Safety and Tolerability of Inhaled Loxapine in Subjects with Asthma and Chronic Obstructive Pulmonary Disease—Two Randomized Controlled Trials

Abstract

Background: Loxapine, a first-generation antipsychotic, delivered with a novel inhalation delivery device developed for the acute treatment of agitation in patients with schizophrenia or bipolar disorder was evaluated in subjects with asthma or chronic obstructive pulmonary disease (COPD). Methods: Separate randomized, double-blind, parallel-arm, placebo-controlled trials compared two administrations of inhaled loxapine (10 mg) 10 hr apart with placebo in 52 subjects with asthma and in 53 subjects with COPD. A thermally-generated drug aerosol of loxapine was delivered to the deep lung for rapid systemic absorption. Controller medications were continued throughout the study, but quick-relief bronchodilators were withheld from 6-8 hr before through 34 hr after dose 1, unless indicated as rescue. Results: All airway adverse events (AEs) were of mild or moderate severity. Symptomatic bronchospasm occurred in 53.8% of subjects with asthma after inhaled loxapine and 11.5% after placebo; and in 19.2% of COPD subjects after inhaled loxapine and 11.1% after placebo. Subjects required inhaled albuterol as follows: asthma: 53.8% after inhaled loxapine and 11.5% after placebo; and COPD: 23.1% after inhaled loxapine and 14.8% after placebo. Respiratory signs/symptoms requiring treatment responded to rescue bronchodilator [forced expiratory volume in 1 sec (FEV 1 ) return to within 10% of baseline] within 1 hr in 11 of 15 events in asthma subjects and four of seven events in COPD subjects, the remainder by the last spirometry. Conclusions: In subjects with either asthma or COPD, FEV 1 decline and bronchospasm can occur following inhaled loxapine, but more frequently in asthmatic subjects. Most subjects with bronchospasm responded to rescue bronchodilator within 1 hr. No treatment-related serious AE occurred. Although inhaled loxapine is contraindicated in patients with active airways disease per the current approved US labeling, these studies demonstrated that rescue bronchodilator mitigated the symptomatic bronchospasms that may occur in case of inadvertent use.

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

“…Subjects with respiratory disease were excluded, consistent with the contraindications on the product label. However, despite some concerns regarding potential bronchospasm induction by inhaled loxapine [ 25 ], no airway-related AEs were observed in this study.…”

<b>New drugs for the treatment of agitation in schizophrenia: a systematic review and meta-analysis of inhaled loxapine and infused sodium nitroprusside

“…This information is relevant to the safety limits as well as to the indications and contraindications for the treatment. No other serious adverse events have been reported with the use of this drug (Gross et al, 2014;Spyker et al, 2014).…”

“…The administration of LOXi was approved by the FDA in 2012 (it has been available on the US market since 2014) as a single dose for the treatment of agitation in schizophrenic or bipolar patients. Additionally, this product was approved in 2013 by the European Medical Association for use in two doses (Gross et al, 2014;Citrome, 2012). This drug is not yet available in Brazil, although the pharmaceutical industry is interested in its registration (Ferrer International, 2015).…”

Inhaled Loxapine for the Management of Acute Agitation in Bipolar Disorder and Schizophrenia: Expert Review and Commentary in an Era of Change

“…Although not observed in the phase III clinical trials, the product label for inhaled loxapine contains a warning for bronchospasm and the potential for subsequent respiratory distress and respiratory arrest [ 31 , 32 , 37 ]. The safety and tolerability of inhaled loxapine with regard to respiratory adverse events have been evaluated in two randomised controlled trials, one in patients with asthma ( n = 52) and a second in patients with chronic obstructive pulmonary disease (COPD; n = 53) [ 44 ]. The studies compared two doses of inhaled loxapine 9.1 mg (delivered 10 h apart) with placebo.…”