Low Incidence of Paradoxical Bronchoconstriction with Bronchodilator Drugs Administered by Respimat® Soft Mist™ Inhaler: Results of Phase II Single-Dose Crossover Studies

Abstract

Background and Objectives: Respimat^® Soft Mist™ Inhaler (SMI) is an innovative device that offers improved lung deposition and is an environmentally friendly alternative to conventional, chlorofluorocarbon-containing metered-dose inhalers (CFC-MDIs). The aqueous formulations of bronchodilator drugs administered from Respimat SMI contain low concentrations of ethylene diamine tetra-acetic acid (EDTA), a stabilising agent, and benzalkonium chloride (BAC), an antibacterial agent, both of which have been associated with bronchoconstriction when administered via nebulisers. The aim of this retrospective analysis was to compare the incidence of paradoxical bronchoconstriction with bronchodilator drugs administered via Respimat SMI or a CFC-MDI in patients with asthma or chronic obstructive pulmonary disease (COPD). Methods: Nine randomised, active- and/or placebo-controlled, double-blind, crossover studies, in which asthmatic and COPD patients (n = 444 and n = 216, respectively) received a β₂-agonist and/or anticholinergic or placebo via Respimat SMI or CFC-MDI, were included in the analysis. The incidence of conditions indicative of paradoxical bronchoconstriction were collated and divided into four categories: (1) ‘bronchospasm’; (2) two or more of the following events: ‘other respiratory adverse events’, ‘rescue medication use’ or ‘asymptomatic drop in forced expiratory volume in one second’ (FEV₁); (3) either ‘rescue medication use’ or ‘other respiratory adverse event’; (4) ‘asymptomatic drop in FEV₁’. Results: The incidence of adverse events indicative of paradoxical bronchoconstriction was low in those patients using the Respimat SMI device, and similar to that seen in the CFC-MDI group. In addition, the incidence of adverse events indicative of paradoxical bronchoconstriction observed in the Respimat SMI group was similar for BAC + EDTA and BAC-only drug formulations. Conclusions: These studies demonstrate that, due to the extremely low absolute amounts of BAC and EDTA delivered to the lungs by the device, Respimat SMI is safe with regard to paradoxical bronchoconstriction in patients with asthma or COPD.