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Long-term safety of tiotropium delivered by Respimat^® SoftMist™ Inhaler: patient selection and special considerations.

ABSTRACT: Tiotropium bromide is a long-acting inhaled muscarinic antagonist used in patients with chronic respiratory disease. It has been available since 2002 as a single-dose dry powder formulation via the HandiHaler^® dry powder inhaler (DPI) device, and since 2007 as the Respimat^® SoftMist™ Inhaler (SMI). The latter is a novel method of medication delivery that utilizes a multidose aqueous solution to deliver the drug as a fine mist. Potential benefits include more efficient drug deposition throughout the respiratory tract, reduced systemic exposure, and greater ease of use and patient satisfaction compared with the use of HandiHaler DPI. Although tiotropium bromide delivered via the HandiHaler DPI has been clearly shown to improve lung function, dyspnea, and quality of life and to reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD), there is accumulating evidence regarding the use of tiotropium HandiHaler in other respiratory diseases characterized by airflow limitation, such as asthma and cystic fibrosis. Developed more recently, tiotropium delivered via the Respimat SMI appears to have a similar efficacy and safety profile to the HandiHaler DPI, and early data raising the possibility of safety concerns with its use in COPD have been refuted by more recent evidence. The benefits over the HandiHaler DPI, however, remain unclear. This paper will review the evidence for tiotropium delivered via the Respimat SMI inhaler, in particular as an alternative to the HandiHaler DPI, and will focus on the safety profile for each of the chronic lung diseases in which it has been trialed, as well as an approach to appropriate patient selection.

SUBMITTER: Tan CK

PROVIDER: S-EPMC5036544 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Long-term safety of tiotropium delivered by Respimat® SoftMist™ Inhaler: patient selection and special considerations.

Tan Ching Kuo CK Say Gui Quan GQ Geake James B JB

Therapeutics and clinical risk management 20160921

Tiotropium bromide is a long-acting inhaled muscarinic antagonist used in patients with chronic respiratory disease. It has been available since 2002 as a single-dose dry powder formulation via the HandiHaler® dry powder inhaler (DPI) device, and since 2007 as the Respimat® SoftMist™ Inhaler (SMI). The latter is a novel method of medication delivery that utilizes a multidose aqueous solution to deliver the drug as a fine mist. Potential benefits include more efficient drug ...[more]

PMID: 27703365

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Project description:IntroductionTiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler(®) (18 μg once daily) or Respimat(®) Soft Mist™ inhaler (5 μg once daily). The recent TIOtropium Safety and Performance In Respimat(®) (TIOSPIR™) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium(®) using data from placebo-controlled HandiHaler(®) and Respimat(®) trials.MethodsPooled analysis of adverse event (AE) data from tiotropium HandiHaler(®) 18 μg and Respimat(®) 5 μg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler(®) and Respimat(®) trials, both together and separately.ResultsIn the 28 HandiHaler(®) and 7 Respimat(®) trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler(®); 2,440 with Respimat(®)) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler(®) and Respimat(®) pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.ConclusionThis analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler(®) or Respimat(®) (overall and separately) in patients with COPD.

Project description:BackgroundTiotropium Safety and Performance in Respimat® (TIOSPIR®) compared the safety and efficacy of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups.MethodsTIOSPIR® was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial.ResultsThe substudy included 1370 patients who received once-daily tiotropium Respimat® 5 μg (n = 461), 2.5 μg (n = 464), or tiotropium HandiHaler® 18 μg (n = 445). Adjusted mean trough FEV1 (average 24-120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups (difference versus HandiHaler® [95 % CI]: -10 [-38, 18] mL for Respimat® 5 μg and, -37 [-65, -9] mL for Respimat® 2.5 μg); achieving noninferiority to tiotropium HandiHaler® 18 μg for tiotropium Respimat® 5 but not for 2.5 μg (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups. The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat® 5-μg, 2.5-μg, and HandiHaler® 18-μg groups). The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not.ConclusionsThe TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV1, but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV1 decline. The rate of FEV1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction.Trial registrationNCT01126437.

Project description:IntroductionThe safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies.MethodsThese were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat®) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies.ResultsOf 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment.ConclusionOver half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Project description:BackgroundPatients with chronic obstructive pulmonary disease (COPD) show signs of reduced physical activity from the early stages of the disease, impacting morbidity and mortality. Data suggest treatment with tiotropium, a long-acting muscarinic antagonist, and olodaterol, a long-acting ß2-agonist (LABA), as monotherapies and in combination, increases exercise capacity. This study assessed the effects of fixed-dose tiotropium/olodaterol (delivered via Respimat®) on physical function in Global Initiative for Chronic Obstructive Lung Disease A-D patients requiring long-acting dual bronchodilation treatment in a real-world setting.MethodsThis open-label, single arm, noninterventional study measured changes in physical function in COPD patients treated with tiotropium/olodaterol 5/5 μg for approximately 6 weeks (between Visit 1 [baseline] and Visit 2). Primary end point was therapeutic success, defined as a minimum 10-point increase in Physical Functioning Questionnaire (PF-10) score. Secondary end points included change in PF-10 from Visit 1 to Visit 2, the patient's general condition (measured by Physician's Global Evaluation score) at Visit 1 and Visit 2, and patient satisfaction with treatment delivered via the Respimat® device (assessed by Patient Satisfaction Questionnaire) at study end.ResultsTherapeutic success was observed in 51.5% of 1578 patients (95% confidence interval [CI] 49.0, 54.0) after approximately 6 weeks of treatment with tiotropium/olodaterol. Mean change in PF-10 score between Visit 1 and Visit 2 was 11.6 points (95% CI 10.7, 12.6). Patient general condition improved as indicated by a general improvement in scores between visits. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment (82.5%), inhalation (87.5%), and handling of Respimat® (85.2%). One percent of patients reported an investigator-defined drug-related adverse events (AE).ConclusionTiotropium/olodaterol treatment improved physical functioning in COPD patients. An associated increase in patient general condition was observed. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment, inhaling, and handling of the Respimat® device. No unexpected drug-related AE occurred.

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Long-term safety of tiotropium delivered by Respimat^® SoftMist™ Inhaler: patient selection and special considerations.

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Long-term safety of tiotropium delivered by Respimat<sup>®</sup> SoftMist™ Inhaler: patient selection and special considerations.

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