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CNS Drugs

, Volume 32, Issue 3, pp 241–257 | Cite as

Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents

  • Michael W. Jann
  • Scott R. Penzak
Review Article

Abstract

Schizophrenia is a chronic medical condition with periods of remission and relapses over a patient’s lifetime. Antipsychotic medications represent the mainstay of treatment for this disease. Long-acting injectable (LAI) formulations of antipsychotics are an attractive alternative to their oral counterparts, as they enhance patient adherence. A number of second-generation antipsychotics (SGAs) are available in LAI formulations. These include paliperidone, aripiprazole, olanzapine, and risperidone. This article reviews the most recently developed and approved of these formulations—aripiprazole monohydrate, aripiprazole lauroxil, and paliperidone palmitate. While all were initially available as once-monthly formulations, a paliperidone palmitate 3-monthly injection formulation has been approved and is the first LAI agent to extend the dosing administration beyond the typical monthly time period. In addition, aripiprazole lauroxil every 6-week and 8-week administration preparations have been developed. LAI preparations of the SGAs have all demonstrated superiority over placebo and are comparable to their oral counterparts in terms of safety and tolerability, if injection site reactions are not taken into account. First-generation antipsychotic LAI preparations (e.g., haloperidol decanoate) have recently been compared with SGA LAI agents, and both formulations demonstrated comparable efficacy with the expected adverse events seen with each drug. Despite their availability, barriers to the use of LAIs remain. Education of both patients and clinicians on the use of LAI formulations and the continued development of these agents are important steps in ensuring these medications are available to the patients they would be most likely to benefit.

Notes

Compliance with Ethical Standards

Funding

No funds from any sources were used to assist with the preparation of this review article.

Conflict of interest

Michael W. Jann is on Janssen’s Speaker Bureau. Scott R. Penzak has no conflicts of interest.

References

  1. 1.
    Rauch A, Fleischhacker WW. Long-acting injectable formulations of new-generation antipsychotics: a review from a clinical perspective. CNS Drugs. 2013;27:637–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Spanarello S, La Ferla T. The pharmacokinetics of long-acting antipsychotic medications. Curr Clin Pharmacol. 2014;9:310–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Patel MX, Taylor M, David AS. Antipsychotic long-acting injections: mind the gap. Br J Psychiatry. 2009;195:S51–4.CrossRefGoogle Scholar
  4. 4.
    Parellada E, Bioque M. Barriers to the use of long-acting injectable antipsychotics in the management of schizophrenia. CNS Drugs. 2016;30:689–701.CrossRefPubMedGoogle Scholar
  5. 5.
    Hunter J. Intramuscular injection techniques. Nurs Stand. 2008;22:35–40.Google Scholar
  6. 6.
    Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl. 3):1–24.CrossRefPubMedGoogle Scholar
  7. 7.
    Rememar JF. Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics. Mol Pharm. 2014;11:1739–49.CrossRefGoogle Scholar
  8. 8.
    Risperdal® Consta® (risperidone) package insert, Ortho-McNeil Janssen Pharmaceuticals, Inc. revised 2010.Google Scholar
  9. 9.
    Zyprexa® Relprevv® (olanzapine pamoate) package insert, Eli Lilly and Company, 2009.Google Scholar
  10. 10.
    Invega® Sustenna® (paliperidone palmitate) package insert, Janssen Pharmaceuticals, Inc. 2009.Google Scholar
  11. 11.
    Invega® Trinza™ (paliperidone palmitate) package insert, Janssen Pharmaceuticals, Inc. 2015.Google Scholar
  12. 12.
    Salzman PM, Raoufina A, Legacy S, Such P, Eramo A. Plasma concentrations and dosing of 2 long-acting injectable formulations of aripiprazole. Neuropsychiatr Dis Treat. 2017;13:1125–9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rohde M, Mork N, Hakansson A, et al. Biological conversion of aripiprazole lauroxil—an N-acyloxymethyl aripiprazole prodrug. Results Pharm Sci. 2014;4:19–25.CrossRefGoogle Scholar
  14. 14.
    Abilify® Maintena® (aripiprazole monohydrate) package insert, Otsuka Pharmaceuticals, 2017.Google Scholar
  15. 15.
    Aristada™ (aripiprazole lauroxil) package insert, Alkermes, Inc. 2015.Google Scholar
  16. 16.
    Kennedy WK. Where and how to use long-acting injections. Curr Psychiatry. 2012;11:1–8.Google Scholar
  17. 17.
    Hill CL, Phadke D, Boyce KM. Four-week iloperidone depot injectable: safety and pharmacokinetic profile in patients with schizophrenia and schizoaffective disorder. In: Poster presented at: 161st annual meeting of the American Psychiatric Association; May 3–8, 2008; Washington DC.Google Scholar
  18. 18.
    Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet. 1985;10:315–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Altamura AC, Sassella F, Santini A, et al. Intramuscular preparations of antipsychotics: uses and relevance in clinical practice. Drugs. 2003;63:493–512.CrossRefPubMedGoogle Scholar
  20. 20.
    Jann MW, Antipsychotics Kennedy WK. In: Jann MW, Penzak SR, Cohen LJ, editors. Applied Clinical pharmacokinetics and pharmacodynamics of psychopharmacological agents. Switzerland: Springer International Publishing; 2016. p. 139–74.CrossRefGoogle Scholar
  21. 21.
    Hoy SM, Scott LJ. Keating GM Intramuscular paliperidone palmitate. CNS Drugs. 2010;24:227–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Citrome L. Olanz2016apine pamoare: a stick in time? Int J Clin Pract. 2009;63:140–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia. Clin Pharmacokinet. 2009;48:585–600.CrossRefPubMedGoogle Scholar
  24. 24.
    Magnusson MO, Samtani MN, Plan EL, et al. Population pharmacokinetics of a novel once-every 3 months intramuscular formulation of paliperidone palmitate in patients with schizophrenia. Clin Pharmacokinet. 2016.  https://doi.org/10.1007/s40262-016-0459-3.Google Scholar
  25. 25.
    Zhou H. Pharmacokinetic strategies in deciphering atypical drug absorption profiles. J Clin Pharmacol. 2003;43:211–27.CrossRefPubMedGoogle Scholar
  26. 26.
    Evans EF, Proctor JD, Fratkin MJ, Velandia J, Wasserman AJ. Blood flow in muscle groups and drug absorption. Clin Pharmacol Ther. 1975;17:44–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Thyssen A, Rusch S, Herben V, Quiroz J, Mannaert E. Risperidone long-acting injection: pharmacokinetics following administration in deltoid versus gluteal muscle in schizophrenic patients. J Clin Pharmacol. 2010;50:1011–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Turncliff R, Hard M, Du Y, Risinger R, Ehrich EW. Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia. Schizophr Res. 2014;159:404–10.CrossRefPubMedGoogle Scholar
  29. 29.
    Raoufina A, Peters-Strickland T, Nylander AG, et al. Aripiprazole mone-monthly 400 mg: comparison of pharmacokinetics, tolerability, and safety of deltoid versus gluteal administration. Int J Neuropsychopharmacol. 2017;20:295–304.CrossRefGoogle Scholar
  30. 30.
    Hough D, Lindenmayer JP, Gopal S, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuro-psychopharmacol Biol Psychiatry. 2009;33:1022–31.CrossRefGoogle Scholar
  31. 31.
    Cleton A, Rossenu S, Crauwels H, et al. A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia. J Clin Pharmacol. 2014;54:1048–57.CrossRefPubMedGoogle Scholar
  32. 32.
    Ravenstin P, Remmerie B, Eng C, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase I, single-dose randomized, open-label study. J Clin Pharmacol. 2016;56:330–9.CrossRefGoogle Scholar
  33. 33.
    Lee LHN, Choi C, Gershkovich P, et al. Proposing the use of partial AUC as an adjunctive measure in establishing bioequivalence between deltoid and gluteal administration of long-acting injectable antipsychotics. Eur J Drug Metab Pharmacokinet. 2016;41:659–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Elliott ER, Purvis TL, Nelson LA, Sommi RW. Inconsistency in risperidone long-acting injection steady-state plasma levels when switching from deltoid to gluteal administration. J Clin Pharmacol. 2010;50:721–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Procyshyn RM, Banasch JL, Barr AM, Honer WG. Breakthrough symptoms after switching long-acting injectable paliperidone palmitate from gluteal to the deltoid site of administration. J Psychiatr Neurosci. 2016;41:E56–7.CrossRefGoogle Scholar
  36. 36.
    Yin J, Collier AC, Barr AM, Honer WG, Procyshyn RM. Paliperidone palmitate long-acting injectable given intramuscularly in the deltoid vesrus gluteal muscle. Are they therapeutically equivalent? J Clin Psychopharmacol. 2015;35:447–9.PubMedGoogle Scholar
  37. 37.
    Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: an update 2011. Pharmacopsychiatry. 2011;44:195–235.CrossRefGoogle Scholar
  38. 38.
    Lopez LV, Kane JM. Recommendations for the monitoring of serum concentrations of antipsychotic drugs in the treatment of schizophrenia. J Clin. 2015;76:1249–50.Google Scholar
  39. 39.
    Bowskill SVJ, Handley SA, Fisher DS, Flanagan RJ, Patel MX. Rsiperidone and total 9-hydroxyrisperidone in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2002–2010. Ther Drug Monit. 2012;34:349–55.CrossRefPubMedGoogle Scholar
  40. 40.
    Muly EC, Votaw JR, Ritchie J, Howell LL. Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone. J Pharmacol Exp Ther. 2012;341:81–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Arakawa R, Ito H, Taknao A, et al. Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia. Psychopharmacol. 2008;197:229–35.CrossRefGoogle Scholar
  42. 42.
    Lako IM, vanden Heuvel ER, Knegtering H, Bruggeman R, Taxis K. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics. J Clin Psychopharmacol. 2013;33:675–81.CrossRefPubMedGoogle Scholar
  43. 43.
    Sparshatt A, Taylor D, Patel MX, Kapur S. A systematic review of aripiprazole—dose, plasma concentration, receptor occupancy, and response: implications for therapeutic drug monitoring. J Clin Psychiatry. 2010;71:1447–56.CrossRefPubMedGoogle Scholar
  44. 44.
    Kim E, Howes OD, Turkheimer FE, et al. The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory. Psychopharmacol. 2013;227:221–9.CrossRefGoogle Scholar
  45. 45.
    Pandina GJ, Lindenmayer JP, Lull J, et al. A randomized, placebo-controlled study to assess the efficacy and sagety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol. 2010;30:235–44.CrossRefPubMedGoogle Scholar
  46. 46.
    Hough D, Gopal S, Vijapurkar Y, et al. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2010;116:107–17.CrossRefPubMedGoogle Scholar
  47. 47.
    Magnusson MO, Santani MN, Plan EL, et al. Dosing and switching strategies of paliperidone palmitate 3-month formulation in patients with schizophrenia based on population pharmacokinetic modeling and simulation, and clinical trial data. CNS Drugs. 2017;31:273–88.CrossRefPubMedGoogle Scholar
  48. 48.
    Berwaerts J, Yanning L, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmotate vs placebo for relapse prevention of schizophrenia. JAMA Psychiatry. 2015;72:830–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Savitz AJ, Xu H, Gopal S, et al. Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol. 2016;19:1–14.CrossRefGoogle Scholar
  50. 50.
    Joshi K, Lafeuille MH, Brown B, et al. Baseline characteristics and treatment patterns of patients with schizophrenia initiated on once-every-three months paliperidone palmitate in a real-world setting. Curr Med Res. 2017;33:1763–72.CrossRefGoogle Scholar
  51. 51.
    Mallikaarjun S, Kane JM, Bricmont P, et al. Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel-arm, multiple-dose study. Schizophren Res. 2013;150:281–8.CrossRefGoogle Scholar
  52. 52.
    Kane JM, Peters-Strickland T, Baker RA, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatr. 2014;75:1254–60.CrossRefGoogle Scholar
  53. 53.
    Ismail Z, Peters-Strickland T, Miguelez M, et al. Aripiprazole once-monthly in the treatment of acute psychotic episodes in schizophrenia. J Clin Psychopharmacol. 2017;37:347–50.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73:617–24.CrossRefPubMedGoogle Scholar
  55. 55.
    Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomized, non-inferiority study. Br J Psychiatry. 2014;205:135–44.CrossRefPubMedGoogle Scholar
  56. 56.
    Ishigooka J, Nakamura J, Fujii Y, et al. Efficacy and safety of aripiprazole once-monthly in Asian patients with schizophrenia: a multicenter, randomized, double-blind, non-inferiority study versus oral aripiprazole. Schizophr Res. 2015;161:421–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Oya K, Kishi T, Iwata N. Efficacy and tolerability of aripiprazole once monthly for schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Neuropsychiatry Dis Treat. 2015;11:2299–307.CrossRefGoogle Scholar
  58. 58.
    Naber D, Baker RA, Eramo A, et al. Long-term effectiveness of aripiprazole once-monthly for schizophrenia is maintained in the QUALIFY extension study. Schizo Res. 2017.  https://doi.org/10.1016/jschres.2017.04.013.Google Scholar
  59. 59.
    Calabrese JR, Sanchez R, Jin N, et al. Efficacy and safety of aripiprazole once-monthly in the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled, 52-week randomized withdrawal study. J Clin Psychiatr. 2017;78:324–31.CrossRefGoogle Scholar
  60. 60.
    Hard ML, Mills R, Sadler BM, Turncliff RZ, Citrome L. Aripiprazole lauroxil. Pharmacokinetic profile of this long-acting injectable antipsychotic in persons with schizophrenia. J Clin Psychopharmacol. 2017;37:289–95.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hard ML, Mills RJ, Sadler BM, Wehr AY, Weiden PJ, von Moltke L. Pharmacokinetic profile of a 2-month dose regimen of aripiprazole lauroxil: a phase I study and a population pharmacokinetic model. CNS Drugs. 2017.  https://doi.org/10.1007/s40263-017-0447-7.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Meltzer HY, Risinger R, Nasarallah HA, et al. A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015;76:1085–90.CrossRefPubMedGoogle Scholar
  63. 63.
    Potkin SG, Risinger R, Du Y, et al. Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during acute exacerbation. Schizophr Res. 2017.  https://doi.org/10.1016/j.schres.2017.03.003.Google Scholar
  64. 64.
    Nasrallah HA, Newcomer JW, Risinger R, et al. Effect of aripiprazole lauroxil metabolic and endocrine profiles and related safety considerations among patients with acute schizophrenia. J Clin Psychiatry. 2016;77:1519–25.CrossRefPubMedGoogle Scholar
  65. 65.
    Raedler LA. Aripiprazole lauroxil (Aristada): long-acting atypical antipsychotic injection approved for the treatment of patients with schizophrenia. Am Health Drug Benefits. 2016;9:40–3.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Luedecke D, Schottle D, Karow A, Lambert M, Naber D. Post-injection delirium/sedation syndrome in patients treated with olanzapine pamoate: mechanism, incidence, and management. CNS Drugs. 2015;29:41–6.CrossRefPubMedGoogle Scholar
  67. 67.
    Detke HC, McDonnell DP, Brunner E, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases. BMC Psychiatr. 2010.  https://doi.org/10.1186/1471-244X-10-43.Google Scholar
  68. 68.
    Bushe CJ, Falk D, Anand E, et al. Olanzapine long-acting injection: a review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice. BMC Psychiatry. 2015;15:65.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Anand E, Berrgren L, Toth A, Detke HC. Clinical outcomes with olanzapine long-acting injection: impact of the 3-h observation period on patient satisfaction and well-being. Neuropsychiatric Dis Treat. 2016;12:2737–43.CrossRefGoogle Scholar
  70. 70.
    Anand E, Berggren L, Deix C, Toth A, McDonnell DP. A 6-year open-label study of the efficacy and safety of olanzapine long-acting injection in patients with schizophrenia: a post hoc analysis based on the European label recommendation. Neuropsychiatry Dis Treat. 2015;11:1349–57.CrossRefGoogle Scholar
  71. 71.
    McEvoy JP, Byerly M, Hamer RM, et al. Effecitiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia. JAMA. 2014;311:1978–86.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Naber D, Hansen K, Forray C, et al. Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia. Schizophr Res. 2015;168:498–504.CrossRefPubMedGoogle Scholar
  73. 73.
    Schreiner A, Caspi A, Bergmans P, et al. Switching from oral atypical antipsychotic monotherapy to paliperidone palmitate once-monthly in non-acute patients with schizophrenia: a prospective, open-label, interventional study. Psychopharmacol. 2017;234:3–13.CrossRefGoogle Scholar
  74. 74.
    Schreiner A, Bergmans P, Cherubin P, Hargarter L. The effect of long-acting paliperidone palmitate once-monthly on negative and depressive symptoms in patients with schizophrenia switched from previous unsuccessful treatment with oral aripiprazole. Ther Adv Psychopharmacol. 2017;7:59–65.CrossRefPubMedGoogle Scholar
  75. 75.
    Dammerman R, Kim S, Adera M, Schwarz A. Pharmacokinetics and safety of risperidone subcutaneous implants in stable patients with schizophrenia. Clin Pharmacol Drug Dev. 2018.  https://doi.org/10.1002/cpdd.428.PubMedGoogle Scholar
  76. 76.
    Anderson JP, Icten Z, Alas V, Benson C, Joshi K. Comparison and predictors of treatment adherence and remission among patients with schizophrenia treated with paliperidone palmitate or atypical oral antipsychotics in community behavioral health organizations. BMC Psychiatry. 2017;17:346.  https://doi.org/10.1186/212888-071-1507-8.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Tiihonen J, Mittendorfer-Ruiz E, Majak J, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29,823 patients with schizophrenia. JAMA Psychiatry. 2017;74:686–93.CrossRefPubMedGoogle Scholar
  78. 78.
    Meyer JM. Converting oral to long-acting injectable antipsychotics: a guide for the perplexed. CNS Spectr. 2017;22:17–27.Google Scholar
  79. 79.
    Citrome L. Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications. Expert Rev Neurother. 2017;17:1029–43.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacotherapyUniversity of North Texas System College of Pharmacy (UNTSCP), University of North Texas Health Science Center (UNTHSC)Fort WorthUSA

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