-acting injection antipsychotic medications in the management of schizophrenia. Evidence-based Psychiatric Care 1: 27-36. Thyssen A, Rusch S, Herben V, Quiroz J and Mannaert E (2010). Risperidone long-acting injection: pharmacokinetics following administration in deltoid versus gluteal in schizophrenic patients. J Clin Pharmacol 50: 1011-1021. Voss EA, Ryan PB, Stang PE, Hough D and Alphs L (2015). Switching from risperidone long-acting injectable to paliperidone long-acting injectable or oral antipsychotics: analysis of Medicaid claims database. Int Clin Psychopharmacol 30: 151-157. Address correspondence to: Dr. Rajender R. Aparasu, Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston Texas Medical Center Suite 425, 1441 Moursund Street Houston, Texas 77030, USA. E-mail: rraparasu@uh.edu