Skip to main content
Log in

Alternative Routes of Administration of Clozapine

  • Current Opinion
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Clozapine is the only antipsychotic with proven effectiveness in treatment-resistant schizophrenia. It is usually administered using commercially available oral tablets, but not all patients are willing or able to take medicines in this way. Orodispersible clozapine tablets are available from several manufacturers and may be useful where swallowing solid dosage forms is difficult, or as an aid to observe compliance. Liquid formulations of clozapine can be prepared extemporaneously or purchased commercially, but most preparations are suspensions (clozapine is poorly soluble) and patients may find them unpalatable. The administration of clozapine (suspension or crushed tablets) via enteral feeding tubes (predominantly nasogastric) has been reported both in medically unwell patients and in patients refusing clozapine. Enteral administration is likely to be superseded by intramuscular clozapine, which has recently been re-introduced and is being widely used in some countries. Successful use of this formulation in enforced treatment strategies has been described by several authors with good long-term outcomes when switched to oral treatment. Intramuscular clozapine has also been used in physically ill patients who are unable to take any form of enteral medication. Other methods of delivery (transdermal, nasal) are not yet commercially available, but offer promise of further treatment options for this group of seriously ill patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Hippius H. A historical perspective of clozapine. J Clin Psychiatry. 1999;60:22–3.

    PubMed  Google Scholar 

  2. Kane J, et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch General Psychiatry. 1988;45(9):789.

    CAS  Google Scholar 

  3. Meltzer HY. An overview of the mechanism of action of clozapine. J Clin Psychiatry. 1994;55 Suppl B:47–52.

    CAS  PubMed  Google Scholar 

  4. McQueen G, et al. Changes in brain glutamate on switching to clozapine in treatment-resistant schizophrenia. Schizophr Bull. 2021;47(3):662–71.

    PubMed  PubMed Central  Google Scholar 

  5. Cheng YF, et al. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol. 1988;34(5):445–9.

    CAS  PubMed  Google Scholar 

  6. Choc MG, et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res. 1987;4(5):402–5.

    CAS  PubMed  Google Scholar 

  7. Novartis, Clozaril (clozapine) tablets. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019758s062lbl.pdf.

  8. Schaber G, et al. Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance. Br J Clin Pharmacol. 1998;46(5):453–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jann MW, et al. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet. 1993;24:161–76.

    CAS  PubMed  Google Scholar 

  10. Guitton C, et al. Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol. 1998;18(6):470–6.

    CAS  PubMed  Google Scholar 

  11. Dain JG, Nicoletti J, Ballard F. Biotransformation of clozapine in humans. Drug Metab Dispos. 1997;25(5):603–9.

    CAS  PubMed  Google Scholar 

  12. Ismail Z, et al. Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia. Am J Geriatric Psychiatry. 2012;20(1):53–60.

    Google Scholar 

  13. Choc MG, et al. Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharm Res. 1990;7(4):347–51.

    CAS  PubMed  Google Scholar 

  14. de Leon J et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry. 2021.

  15. Albitar O, et al. Population pharmacokinetics of clozapine: a systematic review. BioMed Res Int. 2020;2020:1–10.

    Google Scholar 

  16. Golden G, Honigfeld G. Bioequivalence of clozapine orally disintegrating 100-mg tablets compared with clozapine solid oral 100-mg tablets after multiple doses in patients with schizophrenia. Clin Drug Investig. 2008;28(4):231–9.

    CAS  PubMed  Google Scholar 

  17. DiSanto AR, Golden G. Effect of food on the pharmacokinetics of clozapine orally disintegrating tablet 12.5mg: a randomized, open-label, crossover study in healthy male subjects. Clin Drug Investig. 2009;29(8):539–49.

    CAS  PubMed  Google Scholar 

  18. Walker SE, Baker D, Law S. Stability of clozapine stored in oral suspension vehicles at room temperature. Can J Hosp Pharm. 2005;58(5):279–84.

    Google Scholar 

  19. Walker SE, Sachedina H, Bichar K. Stability of compounded clozapine 25 mg/mL and 50 mg/mL suspensions in plastic bottles. Can J Hosp Pharm. 2021. https://doi.org/10.4212/cjhp.v74i3.3150.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ramuth S, Flanagan RJ, Taylor DM. A liquid clozapine preparation for oral administration in hospital. Pharm J. 1996;257:6904.

    Google Scholar 

  21. The Royal Pharmaceutical Society, Syrup BP 2020, in Martindale: the complete drug reference. Pharmaceutical Press: Medicines Complete Database.

  22. Oloyede E, et al. Clozapine and norclozapine plasma levels in patients switched between different liquid formulations. Ther Drug Monit. 2020;42(3):491–6.

    CAS  PubMed  Google Scholar 

  23. Coker-Adeyemi F, Taylor D. Clozapine plasma levels in patients switched from clozapine liquid to tablets. Pharm J. 2002;269(7222):650–2.

    Google Scholar 

  24. Keshavarzi F, et al. Change in plasma concentration of clozapine and norclozapine following a switch of oral formulation. Therap Adv Psychopharmacol. 2020;10:204512531989926.

    Google Scholar 

  25. Glue P, et al. Evaluation of bioequivalence between clozapine suspension and tablet formulations: a multiple-dose, fed and fasted study. Clin Drug Investig. 2012;32(11):723–7.

    CAS  PubMed  Google Scholar 

  26. Andersen TH, et al. Involuntary treatment of schizophrenia patients 2004–2010 in Denmark. Acta Psychiatr Scand. 2014;129(4):312–9.

    CAS  PubMed  Google Scholar 

  27. Fisher WA. Elements of successful restraint and seclusion reduction programs and their application in a large, urban, state psychiatric hospital. J Psychiatr Pract. 2003;9:7–15.

    PubMed  Google Scholar 

  28. Till A, Selwood J, Silva E. The assertive approach to clozapine: nasogastric administration. B J Psych Bull. 2019;43(1):21–6.

    Google Scholar 

  29. Kuzin M, et al. Changes in clozapine bioavailability in a percutaneous endoscopic gastrostomy-fed patient with treatment-resistant schizophrenia. J Clin Psychopharmacol. 2020;40:303–6.

    Google Scholar 

  30. Kurien M, Penny H, Sanders DS. Impact of direct drug delivery via gastric access devices. Expert Opin Drug Deliv. 2015;12(3):455–63.

    CAS  PubMed  Google Scholar 

  31. Gee S, et al. Intramuscular clozapine in the acute medical hospital: experiences from a liaison psychiatry team. SAGE Open Med Case Rep. 2021;9:2050313X2110047.

    Google Scholar 

  32. McIntyre CM, Monk HM. Medication absorption considerations in patients with postpyloric enteral feeding tubes. Am J Health Syst Pharm. 2014;71:549–56.

    CAS  PubMed  Google Scholar 

  33. Lokshin P, et al. Parenteral clozapine: five years of experience. J Clin Psychopharmacol. 1999;19(5):479–80.

    CAS  PubMed  Google Scholar 

  34. Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull. 1992;18(3):515–42.

    CAS  PubMed  Google Scholar 

  35. Munzar B, Nemets B. Clinical experience with intramuscular clozapine. Cureus. 2021. https://doi.org/10.7759/cureus.18267.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kasinathan J, Mastroianni T. Evaluating the use of enforced clozapine in an Australian forensic psychiatric setting: two cases. BMC Psychiatry. 2007. https://doi.org/10.1186/1471-244X-7-S1-P13.

    Article  PubMed Central  Google Scholar 

  37. Schulte PF, et al. Compulsory treatment with clozapine: a retrospective long-term cohort study. Int J Law Psychiatry. 2007;30(6):539–45.

    PubMed  Google Scholar 

  38. Henry R, et al. Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series. BJPsych Bull. 2020;6:239–43.

    Google Scholar 

  39. Casetta C, et al. A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis. Br J Psychiatry. 2020;217:506–13.

    PubMed  Google Scholar 

  40. Whiskey E, et al. Resolution without discontinuation: heart failure during clozapine treatment. Therap Adv Psychopharmacol. 2020;10:204512532092478.

    Google Scholar 

  41. McLean G, Juckes L. Parenteral clozapine (Clozaril). Australas Psychiatry. 2001;9(4):371–371.

    Google Scholar 

  42. Gaszner P, Makkos Z, Kosza P. Agranulocytosis during clozapine therapy. Prog Neuro-Psychopharmacol Biol Psychiatry. 2002;26(3):603–7.

    CAS  Google Scholar 

  43. Schulte PFJ, et al. Compulsory treatment with clozapine: a retrospective long-term cohort study. Int J Law Psychiatry. 2007;30:539–45.

    PubMed  Google Scholar 

  44. Marinkovic D, et al. The side-effects of clozapine: a four year follow-up study. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(3):537–44.

    CAS  PubMed  Google Scholar 

  45. Barak Y, et al. Clozapine in elderly psychiatric patients: tolerability, safety, and efficacy. Compr Psychiatry. 1999;40(4):320–5.

    CAS  PubMed  Google Scholar 

  46. Heim M, Rhein C. Early dyskinesia with administration of clozapine (Leponex). Nervenarzt. 1994;65(7):486–7.

    CAS  PubMed  Google Scholar 

  47. Grohmann R, et al. Adverse effects of clozapine. Psychopharmacology. 1989;99(1 Supplement):S101-107.

    PubMed  Google Scholar 

  48. Park HS, et al. In vivo tissue pharmacokinetics of carbon-11-labeled clozapine in healthy volunteers: a positron emission tomography study. CPT Pharmacomet Syst Pharmacol. 2015;4(5):305–11.

    CAS  Google Scholar 

  49. Török B, et al. Ameliorating schizophrenia-like symptoms in vasopressin deficient male Brattleboro rat by chronic antipsychotic treatment. Eur J Pharmacol. 2021;909:174383.

    PubMed  Google Scholar 

  50. Raper J, et al. Metabolism and distribution of clozapine-N-oxide: implications for nonhuman primate chemogenetics. ACS Chem Neurosci. 2017;8(7):1570–6.

    CAS  PubMed  Google Scholar 

  51. Chau DT, et al. Clozapine chronically suppresses alcohol drinking in Syrian golden hamsters. Neuropharmacology. 2010;58(2):351–6.

    CAS  PubMed  Google Scholar 

  52. Liu J, et al. Whole-body tissue distribution study of drugs in neonate mice using desorption electrospray ionization mass spectrometry imaging. Rapid Commun Mass Spectrom. 2014;28(2):185–90.

    CAS  PubMed  Google Scholar 

  53. Tareen FK, et al. Proniosomes as a carrier system for transdermal delivery of clozapine. Drug Dev Ind Pharm. 2020;46(6):946–54.

    CAS  Google Scholar 

  54. Patel M. Formulation, optimization, and in vivo evaluation of clozapine loaded transdermal drug delivery system for the treatment of schizophrenia. Asian J Pharm. 2020;14(4):556–71

    Google Scholar 

  55. Agrawal MB, Patel MM. Design, development and in vivo evaluation of clozapine loaded adhesive diffusion controlled system for the treatment of schizophrenia. J Drug Deliv Sci Technol. 2021;64:102629.

    CAS  Google Scholar 

  56. Tan MSA, et al. Clozapine-encapsulated binary mixed micelles in thermosensitive Sol–Gels for intranasal administration. Gels. 2022;8(1):38.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sayed S, et al. Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m. Drug Deliv. 2021;28(1):1524–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Patel HP, et al. Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: optimization and in vivo pharmacokinetic studies. Int J Pharm. 2021;600:120474.

    CAS  PubMed  Google Scholar 

  59. Royal College Of Psychiatry. Use of licensed medicines for unlicensed applications in psychiatric practice. Psychiatr Bull. 2007;31(7):275.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Siobhan Gee.

Ethics declarations

Funding

There was no funding source associated with this manuscript.

Conflicts of interest

SG has received speaker honoraria from Sunovion, Otsuka and Janssen, and consultancy fees from Sunovion and Invisio. DT has received research funding and consulting payments from Sunovion, Lundbeck, Janssen, Mylan HLS and Recordati.

Availability of data and material

Not applicable.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

Author contributions

SG wrote the manuscript and DT provided revision of the manuscript. Both authors approved the final version of the manuscript for submission and agree to be accountable for the work presented.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gee, S., Taylor, D. Alternative Routes of Administration of Clozapine. CNS Drugs 36, 105–111 (2022). https://doi.org/10.1007/s40263-022-00900-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-022-00900-w

Navigation