Spiriva Respimat

Spiriva Respimat is part of the drug class:

• Anticholinergics

Do not use Spiriva Respimat if you are allergic to tiotropium, ipratropium (Atrovent), or any of the ingredients in Spiriva Respimat.

Spiriva Respimat can cause serious side effects, including: 

Allergic reaction. Symptoms may include:

• raised red patches on your skin (hives)
• itching
• rash
• swelling of the lips, tongue, or throat that may cause difficulty in breathing or swallowing

If you have these symptoms of an allergic reaction, stop taking tiotropium and call your doctor right away or go to the nearest hospital emergency room.

Sudden narrowing and blockage of the airways into the lungs (bronchospasm). If your breathing suddenly gets worse, stop taking tiotropium and call your doctor right away or go to the nearest hospital emergency room.

New or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-angle glaucoma may include:

• eye pain
• blurred vision
• seeing halos (visual halos) or colored images along with red eyes

Using only eye drops to treat these symptoms may not work. If you have these symptoms, stop taking Spiriva Respimat and call your doctor right away.

New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: 

• difficulty passing urine
• painful urination.

If you have these symptoms of urinary retention, stop taking Spiriva Respimat and call your doctor right away.

Spiriva Respimat can cause dizziness and blurred vision. Should you experience these symptoms you should use caution when engaging in activities such as driving a car or operating appliances or other machines.

Spiriva Respimat

• Do not use the inhaler after the expiry date which is stated on the carton and on the inhaler.
• Keep the inhaler and all medicines out of the reach of children.

• Store Spiriva Respimat at Room Temperature between 59ºF to 86ºF (15ºC to 30ºC).
• Do not freeze your Spiriva Respimat cartridge and inhaler.

Ask your doctor or pharmacist if you have any questions about storing your medication.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Change in eyesight, eye pain, or very bad eye irritation.
• Eye redness.
• Seeing halos or bright colors around lights.
• Trouble passing urine.
• Pain when passing urine.
• Chest pain or pressure.
• This medicine can cause very bad breathing problems right after you take a dose. Sometimes, this may be life-threatening. If you have trouble breathing, breathing that is worse, wheezing, or coughing after using Spiriva Respimat, use a rescue inhaler and get medical help right away.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Spiriva Respimat (tiotropium inhalation spray) or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Spiriva Respimat. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

 Maintenance Treatment of Chronic Obstructive Pulmonary Disease

Spiriva Respimat (tiotropium bromide) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Spiriva Respimat is indicated to reduce exacerbations in COPD patients.

Important Limitation of Use:
Spiriva Respimat is NOT indicated for the relief of acute bronchospasm.

 Maintenance Treatment of Asthma

Spiriva Respimat is a bronchodilator indicated for the long-term, once-daily, maintenance treatment of asthma in patients 6 years of age and older.

Important Limitation of Use:
Spiriva Respimat is NOT indicated for the relief of acute bronchospasm.

The active component of Spiriva Respimat is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol.

The structural formula is:

Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O.

The drug product, Spiriva Respimat, is composed of a sterile, aqueous solution of tiotropium bromide filled into a 4.5 mL plastic container crimped into an aluminum cylinder (SPIRIVA RESPIMAT cartridge) for use with the Spiriva Respimat inhaler. Excipients include water for injection, edetate disodium, benzalkonium chloride and hydrochloric acid. The Spiriva Respimat cartridge is only intended for use with the Spiriva Respimat inhaler. The RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow moving aerosol cloud of medication from a metered volume of the drug solution.

When used with the Spiriva Respimat inhaler, each cartridge containing 4 grams of sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each dose (one dose equals two actuations) from the Spiriva Respimat inhaler delivers 2.5 mcg or 5 mcg of tiotropium in 22.1 mcL from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).

Prior to first use, the Spiriva Respimat cartridge is inserted into the Spiriva Respimat inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use [see Patient Counseling Information (17)].

 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101‑week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0.5, times the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m2 basis, respectively.

Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay.

In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately 40 times the MRHDID on a mcg/m2 basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on a mcg/m2 basis). The fertility index, however, was not affected at inhalation doses up to 1689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m2 basis).

 Chronic Obstructive Pulmonary Disease

The efficacy of Spiriva Respimat compared to placebo was evaluated in 6 clinical trials: one dose-ranging trial and 5 confirmatory trials (Trials 1-5). In addition, Spiriva Respimat was compared to SPIRIVA HandiHaler in a long-term active-controlled trial in COPD (Trial 6).

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.

Effect on Lung Function
Spiriva Respimat 5 mcg demonstrated significant improvement in trough FEV1 compared to placebo in all 5 confirmatory trials (Table 4). The change from baseline in trough FEV1 over time from Trial 4 is depicted in Figure 1 and is representative of the other two 48-week trials. In Trials 3 and 4 patients treated with Spiriva Respimat 5 mcg also used less rescue medication compared to patients on placebo.

Figure 1 Trough FEV1 Change from Baseline over 48 weeks (Trial 4), Spiriva Respimat 5 mcg

Exacerbations
Trials 3, 4, and 5 also evaluated the effect of Spiriva Respimat 5 mcg on COPD exacerbations. For Trials 3 and 4, a pooled analysis of exacerbation rate per patient year was pre-specified as a primary endpoint, while the primary endpoint for Trial 5 was time to first exacerbation. Trial 5 also included exacerbation rate per patient year as a secondary endpoint. Exacerbations were defined as a complex of respiratory events/symptoms with a duration of ≥3 days with ≥2 of the following (increase of symptoms or new onset): shortness of breath/dyspnea/shallow, rapid breathing; sputum production (volume); occurrence of purulent sputum; cough; wheezing; chest tightness.

In the pooled analysis of Trials 3 and 4, Spiriva Respimat 5 mcg significantly reduced the number of COPD exacerbations compared to placebo with 0.78 exacerbations/patient year versus 1.0 exacerbations/patient year, respectively, with a rate ratio of 0.78 (95% CI 0.67, 0.92). Time to first exacerbation was also delayed in Spiriva Respimat 5 mcg patients. For Trial 5, in addition to the definition above, an exacerbation also had to result in a change in or requirement of treatment. In Trial 5, treatment with SPIRIVA RESPIMAT 5 mcg delayed the time to first COPD exacerbation compared to treatment with placebo [hazard ratio of 0.69 (95% CI 0.63, 0.77)]. Consistent with the pooled analysis of Trials 3 and 4, for Trial 5, exacerbation rate was also lower in Spiriva Respimat 5 mcg compared to placebo. In Trial 5, Spiriva Respimat 5 mcg also reduced the risk of COPD exacerbation-related hospitalization (HR = 0.73; 95% CI = 0.59, 0.90) compared to placebo.

Long-term Active-Controlled Mortality Trial
Survival
In a pooled analysis of Spiriva Respimat placebo-controlled clinical trials with complete vital status (mortality) follow-up, including the three 48-week trials (Trial 3, 4, and 5) and one 24-week placebo-controlled trial, 68 deaths (Incidence Rate 2.64 deaths per 100 patient years) were observed in the Spiriva Respimat 5 mcg treatment group compared to 51 deaths (Incidence Rate 1.98 deaths per 100 patient years) in those treated with placebo. In a 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial of tiotropium bromide inhalation powder (SPIRIVA HandiHaler) in 5992 COPD patients a similar incidence rate of death had been observed between SPIRIVA HandiHaler and placebo treated groups.

For clarification of the observed difference in fatal events, a long-term, randomized, double-blind, double dummy, active-controlled trial with an observation period up to 3 years was conducted to evaluate the risk of all-cause mortality associated with the use of Spiriva Respimat compared to SPIRIVA HandiHaler (Trial 6). The objective of this trial was to rule out a relative excess mortality risk of 25% for Spiriva Respimat versus SPIRIVA HandiHaler. The primary endpoints were all-cause mortality and time to first COPD exacerbation. Trial 6 also included a lung function sub-study which measured trough FEV1 measured every 24 weeks for 120 weeks (461 patients receiving Spiriva Respimat 5 mcg, 445 patients receiving SPIRIVA HandiHaler).

In Trial 6, 5711 patients received SPIRIVA RESPIMAT 5 mcg and 5694 patients received SPIRIVA HandiHaler. All patients were followed for vital status (mortality) at the end of the trial. At baseline, patient characteristics were balanced between the two treatment arms. The mean age was 65 years and approximately 70% of subjects were male. Approximately, 82% of patients were Caucasian, 14% were Asian, and 2% were Black. Mean post-bronchodilator FEV1 was 1.34 L with a mean FEV1/FVC ratio of 50%. The majority of patients were GOLD II or III (48% and 40%, respectively).

The vital status was confirmed in 99.7% of patients. The median exposure to treatment was 835 days for both treatment groups. All-cause mortality was similar between Spiriva Respimat 5 mcg and SPIRIVA HandiHaler with an estimated hazard ratio of 0.96 [(95% CI of (0.84 to 1.09), Table 5].

Cause of death was adjudicated by a blinded, independent committee. Cardiovascular deaths included cardiac death, sudden cardiac death, and sudden death; as well as fatal events caused by a cardiac disorder, vascular disorder, or stroke. There were 113 patients (2%) treated with Spiriva Respimat 5 mcg who had cardiovascular deaths compared to 101 (2%) patients treated with SPIRIVA HandiHaler. Of the cardiovascular deaths, 11 (0.2%) and 3 (0.1%) deaths were due to myocardial infarction in Spiriva Respimat 5 mcg patients and SPIRIVA HandiHaler patients, respectively. For cardiac deaths, sudden cardiac death, and sudden death, there were a total of 69 (1.2%) and 68 (1.2%) deaths in Spiriva Respimat 5 mcg patients and SPIRIVA HandiHaler patients, respectively.

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)].

 Asthma

The Spiriva Respimat clinical development program included six 4-week to 8-week cross-over design trials and ten 12-week to 48-week parallel-arm design trials in adult, adolescent (aged 12 to 17 years) and pediatric (aged 1 to 11 years) patients with asthma symptomatic on at least ICS. In all trials, Spiriva Respimat was administered on a background of ICS therapy.

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, 0-3h at week 12. The co-primary efficacy endpoints in Trials 2 and 3 were change from pre-treatment baseline in peak FEV1, 0-3 hr 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.

Spiriva Respimat Inhalation Spray is supplied in a carton containing one Spiriva Respimat cartridge and one Spiriva Respimat inhaler.

The Spiriva Respimat cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The Spiriva Respimat cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler and should not be interchanged with any other RESPIMAT device delivered product.

The Spiriva Respimat inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The written information on the label of the gray inhaler body indicates that it is labeled for use with the Spiriva Respimat cartridge.

Spiriva Respimat Inhalation Spray is available in two dosage strengths, identified by dose delivered per actuation and by the color of the cap and associated container label: aqua represents 2.5 mcg per actuation; blue represents 1.25 mcg per actuation.

To deliver the recommended dosage for COPD:

• Spiriva Respimat Inhalation Spray  2.5 mcg/actuation  60 metered actuations  (NDC 0597-0100-61)

To deliver the recommended dosage for asthma:

• Spiriva Respimat Inhalation Spray  1.25 mcg/actuation  60 metered actuations  (NDC 0597-0160-61)

The Spiriva Respimat cartridge for each strength has a net fill weight of 4 grams and when used with the Spiriva Respimat inhaler, is designed to deliver the labeled number of metered actuations after preparation for use. Each actuation from the Spiriva Respimat inhaler delivers 1.25 or 2.5 mcg of tiotropium (equivalent to 1.562 or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece.

When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.

After assembly, the Spiriva Respimat inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.

Keep out of reach of children. Do not spray into eyes.

Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid freezing.