Professional Slides: Safety

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Overall, the safety profile of Respimat® SMI was comparable to that of the CFC-MDI.
As expected in an asthma population, the most common adverse events were related to the respiratory system.
The frequency of adverse events considered to be treatment-related was generally low across all groups. Most adverse events were of mild or moderate intensity.
There were no reports of paradoxical bronchoconstriction (PB) in patients using Respimat® SMI.

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The safety profiles of IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI were comparable to that of IB/FEN 40/100 µg via CFC-MDI.

The overall incidence rate of adverse events was higher in the IB/FEN 40/100 µg via CFC-MDI group (34%) than in the IB/FEN 10/25 µg (25%) and IB/FEN 20/50 µg (24%) via Respimat® SMI groups. However, no clinically relevant between-treatment differences were observed. Asthma exacerbation and coughing were the most frequent adverse events in all treatment groups and were slightly more common in those receiving IB/FEN via CFC-MDI (9.0% and 7.9%, respectively) than in the two Respimat® SMI groups (5.6-6.7%). Most adverse events were of mild or moderate intensity.

There were no spontaneous reports of PB.

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Overall, the safety profiles of both IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI were comparable to that of IB/FEN 40/100 µg via CFC-MDI.

The incidences of adverse events and withdrawals were similar between treatment groups. There were no spontaneous reports of paradoxical or administration-related bronchoconstriction during the study.

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In two placebo- and active-controlled phase III clinical studies in COPD patients (study 1: IB 20 µg and 40 µg qid; study 2: IB/FEN 10/25 µg and 20/50 µg qid) Respimat® SMI cartridges were collected to determine whether microbial contamination of the medication solution had occurred.

Each cartridge was tested after 4 weeks’ use (n=171). Active and placebo cartridges were tested from devices that had been used for 4 and 12 weeks (study 2) or 20 weeks (study 1).

All the cartridges tested met the microbiological acceptance criteria for the respective pharmaceutical preparations in the current European and US Pharmacopoeias. Patient use of cartridges did not result in microbial contamination of the medication solution.

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PB following inhalation via nebulisers is well documented. Bronchodilators administered via Respimat® SMI are preserved and stabilised with low concentrations of benzalkonium chloride (BAC) and ethylene diamine tetra-acetic acid (EDTA), both of which have been reported to cause dose-related PB.

Safety data from single-dose and long-term studies involving 2829 asthma and COPD patients were analysed for adverse respiratory outcomes following treatment with active drug or placebo delivered via Respimat® SMI or CFC-MDI.
Total incidence of PB was very low in patients using Respimat® SMI and similar to that in patients using a CFC-MDI.

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The aim of this randomised, 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 hyper-reactive asthma patients via Respimat® SMI.

Thirty-seven patients with hyper-reactive asthma (indicated by a PC20 to methacholine ≦8 mg/ml) were randomised to receive four puffs of each of the following three treatments via Respimat® SMI, one on each of three study days: ethanolic placebo (96% + 0.13 µg EDTA/puff), aqueous placebo (5.5 µg EDTA + 1.1 µg BAC/puff), and normal saline (0.9% sodium chloride). Pulmonary function tests were performed at baseline and at 5, 15, 30, 60, 120 and 180 minutes post-inhalation. The primary endpoint was the lowest FEV ₁ recorded between 0 and 30 minutes post-inhalation of randomised treatment.

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The mean lowest FEV1 recorded between 0 and 30 minutes post-inhalation minus the study day baseline was -0.090 L for ethanolic placebo, -0.121 L for aqueous placebo and -0.094 L for normal saline (SEM 0.034 L for all). The mean treatment differences were: ethanolic placebo vs. normal saline: 0.004 L, 90% CI -0.075 to 0.083 L, p=0.002; aqueous placebo vs. normal saline: -0.028 L, 90% CI -0.107 to 0.052 L, p=0.006.

Since both 90% CIs fell within the pre-determined equivalence region of ± 0.15 L, both the ethanolic and aqueous placebo treatments were considered equivalent to normal saline.

Ethanolic and aqueous solutions administered via Respimat® SMI are safe with regard to PB in patients with hyper-reactive asthma, even when used without bronchoprotective medication.