|Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergicsATC code: R03B B04|
Mechanism of actionTiotropium bromide is a long-acting, specific, muscarinic receptor antagonist, in clinical medicine often called an anticholinergic. By binding to the muscarinic receptors in the bronchial smooth musculature, tiotropium bromide inhibits the cholinergic (bronchoconstrictive) effects of acetylcholine, released from parasympathetic nerve endings. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, tiotropium bromide competitively and reversibly antagonises the M3 receptors, resulting in relaxation. The effect was dose dependent and lasted longer than 24h. The long duration is probably due to the very slow dissociation from the M3 receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur. Pharmacodynamic effectsThe bronchodilation is primarily a local effect (on the airways), not a systemic one. Dissociation from M2-receptors is faster than from M3, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M3 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
Cardiac electrophysiologyElectrophysiology: In a dedicated QT study involving 53 healthy volunteers, SPIRIVA 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG.
Clinical efficacyThe clinical development programme included four one-year and two six-month randomised, double-blind studies in 2663 patients (1308 receiving tiotropium bromide). The one-year programme consisted of two placebo-controlled trials and two trials with an active control (ipratropium). The two six-month trials were both, salmeterol and placebo controlled. These studies included lung function and health outcome measures of dyspnea, exacerbations and health-related quality of life.In the aforementioned studies, tiotropium bromide, administered once daily, provided significant improvement in lung function (forced expiratory volume in one second, FEV1 and forced vital capacity, FVC) within 30 minutes following the first dose which was maintained for 24 hours. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. Tiotropium bromide significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings. The bronchodilator effects of tiotropium bromide were maintained throughout the one-year period of administration with no evidence of tolerance.A randomised, placebo-controlled clinical study in 105 COPD patients demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether the drug was administered in the morning or in the evening.The following health outcome effect was demonstrated in the long term (6-month and one-year) trials:Tiotropium bromide significantly improved dyspnea (as evaluated using the Transition Dyspnea Index.). This improvement was maintained throughout the treatment period.The impact of improvements in dyspnea on exercise tolerance was investigated in two randomised, double-blind, placebo-controlled trials in 433 patients with moderate to severe COPD. In these trials, six weeks of treatment with SPIRIVA significantly improved symptom-limited exercise endurance time during cycle ergometry at 75% of maximal work capacity by 19.7% (Trial A: 640 seconds with SPIRIVA vs. 535 seconds with placebo, compared with a pre-treatment baseline of 492 seconds) and 28.3% (Trial B: 741 seconds with SPIRIVA vs. 577 seconds with placebo, compared with a pre-treatment baseline of 537 seconds).In a randomized, double-blind, placebo controlled trial of 1,829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the proportion of patients who experienced exacerbations of COPD (32.2% to 27.8%) and statistically significantly reduced the number of exacerbations by 19% (1.05 to 0.85 events per patient year of exposure). In addition, 7.0% of patients in the tiotropium bromide group and 9.5% of patients in the placebo group were hospitalized due to a COPD exacerbation (p=0.056). The number of hospitalizations due to COPD was reduced by 30% (0.25 to 0.18 events per patient year of exposure).In a 9-month, randomized, double-blind, placebo-controlled clinical trial of 492 patients, SPIRIVA improved health-related quality of life as determined by the St. George's Respiratory Questionnaire (SGRQ) total score. The proportion of patients treated with SPIRIVA which achieved a meaningful improvement in the SGRQ total score (i.e. > 4 units) was 10.9% higher compared with placebo (59.1% in the SPIRIVA groups vs. 48.2% in the placebo group (p=0.029). The mean difference between the groups was 4.19 units (p=0.001; confidence interval: 1.69 6.68). The improvements of the subdomains of the SGRQ-score were 8.19 units for symptoms, 3.91 units for activity and 3.61 units for impact on daily life. The improvements of all of these separate subdomains were statistically significant.In a 4-year, randomised, double-blind, placebo-controlled clinical trial of 5,993 randomised patients (3,006 receiving placebo and 2,987 receiving Spiriva), the improvement in FEV1 resulting from Spiriva, compared with placebo, remained constant throughout 4 years. A higher proportion of patients completed ≥ 45 months of treatment in the Spiriva group compared with the placebo group (63.8% vs. 55.4%, p<0.001). The annualized rate of decline of FEV1 compared to placebo was similar between Spiriva and placebo. During treatment, there was a 16% reduction in the risk of death. The incidence rate of death was 4.79 per 100 patient years in the placebo group vs. 4.10 per 100 patient years in the tiotropium group (hazard ratio (tiotropium/placebo) = 0.84, 95% CI = 0.73, 0.97). Treatment with tiotropium reduced the risk of respiratory failure (as recorded through adverse event reporting) by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 0.999).A one-year randomised, double-blind, double-dummy, parallel-group trial compared the effect of treatment with 18 microgram of SPIRIVA once daily with that of 50 microgram of salmeterol HFA pMDI twice daily on the incidence of moderate and severe exacerbations in 7,376 patients with COPD and a history of exacerbations in the preceding year.Table 1: Summary of exacerbation endpoints
Time [days] refers to 1st quartile of patients. Time to event analysis was done using Cox's proportional hazards regression model with (pooled) centre and treatment as covariate; ratio refers to hazard ratio.§ Time to event analysis was done using Cox's proportional hazards regression model with (pooled) centre and treatment as covariate; ratio refers to hazard ratio. Time [days] for the 1st quartile of patients cannot be calculated, because proportion of patients with severe exacerbation is too low.* Number of patients with event were analysed using Cochran-Mantel-Haenszel test stratified by pooled centre; ratio refers to risk ratio.Compared with salmeterol, SPIRIVA increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). SPIRIVA also increased the time to the first severe (hospitalised) exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001).
|Endpoint ||SPIRIVA 18 microgram (HandiHaler)
N = 3,707 ||Salmeterol 50 microgram (HFA pMDI)
N = 3,669||Ratio (95% CI)||p-value |
|Time [days] to first exacerbation||187
(0.77 - 0.90)
|Time to first severe (hospitalised) exacerbation§||-
(0.61 - 0.85)
|Patients with ≥1 exacerbation, n (%)*
||0.90 (0.85 - 0.95)
|Patients with ≥1 severe (hospitalised) exacerbation, n (%)*
(0.66 - 0.89)
Paediatric populationThe European Medicines Agency has waived the obligation to submit results of studies with Spiriva in all subsets of the paediatric population in COPD and cystic fibrosis (see section 4.2 for information on paediatric use).