Rationale Tiotropium has been approved and marketed via HandiHaler® (18 µg once daily [qd]) since 2002 and via Respimat® (5 µg qd) since 2007. The recent TIOSPIR™ (TIOtropium Safety and Performance In Respimat®) study demonstrated that both products had comparable safety profiles; the objective of this analysis was to provide an updated safety evaluation of tiotropium in both formulations.
Methods Analysis of pooled adverse events (AEs) from randomised, double-blind, parallel-group, placebo-controlled clinical trials of ≥4 weeks’ duration where either tiotropium HandiHaler® 18 µg or tiotropium Respimat® 5 µg was indicated for chronic obstructive pulmonary disease (COPD). Rate ratios (RRs), incidence rates (IRs) and 95% confidence intervals (CIs) were determined for HandiHaler® and Respimat® trials together and separately.
Results This analysis of 28 HandiHaler® and seven Respimat® studies provided 14,909 (12,469 and 2440 with HandiHaler® and Respimat®, respectively) patient-years’ exposure to tiotropium. Mean age was 65 years and mean forced expiratory volume in 1 second was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and serious AEs (0.94 [0.89, 0.99]) was significantly lower with a numerically lower risk of death (0.90 [0.79, 1.01]) in the tiotropium group (pooled results) (Table). When separated by device, the risk of AEs and serious AEs remained lower in the tiotropium groups than placebo: RR 0.88 and 0.94 for HandiHaler® and 0.94 and 0.94 for Respimat® for AEs and serious AEs, respectively. Risks for cardiac events (0.93 [0.85, 1.02]) and major adverse cardiovascular events (MACE) (0.87 [0.75, 1.01]) were numerically lower and risk for respiratory, thoracic and mediastinal disorders (0.76 [0.61, 0.96]) was significantly reduced in the tiotropium group. The typical anticholinergic effects of dry mouth (2.39 [2.01, 2.84]), constipation (1.28 [1.06, 1.54]), intestinal obstruction (3.80 [1.42, 10.12]), dysuria (2.16 [1.31, 3.57]) and urinary retention (1.93 [1.21, 3.09]) were higher in the tiotropium group.
Conclusions The results from this safety review do not indicate an increased overall risk for fatal or cardiovascular events during tiotropium treatment, given via HandiHaler® or Respimat®, in patients with COPD.
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