Advertisement

CNS Drugs

, Volume 27, Issue 6, pp 479–489 | Cite as

Loxapine Inhalation Powder: A Review of its Use in the Acute Treatment of Agitation in Patients with Bipolar Disorder or Schizophrenia

  • Gillian M. KeatingEmail author
Adis Drug Evaluation

Abstract

Loxapine is a well-established, first-generation antipsychotic agent. Loxapine inhalation powder (Adasuve®) was recently approved in the USA and the EU for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. Inhaled loxapine is delivered by a hand-held, single-dose, single-use device that uses the Staccato® drug delivery system. With Adasuve®, maximum plasma loxapine concentrations are reached in a median of 2 min. In two randomized, double-blind, placebo-controlled, multicentre trials, inhaled loxapine 5 or 10 mg significantly reduced agitation (assessed using Positive and Negative Syndrome Scale-Excited Component scores) in patients with bipolar I disorder or schizophrenia, with the onset of effect seen within 10 min of administration. Inhaled loxapine was generally well tolerated in phase III trials (which excluded patients with clinically significant acute or chronic pulmonary disease), with the most commonly occurring adverse events including dysgeusia and sedation. Inhaled loxapine is contraindicated in patients with airways disease associated with bronchospasm or acute respiratory signs or symptoms. In conclusion, inhaled loxapine provides a novel new option for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia, combining a rapid onset of effect with a noninvasive route of administration.

Keywords

Chronic Obstructive Pulmonary Disease Schizophrenia Bipolar Disorder Aripiprazole Atypical Antipsychotic 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

References

  1. 1.
    Sachs GS. A review of agitation in mental illness: burden of illness and underlying pathology. J Clin Psychiatry. 2006;67(Suppl. 10):5–12.PubMedGoogle Scholar
  2. 2.
    Caine ED. Clinical perspectives on atypical antipsychotics for treatment of agitation. J Clin Psychiatry. 2006;67(Suppl 10):22–31.PubMedGoogle Scholar
  3. 3.
    Allen MH, Currier GW, Carpenter D, et al. The expert consensus guideline series: treatment of behavioral emergencies 2005. J Psychiatr Pract. 2005;11(Suppl. 1):5–108.PubMedCrossRefGoogle Scholar
  4. 4.
    Wilson MP, Pepper D, Currier GW, et al. The psychopharmacology of agitation: consensus statement of the American Association for Emergency Psychiatry project BETA psychopharmacology workgroup. West J Emerg Med. 2012;13(1):26–34.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Lukens TW, Wolf SJ, Edlow JA, et al. Clinical policy: critical issues in the diagnosis and management of the adult psychiatric patient in the emergency department. Ann Emerg Med. 2006;47(1):79–99.PubMedCrossRefGoogle Scholar
  6. 6.
    Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry. 2006;67(Suppl. 10):13–21.PubMedGoogle Scholar
  7. 7.
    Nordstrom K. Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: an update. Neuropsychiatry. 2012;2(3):253–60.CrossRefGoogle Scholar
  8. 8.
    Chakrabarti A, Bagnall AM, Chue P, et al. Loxapine for schizophrenia. Cochrane Database Syst Rev. 2007(4):CD001943.Google Scholar
  9. 9.
    Alexza Pharmaceuticals Inc. Adasuve™ (loxapine) inhalation powder, for oral inhalation use: US prescribing information; 2012. http://www.adasuve.com/ (Accessed 9 May 2013).
  10. 10.
    European Medicines Agency. Adasuve (loxapine) inhalation powder: EU summary of product characteristics; 2013. http://ec.europa.eu/health/documents/community-register/2013/20130220125343/anx_125343_en.pdf (Accessed 9 May 2013).
  11. 11.
    Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198(1):51–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Cassella J, Spyker D, Kwentus J, et al. Rapid improvement in the five-item PANSS-EC scale for agitation with inhaled loxapine (AZ-004) [poster]. New Clinical Drug Evaluation Unit 2010 Meeting; 14–17 Jun 2010; Boca Raton (FL).Google Scholar
  13. 13.
  14. 14.
    Dinh K, Myers DJ, Glazer M, et al. In vitro aerosol characterization of Staccato® loxapine. Int J Pharm. 2011;403(1–2):101–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Gao Q, Lew A, Takahashi LH, et al. An investigation into the morphology of loxapine in a thermal aerosolization process from crystalline to amorphous. J Pharm Sci. 2011;100(4):1407–15.PubMedCrossRefGoogle Scholar
  16. 16.
    Dinh KV, Myers DJ, Noymer PD, et al. In vitro aerosol deposition in the oropharyngeal region for Staccato® loxapine. J Aerosol Med Pulm Drug Deliv. 2010;23(4):253–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Li Z, Ichikawa J, Meltzer HY. A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens. Psychopharmacology (Berl). 2003;167(3):315–23.Google Scholar
  18. 18.
    Singh AN, Barlas C, Saeedi H, et al. Effect of loxapine on peripheral dopamine-like and serotonin receptors in patients with schizophrenia. J Psychiatry Neurosci. 2003;28(1):39–47.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Natesan S, VanderSpek S, Nobrega JN, et al. Contrasting loxapine to its isomer isoloxapine: the critical role of in vivo D2 blockade in determining atypicality. Schizophr Res. 2005;77(2–3):189–99.PubMedCrossRefGoogle Scholar
  20. 20.
    Coupet J, Rauh CE. 3H-Spiroperidol binding to dopamine receptors in rat striatal membranes: influence of loxapine and its hydroxylated metabolites. Eur J Pharmacol. 1979;55(2):215–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Singh AN, Barlas C, Singh S, et al. A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes. J Psychiatry Neurosci. 1996;21(1):29–35.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Glazer WM. Does loxapine have ‘atypical’ properties? Clinical evidence. J Clin Psychiatry. 1999;60(Suppl. 10):42–6.PubMedGoogle Scholar
  23. 23.
    Meltzer HY, Matsubara S, Lee J-C. The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull. 1989;25(3):390–2.PubMedGoogle Scholar
  24. 24.
    Leysen JE, Janssen PMF, Schotte A, et al. Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology (Berl). 1993;112(1 Suppl.):S40–54.CrossRefGoogle Scholar
  25. 25.
    Stockmeier CA, DiCarlo JJ, Zhang Y, et al. Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J Pharmacol Exp Ther. 1993;266(3):1374–84.PubMedGoogle Scholar
  26. 26.
    Kapur S, Zipursky R, Remington G, et al. PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am J Psychiatry. 1997;154(11):1525–9.PubMedGoogle Scholar
  27. 27.
    Spyker DA, Gottwald MD, Fishman RS. The cardiovascular safety of inhaled loxapine (AZ-004) [abstract no. NR6-6 plus poster]. 163rd Annual Meeting of the American Psychiatric Association; 22–27 May 2010; New Orleans (LA).Google Scholar
  28. 28.
    US Food and Drug Administration. Clinical review: NDA 22549 SD-28; 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM282897.pdf (Accessed 8 May 2013).
  29. 29.
    Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14(1):31–40.PubMedCrossRefGoogle Scholar
  30. 30.
    Spyker DA, Munzar P, Cassella JV. Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers. J Clin Pharmacol. 2010;50(2):169–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Luo JP, Vashishtha SC, Hawes EM, et al. In vitro identification of the human cytochrome p450 enzymes involved in the oxidative metabolism of loxapine. Biopharm Drug Dispos. 2011;32(7):398–407.PubMedCrossRefGoogle Scholar
  32. 32.
    Reed A, Huie K, Perloff ES, et al. Loxapine p-glycoprotein interactions in vitro. Drug Metab Lett. 2012;6(1):26–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Allen MH, Feifel D, Lesem MD, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72(10):1313–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Cassella J, Fishman R. Treating agitation with inhaled loxapine (AZ-004): efficacy analyses in patients with schizophrenia or bipolar disorder [poster]. 24th Annual US Psychiatry and Mental Health Congress; 7–10 Nov 2011; Las Vegas (NV).Google Scholar
  35. 35.
    Howland RH. Now take a deep breath: inhaled loxapine for the treatment of acute agitation. J Psychosoc Nurs Ment Health Serv. 2012;50(1):16–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Otsuka Pharmaceutical Company. Abilify® (aripiprazole): US prescribing information; 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021436s034,021713s025,021729s018,021866s020lbl.pdf (Accessed 9 May 2013).
  37. 37.
    Tran-Johnson TK, Sack DA, Marcus RN, et al. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68(1):111–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158(7):1149–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 2001;21(4):389–97.PubMedCrossRefGoogle Scholar
  40. 40.
    European Medicines Agency. Abilify (aripiprazole): EU summary of product characteristics; 2013. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000471/WC500020170.pdf (Accessed 9 May 2013).
  41. 41.
    Eli Lilly. Zyprexa (olanzapine): US prescribing information; 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020592s057,021086s036,021253s045lbl.pdf (Accessed 9 May 2013).
  42. 42.
    European Medicines Agency. Zyprexa (olanzapine): EU summary of product characteristics; 2012. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000115/WC500055207.pdf (Accessed 9 May 2013).
  43. 43.
    Pfizer. Geodon (ziprasidone): US prescribing information; 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020825s038,020919s025,021483s005lbl.pdf (Accessed 9 May 2013).
  44. 44.
    European Medicines Agency. Syncrest (asenapine) sublingual tablets: EU summary of product characteristics; 2013. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001177/WC500096895.pdf (Accessed 9 May 2013).
  45. 45.
    Merck and Co. Saphris® (asenapine) sublingual tablets: US prescribing information; 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022117s013lbl.pdf (Accessed 9 May 2013).
  46. 46.
    Citrome L. Aerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorder. Int J Clin Pract. 2011;65(3):330–40.PubMedCrossRefGoogle Scholar
  47. 47.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.AdisNorth ShoreNew Zealand

Personalised recommendations