Inhaled Ethanolic and Aqueous Solutions via Respimat Soft Mist Inhaler Are Well-Tolerated in Asthma Patients

Abstract

Background: Respimat^® Soft Mist^™ Inhaler (SMI) is a new-generation inhaler offering improved lung deposition compared with other devices. Bronchodilators administered via Respimat SMI are preserved and stabilized with benzalkonium chloride (BAC) and ethylene diamine tetra-acetic acid (EDTA); both have been reported to cause paradoxical bronchoconstriction if a threshold dose is exceeded. Objective: The aim of this randomized, double-blind, three-period, crossover study was to establish that the safety of inhaled ethanolic and aqueous placebo solutions (containing BAC and EDTA) is equivalent to that of inhaled normal saline solution when administered to asthma patients via Respimat SMI. Methods: Thirty-seven asthma patients with airway hyper-reactivity were randomized to receive four actuations of each of the following three treatments via Respimat SMI, one on each of 3 study days: ethanolic placebo (12 µl 96% ethanol + 0.13 µg EDTA/actuation), aqueous placebo (12 µl water + 5.5 µg EDTA + 1.1 µg BAC/actuation), and normal saline (12 µl 0.9% sodium chloride/actuation). Pulmonary function tests were performed at baseline and at 5, 15, 30, 60, 120 and 180 min after inhalation; the primary endpoint was the lowest FEV₁ recorded between 0 and 30 min. Results: The mean lowest FEV₁ recorded between 0 and 30 min after inhalation minus the study day baseline was –0.090 litres for ethanolic placebo, –0.121 litres for aqueous placebo and –0.094 litres for normal saline (SEM 0.034 litres for all). The mean treatment differences were: ethanolic placebo versus normal saline 0.004 litres (90% CI –0.075–0.083 litres, p = 0.002), and aqueous placebo versus normal saline –0.028 litres (90% CI –0.107–0.052 litres, p = 0.006). Since both 90% CIs fell within the pre-determined equivalence region of ±0.15 litres, both treatments were considered equivalent to normal saline. Conclusion: Ethanolic and aqueous solutions administered via Respimat SMI are safe with regard to paradoxical bronchoconstriction in asthma patients with airway hyper-reactivity.

Acute Local Tolerability of Acidic Aqueous Vehicles Delivered via Respimat® Soft Mist™ Inhaler in Hyperreactive Asthma Patients

“…However, this was not the case here as there was no evidence of paradoxical bronchoconstriction (i.e., a fall in FEV 1 >15%) during our study. This is consistent with previous findings which also show that delivery of bronchodilators via the Respimat SMI does not lead to paradoxical bronchoconstriction in either asthma or COPD patients [17,18,19]. In these studies, the incidence of bronchospasm was comparable with CFC-MDIs.…”

Lack of paradoxical bronchoconstriction after administration of tiotropium via Respimat® Soft Mist™ Inhaler in COPD

“…In spite of this, our analysis shows that administration-related bronchoconstriction is uncommon when tiotropium is administered via Respimat ® SMI for 48 weeks in COPD patients. Our finding is consistent with results of studies in hyperreactive asthma patients who were given four inhalations of a placebo equivalent of the tiotropium formulation from Respimat ® SMI (twice the usual tiotropium dose) 17,18…”

“…In pooled analyses of studies in which a range of short-acting bronchodilators were given as single and repeated doses from Respimat ® SMI to asthma and COPD patients, no bronchospasm was recorded and levels of paradoxical bronchoconstriction were very low 15,16. In asthma patients with documented hyperreactivity, four inhalations of a placebo equivalent of the tiotropium formulation (the usual dose for COPD is only two inhalations) did not produce paradoxical bronchoconstriction and was associated with less cough than a placebo chlorofluorocarbon (CFC)-pMDI,17 supporting results of an earlier study that showed no difference in the degree of fall in FEV 1 between placebo aqueous or ethanolic inhalations and normal saline (all delivered via Respimat ® SMI) 18…”

The function and performance of aqueous aerosol devices for inhalation therapy

“…Inhalation solutions of tiotropium have been shown to be safe in asthma patients, but an increased risk of mortality has been reported for patients with COPD using Respimat ® . The high efficiency of this device also allows for the delivery of acidic solutions with pH values as low as 2.7, as well as ethanolic solutions, to be safely delivered to asthma patients without causing adverse events . The flexibility of this platform has allowed the use of a novel β 2 ‐agonist solution (olodaterol) in a hydroalcoholic mixture to be evaluated for pulmonary delivery .…”