Share this article on:, Inhaled Loxapine, and Safety Issues

Shader, Richard I. MD

Journal of Clinical Psychopharmacology: April 2017 - Volume 37 - Issue 2 - p 119–121
doi: 10.1097/JCP.0000000000000679

From the Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA.

Reprints: Richard I. Shader, MD, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 75 Kneeland St, Boston, MA 02111 (e-mail:

In a recent article in the New England Journal of Medicine, Dr Maria Makrides makes the following statement: “[Ms X] should not start prenatal fish oil supplements on the basis of the results of a single study. Clinical practice decisions are best made in accordance with practice guidelines based on well-conducted systematic reviews, preferably of several randomized, controlled trials.”1 I wholeheartedly endorse this axiom and would add one of my own: When it comes to establishing the clinical value of any therapeutic intervention, the replication of seminal findings is an essential step. It is my view that, in general, a single positive outcome should provide the impetus to do further work on a hypothesis and to make continued efforts to refute it. I realize that there are exceptions to both of these axioms, especially for treatments of some rare or orphan diseases. The use of historical controls may also suggest an overwhelming benefit from a new, targeted therapy of a life-threatening or otherwise devastating condition.

How is a practicing clinician going to know how the efficacy of any newly marketed therapy was established? The concerned practitioner can and should read the information provided in the product's label—also called the patient package insert (PPI). Better still is a thorough literature search on the product. Unfortunately, it is common knowledge that some positive outcome trials are not published, and even more importantly, most negative trials are not published. The clinician may never discover that, although the agent was approved because of two positive controlled studies, there were also two, perhaps even more, negative trials. It is always possible that there may be good reasons for negative outcomes, but the PPI may not explain them. Issues include sample size, inadequate dosages, or adherence—to cite a few common reasons.

Another important and underused source of information is (CTg). It is a website maintained by the National Library of Medicine; the National Library of Medicine is an institute within the National Institutes of Health (NIH). is intended to serve as a registrational site for clinical trials in humans and as a repository for trial results and protocol amendments. A newly revised set of CTg guidelines went into effect on January 18th of this year. These guidelines, developed jointly by the Food and Drug Administration (FDA) and the NIH, are discussed and elaborated in a document entitled “Clinical Trials Registration and Results Information Submission.” It can be downloaded from It details how protocols, analysis plans, and collected data and results are to be presented. Several points are worth reiterating: (1) no patient-specific data submission is required—I understand this as a means of privacy protection, but it limits any ability to better understand more than results from cohort mean values; (2) data must be submitted in tabular form—summarizing patient flow, demographic and baseline characteristics, primary and secondary outcome measures, unwanted treatment effects, and most importantly, the deposition of results from any scientifically appropriate statistical tests; and (3) trial results must be submitted no later than 1 year after study completion (also referred to as the “primary completion date”), defined as the date of final data collection for the primary outcome measure. Examination of the CTg website in December 2016 suggests that sponsors rarely provide all of these pieces of information.3 Calling these “requirements” may improve adherence to those expectations, but it is not at all clear how they will be enforced or what penalties will be imposed.

The Final Rule, also called FDAAA 801 and the NIH Policy on Clinical Trial Reporting, defines which clinical trials are covered by this newly published document. It applies to all trials of FDA-regulated drug products used in interventional clinical trials, including not only small molecules but also biologics and devices. Specifically, it applies to trials “with one or more arms and with one or more prespecified outcome measures.”2 It does not apply to trials covered under treatment INDs (investigational new drug exemptions) or treatment protocols that facilitate “widespread access, access for intermediate-sized patient populations, or access for individual patients.”2

In my early clinical training years, I was responsible for many acutely psychotic patients. Delusional thinking and agitated behavior were common characteristics of these patients. We had access to several neuroleptic agents (now called first-generation conventional antipsychotic agents). Unfortunately, these powerful drugs usually did not have a prompt onset of action, and they often did not quickly calm agitated patients. We made frequent adjunctive use of parenteral benzodiazepines such as intramuscular lorazepam. By chance, I recently overheard a conversation in which two physicians were discussing the use of intranasal loxapine for their agitated psychotic patients. I was startled for two reasons: (1) I had never heard of intranasal loxapine, and (2) I could not imagine how a truly agitated psychotic patient could be convinced to willingly self-administer an intranasal drug. The trade name for this formulation of loxapine is Adasuve. Reading its PPI did not clarify reason 2 for me. In fact, it increased my skepticism.4 The administering clinician is told to open the inhaler and then pull out the plastic tab at the back of the dispenser. The clinician next looks for a green light that should turn on as evidence that the unit is ready. If the inhaler is not used within 15 minutes, the light will go off, and preprogramed deactivation occurs. As soon as the green light goes on, the patient needs to be receptive to the inhaler's use. The administering clinician has explained the procedures to the patient either during this 15-minute interval or at an earlier time.

In addition to helping the patient to understand the importance of following instructions in a timely manner, the following must also be conveyed4: (1) “…the inhaler may produce a flash of light and a clicking sound,” (2) the inhaler may warm up while in use, (3) the patient must “…hold the inhaler away from the mouth and breathe out fully to empty the lungs,” (4) “…put the mouthpiece of the inhaler between the lips, close the lips, and inhale through the mouthpiece with a steady deep breath,” (5) “…check that the green light turns off indicating that the dose has been delivered,” (6) “…remove the mouthpiece from the mouth and hold the breath for as long as possible, up to 10 seconds,” and (7) the treating clinician is advised to perform a physical examination every 15 minutes for the first hour after the inhaler is used (listening to the chest is a central component of the physical examination). Finally, the administering clinician must then discard the inhaler—it is intended solely for single use.

I wonder how many readers of this Editorial will agree with me that these steps could not be followed by many psychotic patients who are agitated enough to require this intervention. Regarding my second point, I am now even more skeptical.

I readily admit that it has been many years since I have treated a psychotic patient who was agitated. However, I can in no way picture that any of my former patients could have been engaged to follow the use protocol for inhaled loxapine. My next step was to consult CTg for the inclusion and exclusion criteria for the schizophrenia study.5 Here is one of the listed inclusion criteria: patients must have a score of greater than or equal to 14 on the 5-item PANSS Excited Component (PANSS-EC). The elements of this subscale are poor impulse control, tension, hostility, uncooperativeness, and excitement. The telltale clue for me is this exclusion criterion: “Patients who are considered by the investigator, for any reason, to be an unsuitable candidate for receiving loxapine, or unable to use the inhalation device, must be excluded.”5,6

PANSS-EC scores can range from 5 to 35, and scores on each item can range from 1 to 7. Patients in this study entered with baseline scores averaging approximately 17.5. After 2 hours, patients on placebo improved to approximately 11.6, and patients on inhaled loxapine dropped to approximately 8.9. The difference between these two decrements was statistically significant. This means that the difference between the two outcomes was less than 3 points—an amount that is not clinically profound for a scale with a 30-point range. Changes on the five individual items of the PANSS-EC are not provided in the results section of this article.6

In an unrelated validation study of the PANSS-EC in 278 agitated patients seen in emergency departments in Spain, mean PANSS-EC total scores at admission dropped from 20.38 to 13.07 at discharge after a variety of interventions (note that this discharge outcome score is only 1 point higher than the entry level for the study discussed previously). In this validation study, three items were initially of moderate to fairly severe intensity (problems with impulse control, excitement, and tension). Hostility and lack of cooperation were either absent or mild.7 The psychotic patients I have in mind were hostile, agitated, and uncooperative—behaviors that led to the use of adjunctive treatments for their agitation. My conclusion is that inhaled loxapine may be useful for some agitated psychotic patients, but I doubt its use in those who are also hostile and uncooperative.

I first became knowledgeable about loxapine in its succinate form in 1975, the first year it was marketed. In that same year, I included it in the first edition of my Manual of Psychiatric Therapeutics.8 There was little to say at that time. It is a member of the dibenzoxazepine class, the same class designation as clozapine. It undergoes N-demethylation, and one of its active metabolites is amoxapine, a tetracyclic antidepressant that is also a dibenzoxazepine. To my knowledge, loxapine is the only antipsychotic agent that has an antidepressant as a metabolite. CYPs 1A2, 3A4, and 2D6 and flavin-containing monooxygenases are involved in the hepatic metabolism of oral loxapine.9 This raises another curious point. The human nasal mucosa is the site of first contact for nasally administered agents. CYPs 2A6, 2A13, 2B6, 2C, 2J2, and 3A are known to be present and active in human nasal mucosa.10 There is no mention in the PPI for this product of any studies of nasal metabolism. Perhaps, transit time in the nares is too short for a significant degree of metabolism to take place.

What about safety issues with inhaled loxapine? I always wonder how intranasal products will affect airway tone and reactivity. With many inhaled agents, bronchoconstriction, bronchospasm, and other acute forms of respiratory distress can occur. Inhaled loxapine uses a unique delivery system that does not use propellants or excipients—common causes of inhaler-induced respiratory system problems. Furthermore, the particles emitted are said to be sufficiently small that they are not considered to be respiratory tract irritants. This delivery system is called the Staccato System, and it is FDA approved as a medical device.11 Unfortunately, when inhaled loxapine was studied in patients with asthma or chronic obstructive pulmonary disease, clinically significant decreases in forced expiratory volume were observed, and unwanted respiratory effects (eg, chest discomfort, shortness of breath, cough, wheezing, and bronchospasm) occurred in approximately 54% of patients with asthma who received the drug.12 This was unexpected because no respiratory adverse events were seen in studies in 30 Phase 1 volunteer subjects. A black box warning was imposed by the FDA, and the drug can now be used only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) that is called the Adasuve REMS.13

Several other questions arise for me about the development plan for inhaled loxapine, as well as about the FDA's expectations and requirements. Because patients with schizophrenia are known to be at an elevated risk for comorbid chronic obstructive pulmonary disease and contact dermatitis and eczema,14 and psychotic events are more common in children with a history of atopy and increased levels of inflammatory markers,15 why was more research not conducted to look into the possibility that these patients might be at risk for respiratory complications? Other questions are: why exercise-induced respiratory compromise is not specifically mentioned in the PPI, and why were no drug interaction studies required for drugs known to cause respiratory symptoms (eg, angiotensin-converting enzyme inhibitors)?

If one looks at all of the studies of inhaled loxapine registered in CTg, as of January 5, 2017, not one presents any study results, even for major studies completed in 2009. A striking example is a study of the use of inhaled loxapine in patients experiencing migraine headaches (NCT00489476). Completed in 2007, no results are posted, and no published reports are indicated. Although for a few of the registered studies, publications that contain the results of these trials are posted on the CTg site. There are also no reported results for the REMS plan associated with its approval in 2012. Hopefully, the changes to CTg that began in January of this year should result in making CTg a more robust, complete, and useful repository for clinical trial availability and results.

Listing of a trial in CTg or its equivalent in other countries is required for publication in the Journal of Clinical Psychopharmacology.

As of early January 2017, CTg contains 233,881 studies. These come from all 50 states in the United States and from 195 other countries.

Back to Top | Article Outline


The author declares no conflicts of interest.

Back to Top | Article Outline


1. Makrides M. Do not start n-3 LCPUFA supplementation. N Engl J Med. 2016;375:2600–2601.
2. Department of Health and Human Services. 42 CFR part 11. Clinical trials registration and results submission. Available at: Accessed January 6, 2017.
3. National Library of Medicine, National Institutes of Health (NIH). Bethesda, MD. Accessed January 6, 2017.
4. Adasuve. Instructions for using Adasuve. Accessed January 6, 2017.
5. Loxapine. Accessed January 6, 2017.
6. 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;72:1313–1321.
7. Montoya A, Valladares A, Lizán L, et al. Validation of the excited component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room. Health Qual Life Outcomes. 2011;9:18.
8. Shader RI, Jackson AH. Approaches to schizophrenia. In: Shader RI, ed. Manual of Psychiatric Therapeutics. Boston, MA: Little Brown; 1975:63–100.
9. Wikipedia. Loxapine. Accessed January 6, 2017.
10. Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol. 2003;43:149–173.
11. Noymer P, Myers D, Glazer M, et al. The Staccato System: inhaler design characteristics for rapid treatment of CNS disorders. Respiratory Drug Delivery. 2010;1:11–20.
12. Gross N, Greos LS, Meltzer EO, et al. Safety and tolerability of inhaled loxapine in subjects with asthma and chronic obstructive pulmonary disease—two randomized controlled trials. J Aerosol Med Pulm Drug Deliv. 2014;27:478–487.
13. Food and Drug Administration. Center for Drug Evaluation and Research. Accessed January 6, 2017.
14. Weber NS, Cowan DN, Millikan AM, et al. Psychiatric and general medical conditions comorbid with schizophrenia in the National Hospital Discharge Survey. Psychiatr Serv. 2009;60:1059–1067.
15. Khandaker GM, Zammit S, Lewis G, et al. A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophr Res. 2014;152:139–145.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.