Important Limitation of Use:

SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm.

Important Limitation of Use:

SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm.

Less Common Adverse Reactions

Among the adverse reactions observed in the clinical trials with an incidence of <1% and at a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo were: dysphagia, gingivitis, intestinal obstruction including ileus paralytic, joint swelling, dysuria, urinary retention, epistaxis, laryngitis, angioedema, dry skin, skin infection, and skin ulcer.

Adult Patients

SPIRIVA RESPIMAT 2.5 mcg has been compared to placebo in four placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in adult patients (aged 18 to 75 years) with asthma. The safety data described below are based on one 1-year, two 6-month and one 12-week randomized, double-blind, placebo-controlled trials in a total of 2849 asthma patients on background treatment of at least ICS or ICS and long-acting beta agonist (ICS/LABA). Of these patients, 787 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 59.7% were female and 47.5% were Caucasian with a mean age of 43.7 years and a mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1) of 90.0% at baseline.

Table 2 shows all adverse reactions that occurred with an incidence of >2% in the SPIRIVA RESPIMAT 2.5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo.

Other reactions that occurred in the SPIRIVA RESPIMAT 2.5 mcg group at an incidence of 1% to 2% and at a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo included: Nervous system disorders: dizziness; Gastrointestinal disorders: oropharyngeal candidiasis, diarrhea; Respiratory, thoracic, and mediastinal disorders: cough, rhinitis allergic; Renal and urinary disorders: urinary tract infection; General disorders and administration site conditions: pyrexia; and Vascular disorders: hypertension.

Less Common Adverse Reactions

Among the adverse reactions observed in the clinical trials with an incidence of 0.5% to <1% and at a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo were: palpitations, dysphonia, acute tonsillitis, tonsillitis, rhinitis, herpes zoster, gastroesophageal reflux disease, oropharyngeal discomfort, abdominal pain upper, insomnia, hypersensitivity (including immediate reactions), angioedema, dehydration, arthralgia, muscle spasms, pain in extremity, chest pain, hepatic function abnormal, liver function test abnormal.

Adolescent Patients Aged 12 to 17 years

SPIRIVA RESPIMAT 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in adolescent patients with asthma. The safety data described below are based on one 48-week and one 12-week double-blind, placebo-controlled trials in a total of 789 adolescent asthma patients on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 252 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 63.9% were male and 95.6% were Caucasian with a mean age of 14.3 years and a mean post-bronchodilator percent predicted FEV1 of 98.3% at baseline. The adverse reaction profile for adolescent patients with asthma was comparable to that observed in adult patients with asthma.

Pediatric Patients Aged 6 to 11 years

SPIRIVA RESPIMAT 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in pediatric patients aged 6 to 11 years with asthma. The safety data are based on one 48-week and one 12-week double-blind, placebo-controlled trials in a total of 801 pediatric asthma patients aged 6 to 11 years on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 271 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 71.2% were male and 86.7% were Caucasian with a mean age of 8.9 years and a mean post-bronchodilator percent predicted FEV1 of 97.9% at baseline. The adverse reaction profile for pediatric patients aged 6 to 11 years with asthma was comparable to that observed in adult patients with asthma.

SPIRIVA RESPIMAT 5 mcg also has been compared to placebo in seven placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in 4149 adult patients (aged 18 to 75 years) with asthma and in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in 789 adolescent patients (1370 adults and 264 adolescents receiving SPIRIVA RESPIMAT 5 mcg once-daily). The adverse reaction profile for SPIRIVA RESPIMAT 5 mcg in patients with asthma was comparable to that observed with SPIRIVA RESPIMAT 2.5 mcg in patients with asthma.

Risk Summary

The limited human data with SPIRIVA RESPIMAT use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. There are risks to the mother and the fetus associated with poorly controlled asthma in pregnancy [see Clinical Considerations]. Based on animal reproduction studies, no structural abnormalities were observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the period of organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID). Increased post-implantation loss was observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Data

Risk Summary

There are no data on the presence of tiotropium in human milk, the effects on the breastfed infant, or the effects on milk production. Tiotropium is present in milk of lactating rats; however, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SPIRIVA RESPIMAT and any potential adverse effects on the breastfed child from SPIRIVA RESPIMAT or from the underlying maternal condition.

Data

The distribution of tiotropium bromide into milk was investigated after a single intravenous administration of 10 mg/kg to lactating rats. Tiotropium and/or its metabolites are present in the milk of lactating rats at concentrations above those in plasma.

In Vitro Characterization Studies with Valved Holding Chamber

Dose delivery and fine particle fraction of SPIRIVA RESPIMAT when administered via a valved holding chamber (AeroChamber Plus Flow-Vu® with or without face mask) was assessed by in vitro studies.

Inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds were tested. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively.

Table 3 summarizes the results for delivered dose under the respective test conditions and configurations.

The in vitro study data show a reduction of the absolute delivered dose through the valved holding chamber. However, in terms of dose per kilogram of body weight the data suggest that under all tested conditions the dose of SPIRIVA RESPIMAT delivered by the AeroChamber Plus Flow-Vu® valved holding chamber with mask will at least lead to a dosing comparable to that of adults without use of a holding chamber and mask (Table 3). The fine particle fraction (< 5 µm) across the flow rates used in these studies was 69-89% of the delivered dose through the valved holding chamber, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for SPIRIVA RESPIMAT delivered without a holding chamber typically represents approximately 60% of the delivered dose.

Cardiac Electrophysiology

In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the SPIRIVA group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical trials with SPIRIVA did not detect an effect of the drug on QTc intervals.

The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium inhalation powder 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium inhalation powder 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec.

Absorption

Following inhalation of the solution by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected to influence the absorption of tiotropium for the same reason. Following 4-week SPIRIVA RESPIMAT once daily dosing, maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation in COPD and asthma patients.

Distribution

The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg after an intravenous dose to young healthy volunteers. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier.

Elimination

Specific Populations

Drug Interactions

An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once-daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium.

Common concomitant medications (LABA, ICS) used by patients with COPD were not found to alter the exposure to tiotropium. Similarly, common concomitant medications (LABA, ICS+LABA combinations, oral corticosteroids and leukotriene modifiers) used by patients with asthma were not found to alter the exposure to tiotropium.

Dose-Ranging Trial

Dose selection for the Phase III clinical program was supported by a 3-week randomized, double-blind, placebo and active-controlled, parallel group trial in 202 COPD patients. A total of five doses of tiotropium RESPIMAT (1.25 to 20 mcg) were evaluated compared to placebo. Results demonstrated numerical improvements in FEV1 at all doses compared to placebo. The difference in trough FEV1 from placebo for the 1.25, 2.5, 5, 10 and 20 mcg once daily doses were 0.08 L (95% CI -0.03, 0.20), 0.03 L (-0.08, 0.15), 0.13 L (0.02, 0.25), 0.11 L (-0.004, 0.224), and 0.13 L (0.01, 0.24), respectively. Based on these results, the 5 and 10 mcg doses were further evaluated in the confirmatory COPD trials.

Confirmatory Trials

A total of 6614 COPD patients (2801 receiving SPIRIVA RESPIMAT 5 mcg and 2798 receiving placebo) were studied in the five confirmatory trials of SPIRIVA RESPIMAT. Trials 1 and 2 were 12-week, randomized, double-blind, placebo- and active- (ipratropium) controlled trials that evaluated bronchodilation. Trials 3-5 were 48-week, randomized, double-blind, placebo-controlled, trials that evaluated bronchodilation and effects on COPD exacerbations. Trials 1-4 included both the tiotropium RESPIMAT 5 mcg and 10 mcg doses, whereas Trial 5 included only the 5 mcg dose. These trials enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had an FEV1 less than or equal to 60% of predicted and a ratio of FEV1/FVC of less than or equal to 0.7. All treatments were administered once-daily in the morning. Change from baseline in trough FEV1 was a primary endpoint in all trials. Trials 3-5 included COPD exacerbations as primary endpoints.

Baseline patient characteristics were similar across the five individual confirmatory trials, except for race in Trial 5 in which there were more Asian patients (30%) compared to other trials (<1%). The mean age ranged from 62 to 66 years. Most patients were male (64-78%), ex-smokers (57-65%) and Caucasian (69-99%). Mean pre-bronchodilator FEV1 was between 1.03 and 1.26 L with a mean FEV1/FVC ratio of 42-50%. Except for LABAs and other inhaled anticholinergic agents, other pulmonary medications were allowed as concomitant therapy in Trials 1-4. LABA use was permitted in Trial 5.

Long-term Active-Controlled Mortality Trial

Effect on Lung Function and Exacerbations

In the lung function sub-study the effect of SPIRIVA RESPIMAT 5 mcg on trough FEV1 over 120 weeks was similar to SPIRIVA HandiHaler with a mean difference of -0.010 L (95% CI -0.038 to 0.018 L).

Trial 6 also included time to first exacerbation as a co-primary endpoint (exacerbations defined as in Trials 3-5). SPIRIVA RESPIMAT 5 mcg failed to demonstrate superiority to SPIRIVA HandiHaler with a similar time to first COPD exacerbation between treatment groups [hazard ratio of 0.98 (95% CI 0.93 to 1.03)].

Dose Selection

Dose selection for the confirmatory trials was based on three randomized, double-blind, placebo-controlled, 4-week to 8-week, cross-over trials in 256 adult patients, 105 adolescent (age 12 to 17 years) patients, and 101 pediatric (age 6 to 11 years) patients that assessed doses ranging from 1.25 mcg to 10 mcg once daily. Results demonstrated numerical improvements in FEV1 at all doses compared to placebo; however, across the trials, the response was not dose-ordered. For adult patients, in the 4-week trial the difference in peak FEV1 within 3 h post-dosing (peak FEV1, 0-3hr) from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.138 L (95% CI 0.090, 0.186), 0.128 L (0.080, 0.176), and 0.188 L (0.140, 0.236), respectively. For adolescent patients, the difference in peak FEV1, 0-3hr from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.067 L (95% CI −0.005, 0.138), 0.057 L (−0.021, 0.135), and 0.113 L (0.036, 0.190), respectively. For pediatric patients, the difference in peak FEV1, 0-3h from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.075 L (95% CI, 0.030, 0.120), 0.104 L (0.059, 0.149), and 0.087 L (0.042, 0.132), respectively. The 10 mcg dose offered no substantial benefit over lower doses and resulted in more systemic anticholinergic side effects (e.g., dry mouth).

The two dose regimen trials in adults with asthma were randomized, double-blind, 4-week, cross-over trials comparing tiotropium RESPIMAT 2.5 mcg twice-daily with 5 mcg once-daily. 24-hour FEV1 results demonstrated comparable treatment effects for twice-daily and once-daily dosing.

12-week to 48-week Parallel-Arm Design Trials in Adults

The program for persistent asthma in adult patients included one 12-week (Trial 1), two replicate 24-week (Trials 2 and 3), and two replicate 48-week (Trials 4 and 5) randomized, double-blind, placebo-controlled trials in a total of 3476 asthma patients (673 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 1128 receiving SPIRIVA RESPIMAT 5 mcg once-daily, 541 receiving salmeterol 50 mcg twice daily, and 1134 receiving placebo) on background treatment of at least ICS. Trial 1 evaluated three treatments: SPIRIVA RESPIMAT 2.5 mcg once-daily, SPIRIVA RESPIMAT 5 mcg once-daily, and placebo. Trials 2 and 3 evaluated four treatments: SPIRIVA RESPIMAT 2.5 mcg once-daily, SPIRIVA RESPIMAT 5 mcg once-daily, salmeterol 50 mcg twice daily, and placebo. Trials 4 and 5 evaluated two treatments: SPIRIVA RESPIMAT 5 mcg once-daily and placebo. All trials enrolled patients who had a diagnosis of asthma, were 18 to 75 years of age, and were not current smokers. Patients enrolled in Trials 4 and 5 were required to have airway obstruction that was not fully reversible (post-bronchodilator FEV1/FVC, 0.70). The majority of the 3476 patients in the adult asthma trials were female (60%), Caucasian (61%) or Asian (31%), and had never smoked (81%) with a mean age of 46 years. The patient characteristics for the 12 week to 48 week trials in adult patients with asthma are summarized in Table 6.

The primary efficacy endpoint in Trial 1 was change from pre-treatment baseline in peak FEV1, 0-3hr at week 12. The co-primary efficacy endpoints in Trials 2 and 3 were change from pre-treatment baseline in peak FEV1, 0-3hr and change from pre-treatment baseline in trough FEV1 at week 24. Additional efficacy measures included asthma exacerbation, Asthma Control Questionnaire (ACQ), and Asthma Quality of Life Questionnaire (AQLQ).

For Trials 1, 2, and 3, SPIRIVA RESPIMAT 2.5 mcg showed statistically significant improvements in lung function over placebo when used in addition to background treatment of ICS (Table 7).

Trials 1, 2, and 3 also included a SPIRIVA RESPIMAT 5 mcg once daily treatment arm. In these asthma trials, the FEV1 response (change from baseline for tiotropium compared to placebo) was generally lower for the 5 mcg dose compared to the 2.5 mcg dose. The peak FEV1 0-3hr response was 16% to 20% lower for the 5 mcg dose compared to the 2.5 mcg dose in all three trials, and, the trough FEV1 response was 11% higher for the 5 mcg dose compared to the 2.5 mcg dose for one trial (Trial 1) and 18% and 24% lower for the 5 mcg dose compared to the 2.5 mcg dose for the other two trials (Trials 2 and 3).

Improvements in morning and evening peak expiratory flow (PEF) were consistent with the observed FEV1 treatment response. Examination of age, gender, smoking history, and serum IgE level subgroups did not identify differences in response among these subgroups.

The improvement of lung function compared to placebo was maintained for 24 hours (Figure 2). The bronchodilator effects of SPIRIVA RESPIMAT 2.5 mcg were apparent after first dose; however, maximum bronchodilator effect took up to 4 to 8 weeks to be achieved.

Figure 2 FEV1 Response over 24-Hours following 24-Weeks of Treatment, Trial 3

Asthma exacerbation was assessed in Trials 2 and 3 over the 24-week treatment periods. An asthma exacerbation was defined as an episode of progressive increase in ≥1 asthma symptom(s), such as shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms or a decrease of a patient's best morning PEF of 30% from a patient's mean morning PEF for ≥2 consecutive days that required the initiation or increase in treatment with systemic steroids for ≥3 days. Results of asthma exacerbation are shown in Table 8.

Trials 2 and 3 also evaluated the rate of exacerbations and time to first asthma exacerbation for the SPIRIVA RESPIMAT 5 mcg dose. The rate of asthma exacerbations compared to placebo for SPIRIVA RESPIMAT 5 mcg was 0.78 (95% CI 0.55, 1.10) in Trial 2 and 0.76 (0.50, 1.16) in Trial 3. The hazard ratio for time to first asthma exacerbation for SPIRIVA RESPIMAT 5 mcg compared to placebo was 0.72 (95% CI 0.39, 1.35), in Trial 2 and 0.72 (0.36, 1.43) in Trial 3.

ACQ and AQLQ were assessed in Trials 2 and 3 at week 24. In Trial 2, the ACQ-7 (7 items) responder rate (defined as a change in score ≥0.5) for the SPIRIVA RESPIMAT 2.5 mcg treatment arm was 63% compared to 53% for placebo with an odds ratio of 1.47 (95% CI 1.02, 2.11). The ACQ-5 (derived from ACQ 7 by removing the FEV1 component and rescue bronchodilator component) results also had a similar trend. In Trial 2, the AQLQ responder rate (defined as a change in score ≥0.5) for the SPIRIVA RESPIMAT 2.5 mcg treatment arm was 58% compared to 50% for placebo with an odds ratio of 1.34 (95% CI 0.94, 1.93).

12-week and 48-week Parallel-Arm Design Trials in Adolescents 12-17 Years of Age

Efficacy in adolescents was based on partial extrapolation of efficacy in adults and two randomized, double-blind, placebo-controlled trials of 12 and 48 weeks duration in a total of 789 asthma patients 12 to 17 years of age (252 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 264 receiving 5 mcg once-daily, and 273 receiving placebo). The 12-week trial enrolled patients with severe asthma who were on background treatment of ICS plus one or more controller medications (e.g. LABA). The 48-week trial enrolled patients with moderate asthma on background treatment of at least ICS. The majority of the patients in the trials were male (63.4%), Caucasian (93.7%) and had never smoked (99.9%) with a mean age of 14.3 years.

The primary efficacy endpoint in both trials was change from pre-treatment baseline in peak FEV1, 0-3hr. The primary endpoint evaluation for FEV1 was defined at week 24 for the 48-week trial and at end of the treatment period (week 12) for the 12-week trial. Given the demonstration of efficacy in the adult population, the results of the 2 trials support the efficacy of SPIRIVA RESPIMAT 2.5 mcg once daily in adolescent patients 12-17 years of age with asthma (mean difference in peak FEV1, 0-3hr from placebo for SPIRIVA RESPIMAT 2.5 mcg were 0.13 L (95% CI 0.03, 0.23) and 0.11 L (0.002, 0.22) for the 48-week and 12-week trials, respectively).

12-week and 48-week Parallel-Arm Design Trials in Pediatric Patients 6-11 Years of Age

Efficacy in pediatric patients 6-11 years of age was based on partial extrapolation of efficacy in adults and two randomized, double-blind, placebo-controlled trials of 12 and 48 weeks duration in a total of 801 asthma patients 6 to 11 years of age (271 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 265 receiving 5 mcg once-daily, and 265 receiving placebo). The 12-week trial enrolled patients with severe asthma who were on background treatment of ICS plus one or more controller medications (e.g. LABA). The 48-week trial enrolled patients with moderate asthma on background treatment of at least ICS. The primary efficacy endpoint in both trials was change from pre-treatment baseline in peak FEV1, 0-3hr with the evaluation defined at week 24 for the 48-week trial and at end of the treatment period (week 12) for the 12-week trial. The majority of the patients in the trials were male (67.8%) and Caucasian (87.0%) with a mean age of 9.0 years.

Compared to placebo, SPIRIVA RESPIMAT 2.5 mcg once daily had a significant effect on the primary endpoint in the 48 week, but not the 12 week trial, with mean differences in peak FEV1, 0-3hr from placebo of 0.17 L (95% CI 0.11, 0.23) and 0.04 L (95% CI -0.03, 0.10) for the 48-week and 12-week trials, respectively. Given the demonstration of efficacy in the adult and adolescent population, the results support the efficacy of SPIRIVA RESPIMAT 2.5 mcg once daily in pediatric patients 6-11 years of age with asthma.