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.

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 recommended dosage for patients with COPD is 2 inhalations of SPIRIVA RESPIMAT 2.5 mcg per actuation once-daily; total dose equals 5 mcg of SPIRIVA RESPIMAT.

The recommended dosage for patients with asthma is 2 inhalations of SPIRIVA RESPIMAT 1.25 mcg per actuation once-daily; total dose equals 2.5 mcg of SPIRIVA RESPIMAT. In the treatment of asthma, the maximum benefits in lung function may take up to 4 to 8 weeks of dosing [see Patient Counseling Information (17)].

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given SPIRIVA RESPIMAT should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].

SPIRIVA RESPIMAT consists of a SPIRIVA RESPIMAT inhaler and an aluminum cylinder (SPIRIVA RESPIMAT cartridge) containing tiotropium bromide (as the monohydrate). The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler.

{ "type": "p", "children": [], "text": "SPIRIVA RESPIMAT consists of a SPIRIVA RESPIMAT inhaler and an aluminum cylinder (SPIRIVA RESPIMAT cartridge) containing tiotropium bromide (as the monohydrate). The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler." }

SPIRIVA RESPIMAT is available in two dosage strengths. Each actuation from the SPIRIVA RESPIMAT inhaler delivers 1.25 mcg or 2.5 mcg of tiotropium (equivalent to 1.562 mcg or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece. Two actuations equal one dose (2.5 mcg or 5 mcg).

{ "type": "p", "children": [], "text": "SPIRIVA RESPIMAT is available in two dosage strengths. Each actuation from the SPIRIVA RESPIMAT inhaler delivers 1.25 mcg or 2.5 mcg of tiotropium (equivalent to 1.562 mcg or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece. Two actuations equal one dose (2.5 mcg or 5 mcg)." }

SPIRIVA RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product [see Warnings and Precautions (5.2)]. In clinical trials with SPIRIVA RESPIMAT, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "SPIRIVA RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product [see Warnings and Precautions (5.2)]. In clinical trials with SPIRIVA RESPIMAT, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)]." }

SPIRIVA RESPIMAT is intended as a once-daily maintenance treatment for COPD and asthma and should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. In the event of an acute attack, a rapid-acting beta2-agonist should be used.

Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of SPIRIVA RESPIMAT. If such a reaction occurs, therapy with SPIRIVA RESPIMAT should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to SPIRIVA RESPIMAT.

Inhaled medicines, including SPIRIVA RESPIMAT, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with SPIRIVA RESPIMAT should be stopped and other treatments considered.

SPIRIVA RESPIMAT should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

SPIRIVA RESPIMAT should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA RESPIMAT should be monitored closely for anticholinergic side effects [see Clinical Pharmacology (12.3)].

The SPIRIVA RESPIMAT clinical development program included ten placebo controlled clinical trials in COPD. Two trials were four-week cross-over trials and eight were parallel group trials. The parallel group trials included a three-week dose-ranging trial, two 12-week trials, three 48-week trials, and two trials of 4-week and 24-week duration conducted for a different program that contained tiotropium bromide 5 mcg treatment arms. The primary safety database consists of pooled data from the 7 randomized, parallel-group, double-blind, placebo-controlled studies of 4-48 weeks in treatment duration. These trials included 6,565 adult COPD patients (75% males and 25% females) 40 years of age and older. Of these patients, 3,282 patients were treated with SPIRIVA RESPIMAT 5 mcg and 3,283 received placebo. The SPIRIVA RESPIMAT 5 mcg group was composed mostly of Caucasians (78%) with a mean age of 65 years and a mean baseline percent predicted post-bronchodilator FEV1 of 46%.

In these 7 clinical trials, 68.3% of patients exposed to SPIRIVA RESPIMAT 5 mcg reported an adverse event compared to 68.7% of patients in the placebo group. There were 68 deaths in the SPIRIVA RESPIMAT 5 mcg treatment group (2.1%) and 52 deaths (1.6%) in patients who received placebo [see Clinical Studies (14) Long-term Active-Controlled Mortality Trial: Survival]. The percentage of SPIRIVA RESPIMAT patients who discontinued due to an adverse event were 7.3% compared to 10% with placebo patients. The percentage of SPIRIVA RESPIMAT 5 mcg patients who experienced a serious adverse event were 15.0% compared to 15.1% with placebo patients. In both groups, the adverse event most commonly leading to discontinuation was COPD exacerbation (SPIRIVA RESPIMAT 2.0%, placebo 4.0%) which was also the most frequent serious adverse event. The most commonly reported adverse reactions were pharyngitis, cough, dry mouth, and sinusitis (Table 1). Other adverse reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, dysuria, and urinary retention.

Table 1 shows all adverse reactions that occurred with an incidence of >3% in the SPIRIVA RESPIMAT 5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1 Number (Percentage) of COPD Patients Exposed to SPIRIVA RESPIMAT 5 mcg with Adverse Reactions &gt;3% (and Higher than Placebo): Pooled Data from 7 Clinical Trials with Treatment Periods Ranging between 4 and 48 Weeks in COPD Patients</span> </caption> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Body System (Reaction)*</th><th align="left" class="Rrule">SPIRIVA RESPIMAT 5 mcg<br/>[n=3,282]</th><th align="left" class="Rrule">Placebo<br/>[n=3,283]</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">*Adverse reactions include a grouping of similar terms</td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule"><span class="Bold">Gastrointestinal Disorders</span></td><td align="left" class="Rrule"></td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dry mouth</td><td align="left" class="Botrule Lrule Rrule">134 (4.1)</td><td align="left" class="Botrule Lrule Rrule">52 (1.6)</td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">Infections and Infestations</span></td><td align="left" class="Rrule"></td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pharyngitis</td><td align="left" class="Rrule">378 (11.5)</td><td align="left" class="Rrule">333 (10.1)</td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span></td><td align="left" class="Rrule"></td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Cough</td><td align="left" class="Rrule">190 (5.8)</td><td align="left" class="Rrule">182 (5.5)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Sinusitis</td><td align="left" class="Rrule">103 (3.1)</td><td align="left" class="Rrule">88 (2.7)</td> </tr> </tbody> </table></div>

Other reactions that occurred in the SPIRIVA RESPIMAT 5 mcg group at an incidence of 1% to 3% and at a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo included: Cardiac disorders: palpitations; Gastrointestinal disorders: constipation, gastroesophageal reflux disease, oropharyngeal candidiasis; Nervous system disorders: dizziness; Respiratory, thoracic, and mediastinal disorders: dysphonia; Skin and subcutaneous tissue disorders: pruritus, rash; Renal and urinary disorders: urinary tract infection.

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 2,849 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 dosage 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2 Number (Percentage) of Asthma Patients Exposed to SPIRIVA RESPIMAT 2.5 mcg with Adverse Reactions &gt;2% (and Higher than Placebo): Pooled Data from 4 Adult Clinical Trials with Treatment Periods Ranging between 12 and 52 Weeks in Asthma Patients</span> </caption> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Body System (Reaction)*</th><th align="left" class="Rrule">SPIRIVA RESPIMAT 2.5 mcg<br/>[n=787]</th><th align="left" class="Rrule">Placebo<br/>[n=735]</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">*Adverse reactions include a grouping of similar terms</td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule"><span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span></td><td align="left" class="Rrule"></td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Pharyngitis</td><td align="left" class="Rrule">125 (15.9)</td><td align="left" class="Rrule">91 (12.4)</td> </tr> <tr> <td align="left" class="Lrule Rrule">  Sinusitis</td><td align="left" class="Rrule">21 (2.7)</td><td align="left" class="Rrule">10 (1.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Bronchitis</td><td align="left" class="Rrule">26 (3.3)</td><td align="left" class="Rrule">10 (1.4)</td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">Nervous System Disorders</span></td><td align="left" class="Rrule"></td><td align="left" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Headache</td><td align="left" class="Rrule">30 (3.8)</td><td align="left" class="Rrule">20 (2.7)</td> </tr> </tbody> </table></div>

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 dosage 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 4,149 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 (1,370 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.

In addition to the adverse reactions observed during the SPIRIVA RESPIMAT clinical trials in COPD, the following adverse reactions have been observed during post-approval use of SPIRIVA RESPIMAT 5 mcg and another tiotropium formulation, SPIRIVA® HandiHaler® (tiotropium bromide inhalation powder). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

SPIRIVA RESPIMAT has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, and anti-IgE treatment without increases in adverse reactions.

There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SPIRIVA RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].

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

Disease-Associated Maternal and/or Embryo-Fetal Risk

Poorly or moderately controlled asthma in pregnancy increases the maternal risk of preeclampsia and infant prematurity, low birth weight, and small for gestational age. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

Data

Animal Data

In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and 8 times the maximum recommended human daily inhalation dose (MRHDID), respectively (on a mcg/m2 basis at inhalation doses of 1,471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m2 basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

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.

The safety and efficacy of SPIRIVA RESPIMAT 2.5 mcg have been established in pediatric patients aged 6 to 17 years with asthma in 6 clinical trials up to 1 year in duration. In three clinical trials, 327 patients aged 12 to 17 years with asthma were treated with SPIRIVA RESPIMAT 2.5 mcg; in three additional clinical trials, 345 patients aged 6 to 11 years with asthma were treated with SPIRIVA RESPIMAT 2.5 mcg. Patients in these age groups demonstrated efficacy results similar to those observed in patients aged 18 years and older with asthma [see Clinical Studies (14.2)].

The safety and efficacy of SPIRIVA RESPIMAT have not been established in pediatric patients less than 6 years of age. The safety of SPIRIVA RESPIMAT 2.5 mcg has been studied in pediatric patients with asthma aged 1 to 5 years who were on background treatment of at least ICS in one placebo-controlled clinical trial of 12 weeks duration (36 treated with SPIRIVA RESPIMAT 2.5 mcg and 34 with placebo RESPIMAT). In this study, SPIRIVA RESPIMAT or placebo RESPIMAT was delivered with the AeroChamber Plus Flow-Vu® valved holding chamber with facemask once daily. The majority of the patients in the trial were male (60.4%) and Caucasian (76.2%) with a mean age of 3.1 years. The adverse reaction profile was similar to that observed in adults and older pediatric patients [see Adverse Reactions (6.2)].

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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3 In Vitro Medication Delivery through AeroChamber Plus Flow-Vu<span class="Sup">®</span> Valved Holding Chamber with Face Mask at Different Flow Rates and Holding Times Using the Dose 2.5 mcg (as two actuations)</span> </caption> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Flow Rate<br/>(L/min) and corresponding age</th><th align="center" class="Rrule">Mask</th><th align="center" class="Rrule">Holding Time<br/>(seconds)</th><th align="center" class="Rrule">Mean Medication Delivery through AeroChamber Plus Flow-Vu<span class="Sup">®</span> per Dose <br/>(mcg)</th><th align="center" class="Rrule">Body Weight 50<span class="Sup">th</span> Percentile<br/> (kg)<span class="Sup">a</span></th><th align="center" class="Rrule">Medication Delivered per Dose<br/>(ng/kg)<span class="Sup">b</span></th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="6" valign="top"><span class="Sup">a</span> Centers for Disease Control and Prevention growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2009).<br/>Body weight values correspond to the average of the 50 percentile weight for boys and girls at the ages indicated.</td> </tr> <tr class="Last"> <td align="left" colspan="6" valign="top"><span class="Sup">b</span> Inhalation of SPIRIVA RESPIMAT 2.5 mcg dose (as two actuations) in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 2.5 mcg, or 36 ng/kg.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">4.9<br/> (6 to 12 Months)</td><td align="center" class="Lrule Rrule" valign="middle">small</td><td align="center" class="Rrule">0<br/>2<br/>5<br/>10</td><td align="center" class="Rrule">0.85<br/>0.86<br/>0.55<br/>0.62</td><td align="center" class="Rrule" valign="middle">7.5-9.9</td><td align="center" class="Rrule">86-113<br/>87-115<br/>56-73<br/>63-83</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">8.0<br/> (2 to 5 Years)</td><td align="center" class="Rrule" valign="middle">medium</td><td align="center" class="Rrule">0<br/>2<br/>5<br/>10</td><td align="center" class="Rrule">0.74<br/>0.93<br/>0.72<br/>0.57</td><td align="center" class="Rrule" valign="middle">12.3-18.0</td><td align="center" class="Rrule">41-60<br/>52-76<br/>40-59<br/>32-46</td> </tr> <tr class="Botrule Last"> <td align="center" class="Lrule Rrule">12.0<br/> (&gt; 5 Years)</td><td align="center" class="Lrule Rrule" valign="middle">medium</td><td align="center" class="Lrule Rrule">0<br/>2<br/>5<br/>10</td><td align="center" class="Lrule Rrule">1.16<br/>0.96<br/>0.78<br/>0.61</td><td align="center" class="Lrule Rrule" valign="middle">18.0</td><td align="center" class="Lrule Rrule">64<br/>53<br/>43<br/>34</td> </tr> </tbody> </table></div>

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.

Based on available data, no adjustment of SPIRIVA RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

Thirty nine percent of SPIRIVA RESPIMAT clinical trial patients with COPD were between 65 and 75 years of age and 14% were greater than or equal to 75 years of age. Approximately seven percent of SPIRIVA RESPIMAT clinical trial patients with asthma were greater than or equal to 65 years of age. The adverse drug reaction profiles were similar in the older population compared to the patient population overall.

Patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA RESPIMAT should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium dry powder in 6 healthy volunteers. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.

{ "type": "p", "children": [], "text": "High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium dry powder in 6 healthy volunteers. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects." }

Treatment of overdosage consists of discontinuation of SPIRIVA RESPIMAT together with institution of appropriate symptomatic and/or supportive therapy.

{ "type": "p", "children": [], "text": "Treatment of overdosage consists of discontinuation of SPIRIVA RESPIMAT together with institution of appropriate symptomatic and/or supportive therapy." }

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, 2β, 4β, 5α, 7β)-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.

{ "type": "p", "children": [], "text": "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, 2β, 4β, 5α, 7β)-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:

{ "type": "p", "children": [], "text": "The structural formula is:" }

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

{ "type": "p", "children": [], "text": "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 benzalkonium chloride, edetate disodium, hydrochloric acid, and water for injection. 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.

{ "type": "p", "children": [], "text": "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 benzalkonium chloride, edetate disodium, hydrochloric acid, and water for injection. 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 (equivalent to 3.124 mcg or 6.247 mcg, respectively, of tiotropium bromide monohydrate) 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).

{ "type": "p", "children": [], "text": "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 (equivalent to 3.124 mcg or 6.247 mcg, respectively, of tiotropium bromide monohydrate) 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)].

{ "type": "p", "children": [], "text": "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)].\n" }

Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

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.

Tiotropium is administered as an inhalation spray. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) from the HandiHaler resulted in a similar systemic exposure between the two products.

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

Metabolism

The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.

In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Excretion

The terminal half-life of tiotropium in COPD and asthma patients following once daily inhalation is 25 and 44 hours, respectively. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). Following 21-day once daily inhalation of 5 mcg of the solution by patients with COPD, 24-hour urinary excretion is 18.6% (0.93 mcg) of the dose. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. In comparison, 12.8% (0.32 mcg) of the dose was excreted unchanged in the urine over 24 hours at steady state after inhalation of 2.5 mcg in patients with asthma. After chronic once-daily inhalation by COPD and asthma patients, pharmacokinetic steady-state was reached by day 7 with no accumulation thereafter.

Specific Populations

Geriatric Patients

As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (347 mL/min in COPD patients <65 years to 275 mL/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values following inhalation of the solution. Exposure to tiotropium was not found to differ with age in patients with asthma.

Pediatric Patients

The peak and total exposure to tiotropium was not found to differ between pediatric patients (aged 6 to 17 years) and adults with asthma.

Renal Impairment

Following 4-week SPIRIVA RESPIMAT 5 mcg once daily dosing in patients with COPD, mild renal impairment (creatinine clearance 60 - <90 mL/min) resulted in 23% higher AUC0-6,ss and 17% higher Cmax,ss values; moderate renal impairment (creatinine clearance 30 - <60 mL/min) resulted in 57% higher AUC0-6,ss and 31% higher Cmax,ss values compared to COPD patients with normal renal function (creatinine clearance ≥90 mL/min). The influence of mild or moderate renal impairment on the systemic exposure to SPIRIVA RESPIMAT 2.5 mcg in patients with asthma was similar to what has been described for COPD above. There lacks sufficient data of tiotropium exposure in patients with severe renal impairment (creatinine clearance <30 mL/min) following inhalation of SPIRIVA RESPIMAT. However AUC0-4 and Cmax were 94% and 52% higher, respectively, in patients with severe renal impairment following intravenous infusion of tiotropium bromide.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

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.

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 1,689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m2 basis).

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 6,614 COPD patients (2,801 receiving SPIRIVA RESPIMAT 5 mcg and 2,798 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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4 Mean Change from Baseline in Trough FEV<span class="Sub">1</span> (L) at End of Treatment</span> </caption> <col align="left" valign="top" width="35%"/> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="35%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Trial</th><th align="left" class="Rrule">SPIRIVA RESPIMAT 5 mcg<br/>N</th><th align="left" class="Rrule">Placebo<br/>N</th><th align="left" class="Rrule">Trough FEV<span class="Sub">1</span> (L) at End of Treatment Difference from placebo (95% CI)</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="4" valign="top">† at week 12</td> </tr> <tr class="Last"> <td align="left" colspan="4" valign="top">‡ at week 48</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 1†</span></td><td align="left" class="Rrule">85</td><td align="left" class="Rrule">87</td><td align="left" class="Rrule">0.11 (0.04, 0.18)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 2†</span></td><td align="left" class="Rrule">90</td><td align="left" class="Rrule">84</td><td align="left" class="Rrule">0.13 (0.07, 0.18)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 3‡</span></td><td align="left" class="Rrule">326</td><td align="left" class="Rrule">296</td><td align="left" class="Rrule">0.14 (0.10, 0.18)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 4‡</span></td><td align="left" class="Rrule">324</td><td align="left" class="Rrule">307</td><td align="left" class="Rrule">0.11 (0.08, 0.15)</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 5‡</span></td><td align="left" class="Rrule">1,889</td><td align="left" class="Rrule">1,870</td><td align="left" class="Rrule">0.10 (0.09, 0.12)</td> </tr> </tbody> </table></div>

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 5,992 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, 5,711 patients received SPIRIVA RESPIMAT 5 mcg and 5,694 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].

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 5 All-cause Mortality of SPIRIVA RESPIMAT vs SPIRIVA HandiHaler (Trial 6)</span> </caption> <col align="left" valign="top" width="40%"/> <col align="left" valign="top" width="35%"/> <col align="left" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="left" class="Rrule">SPIRIVA RESPIMAT 5 mcg<br/> (N = 5,711)</th><th align="left" class="Rrule">SPIRIVA HandiHaler<br/> (N = 5,694)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Hazard ratios were estimated from a Cox proportional hazard model. </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Number (%) of Deaths</span></td><td align="left" class="Rrule">423 (7.4)</td><td align="left" class="Rrule">439 (7.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Incidence Rate per 100 patient years</span></td><td align="left" class="Rrule">3.22</td><td align="left" class="Rrule">3.36</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule"><span class="Bold">HR (95% CI)<span class="Sup">a</span></span></td><td align="center" class="Rrule" colspan="2">0.96 (0.84, 1.09)</td> </tr> </tbody> </table></div>

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)].

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 3,476 asthma patients (673 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 1,128 receiving SPIRIVA RESPIMAT 5 mcg once-daily, 541 receiving salmeterol 50 mcg twice daily, and 1,134 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 3,476 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6 Summary of Baseline Patient Characteristics, Adult Confirmatory Studies</span> </caption> <col align="left" valign="top" width="25%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Botrule Rrule" colspan="5">Adults, 18 yrs and older</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Trial 1</th><th align="center" class="Rrule">Trial 2</th><th align="center" class="Rrule">Trial 3</th><th align="center" class="Rrule">Trial 4</th><th align="center" class="Rrule">Trial 5</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">Demographics</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Mean age in years (range)</td><td align="center" class="Rrule">42.9 (18 – 74)</td><td align="center" class="Rrule">43.3 (18 – 75)</td><td align="center" class="Rrule">42.9 (18 – 75)</td><td align="center" class="Rrule">53.4 (18-75)</td><td align="center" class="Rrule">52.5 (19-75)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Mean duration of asthma (years)</td><td align="center" class="Rrule">16.2</td><td align="center" class="Rrule">21.7</td><td align="center" class="Rrule">21.8</td><td align="center" class="Rrule">31.5</td><td align="center" class="Rrule">29.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Smoking status, ex-smoker (%)</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">26</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">Laboratory (median)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Absolute eosinophils (10<span class="Sup">9</span>/L)</td><td align="center" class="Rrule">0.33</td><td align="center" class="Rrule">0.36</td><td align="center" class="Rrule">0.35</td><td align="center" class="Rrule">0.35</td><td align="center" class="Rrule">0.38</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Total IgE (microgram/L)</td><td align="center" class="Rrule">536</td><td align="center" class="Rrule">638</td><td align="center" class="Rrule">641</td><td align="center" class="Rrule">601</td><td align="center" class="Rrule">449</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">Pulmonary function test (mean)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pre-bronchodilator FEV<span class="Sub">1</span> (L) </td><td align="center" class="Rrule">2.30</td><td align="center" class="Rrule">2.18</td><td align="center" class="Rrule">2.21</td><td align="center" class="Rrule">1.55</td><td align="center" class="Rrule">1.59</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Reversibility (%)</td><td align="center" class="Rrule">24.8</td><td align="center" class="Rrule">22.8</td><td align="center" class="Rrule">22.0</td><td align="center" class="Rrule">15.4</td><td align="center" class="Rrule">15.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Absolute reversibility (mL)</td><td align="center" class="Rrule">556</td><td align="center" class="Rrule">488</td><td align="center" class="Rrule">477</td><td align="center" class="Rrule">215</td><td align="center" class="Rrule">218</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Post-bronchodilator FEV<span class="Sub">1</span>/FVC (%)</td><td align="center" class="Rrule">74</td><td align="center" class="Rrule">72</td><td align="center" class="Rrule">72</td><td align="center" class="Rrule">60</td><td align="center" class="Rrule">59</td> </tr> </tbody> </table></div>

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).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7 Differences from Placebo in Peak FEV<span class="Sub">1, 0-3 hr</span> and Trough FEV<span class="Sub">1</span>, Adult Confirmatory Studies at Primary Endpoint Time Evaluation</span> </caption> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="20%"/> <col align="center" valign="top" width="5%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <thead> <tr class="First"> <th align="center" class="Lrule Rrule" rowspan="3"> Treatment<br/>(Duration)<br/> <span class="Italics">ICS Background Treatment </span><span class="Sup">b,c</span></th><th align="center" class="Rrule" rowspan="3" valign="middle"> Treatment in mcg/day </th><th align="center" class="Rrule" rowspan="3" valign="middle"> n </th><th align="center" class="Botrule Rrule" colspan="3"> Peak FEV<span class="Sub">1, 0-3hr,</span> in L <span class="Sup">a</span></th><th align="center" class="Botrule Rrule" colspan="3"> Trough FEV<span class="Sub">1</span>, in L <span class="Sup">a</span></th> </tr> <tr class="Botrule"> <th align="center" class="Lrule Rrule" rowspan="2" valign="middle"> Δ from baseline </th><th align="center" class="Rrule" colspan="2"> Difference from placebo </th><th align="center" class="Rrule" rowspan="2" valign="middle"> Δ from baseline </th><th align="center" class="Rrule" colspan="2"> Difference from placebo </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule" valign="middle"> Mean </th><th align="center" class="Rrule" valign="middle"> 95% CI </th><th align="center" class="Rrule"> Mean </th><th align="center" class="Rrule"> 95% CI </th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="9" valign="top"><span class="Sup">a</span> Means adjusted for treatment, center/country, visit, visit*treatment, baseline, baseline*visit. </td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Sup">b</span> Additional asthma medications allowed in stable doses prior to and throughout the trials.</td> </tr> <tr class="Last"> <td align="left" colspan="9" valign="top"><span class="Sup">c</span> Low dose ICS = 200–400 mcg budesonide-equivalent. Medium dose ICS = 400–800 mcg budesonide-equivalent.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="9"><span class="Bold">Adult patients, age 18 years and older</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 1<br/>(12 weeks)</span> <br/> <span class="Italics">Low dose ICS</span></td><td align="left" class="Rrule">SPIRIVA RESPIMAT 2.5 mcg<br/>Placebo</td><td align="center" class="Rrule" valign="top">154<br/>155</td><td align="center" class="Rrule" valign="top">0.29<br/>0.13</td><td align="center" class="Rrule" valign="top">0.16</td><td align="center" class="Rrule" valign="top">0.09, 0.23</td><td align="center" class="Rrule" valign="top">0.13<br/>0.02</td><td align="center" class="Rrule" valign="top">0.11</td><td align="center" class="Rrule" valign="top">0.04, 0.18</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 2<br/>(24 weeks)</span> <br/> <span class="Italics">Medium dose ICS</span></td><td align="left" class="Rrule">SPIRIVA RESPIMAT 2.5 mcg<br/>Salmeterol 100 mcg<br/>Placebo</td><td align="center" class="Rrule">259<br/>271<br/>265</td><td align="center" class="Rrule">0.29<br/>0.27<br/>0.05</td><td align="center" class="Rrule">0.24<br/>0.21</td><td align="center" class="Rrule">0.18, 0.29<br/>0.16, 0.27</td><td align="center" class="Rrule">0.15<br/>0.09<br/>−0.03</td><td align="center" class="Rrule">0.19<br/>0.12</td><td align="center" class="Rrule">0.13, 0.24<br/>0.06, 0.18</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Trial 3<br/>(24 weeks)</span> <br/> <span class="Italics">Medium dose ICS</span></td><td align="left" class="Rrule">SPIRIVA RESPIMAT 2.5 mcg<br/>Salmeterol 100 mcg<br/>Placebo</td><td align="center" class="Rrule">256<br/>264<br/>253</td><td align="center" class="Rrule">0.29<br/>0.25<br/>0.08</td><td align="center" class="Rrule">0.21<br/>0.18</td><td align="center" class="Rrule">0.16, 0.26<br/>0.12, 0.23</td><td align="center" class="Rrule">0.16<br/>0.09<br/>−0.01</td><td align="center" class="Rrule">0.18<br/>0.11</td><td align="center" class="Rrule">0.12, 0.23<br/>0.05, 0.16</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 8 Exacerbations in Patients on ICS over 24-Weeks</span> </caption> <col align="left" valign="top" width="26%"/> <col align="left" valign="top" width="22%"/> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="22%"/> <col align="left" valign="top" width="15%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Trial 2</th><th align="center" class="Rrule" colspan="2">Trial 3</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="left" class="Rrule">SPIRIVA RESPIMAT 2.5 mcg<br/> (N=259)</th><th align="left" class="Rrule">Placebo<br/>(N=265)</th><th align="left" class="Rrule">SPIRIVA RESPIMAT 2.5 mcg<br/>(N=256)</th><th align="left" class="Rrule">Placebo<br/>(N=253)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Number of patients with at least 1 event, n (%)</td><td align="left" class="Rrule">9 (3.5)</td><td align="left" class="Rrule">24 (9.1)</td><td align="left" class="Rrule">13 (5.1)</td><td align="left" class="Rrule">19 (7.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Rate of exacerbations per patient year</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Mean rate of events</td><td align="left" class="Rrule">0.08</td><td align="left" class="Rrule">0.24</td><td align="left" class="Rrule">0.13</td><td align="left" class="Rrule">0.18</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Comparison to Placebo, Rate ratio (95% CI)</td><td align="left" class="Rrule">0.32 (0.20, 0.51)</td><td align="left" class="Rrule"></td><td align="left" class="Rrule">0.70 (0.46, 1.08)</td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Time to first asthma exacerbation</span></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Comparison to Placebo, Hazard ratio (95% CI)</td><td align="left" class="Rrule">0.37 (0.17, 0.80)</td><td align="left" class="Rrule"></td><td align="left" class="Rrule">0.66 (0.33, 1.34)</td><td align="left" class="Rrule"></td> </tr> </tbody> </table></div>

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.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid freezing.

Not for Acute Use

Instruct patients that SPIRIVA RESPIMAT is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems, (i.e., as a rescue medication).

Immediate Hypersensitivity Reactions

Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration of SPIRIVA RESPIMAT. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.

Paradoxical Bronchospasm

Inform patients that SPIRIVA RESPIMAT can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue SPIRIVA RESPIMAT.

Worsening of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs and symptoms develop.

Inform patients that care must be taken not to allow the aerosol cloud to enter into the eyes as this may cause blurring of vision and pupil dilation.

Since dizziness and blurred vision may occur with the use of SPIRIVA RESPIMAT, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

Worsening of Urinary Retention

Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Treatment of Asthma

Instruct asthma patients that the maximum benefits may only be apparent after 4 to 8 weeks of SPIRIVA RESPIMAT treatment.

Instructions for Administering SPIRIVA RESPIMAT

It is important for patients to understand how to correctly administer SPIRIVA inhalation spray using the SPIRIVA RESPIMAT inhaler. Instruct patients that SPIRIVA inhalation spray should only be administered via the SPIRIVA RESPIMAT inhaler and the SPIRIVA RESPIMAT inhaler should not be used for administering other medications.

Instruct patients that priming SPIRIVA RESPIMAT is essential to ensure appropriate content of the medication in each actuation.

When using the unit for the first time, the SPIRIVA RESPIMAT cartridge is inserted into the SPIRIVA RESPIMAT inhaler and the unit is primed. SPIRIVA RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to 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.

Instruct caregivers of children that SPIRIVA RESPIMAT should be used with an adult's assistance.

Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA

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Licensed from: Boehringer Ingelheim International GmbH

{ "type": "p", "children": [], "text": "Licensed from: Boehringer Ingelheim International GmbH" }

Address medical inquiries to: 1-800-542-6257.

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SPIRIVA®, HANDIHALER®, and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH

{ "type": "p", "children": [], "text": "SPIRIVA®, HANDIHALER®, and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH" }

Copyright © 2025 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED

{ "type": "p", "children": [], "text": "Copyright © 2025 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED" }

COL10534BA022025SPL10536D

{ "type": "p", "children": [], "text": "COL10534BA022025SPL10536D" }

SPIRIVA® RESPIMAT® (speh REE vah - RES peh mat)(tiotropium bromide inhalation spray), for oral inhalation use

{ "type": "p", "children": [], "text": "\nSPIRIVA® RESPIMAT® (speh REE vah - RES peh mat)(tiotropium bromide inhalation spray), for oral inhalation use" }

For oral inhalation onlyDo not spray SPIRIVA RESPIMAT into your eyes.

{ "type": "p", "children": [], "text": "\nFor oral inhalation onlyDo not spray SPIRIVA RESPIMAT into your eyes.\n" }

Read this Instructions for Use before you start using SPIRIVA RESPIMAT and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start using SPIRIVA RESPIMAT and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment." }

You will need to use this inhaler 1 time each day, at the same time each day. Each time you use it take 2 puffs.

{ "type": "p", "children": [], "text": "You will need to use this inhaler 1 time each day, at the same time each day. Each time you use it take 2 puffs." }

Use SPIRIVA RESPIMAT exactly as prescribed by your doctor. Do not change your dose or how often you use SPIRIVA RESPIMAT without talking with your doctor. Children should use SPIRIVA RESPIMAT with the help of an adult, as instructed by their doctor.

{ "type": "p", "children": [], "text": "\nUse SPIRIVA RESPIMAT exactly as prescribed by your doctor. Do not change your dose or how often you use SPIRIVA RESPIMAT without talking with your doctor. Children should use SPIRIVA RESPIMAT with the help of an adult, as instructed by their doctor." }

Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SPIRIVA RESPIMAT may affect the way some medicines work and some other medicines may affect the way SPIRIVA RESPIMAT works. Do not use other inhaled medicines with SPIRIVA RESPIMAT without talking to your doctor.

{ "type": "p", "children": [], "text": "\nTell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SPIRIVA RESPIMAT may affect the way some medicines work and some other medicines may affect the way SPIRIVA RESPIMAT works. Do not use other inhaled medicines with SPIRIVA RESPIMAT without talking to your doctor." }

The SPIRIVA RESPIMAT inhaler has a slow-moving mist that helps you inhale the medicine.

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Do not turn the clear base before inserting the cartridge.

{ "type": "p", "children": [], "text": "\nDo not turn the clear base before inserting the cartridge.\n" }

Your SPIRIVA RESPIMAT may have either an aqua or a blue cap, depending on the strength prescribed by your doctor. The steps shown below should be followed.

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How to store your SPIRIVA RESPIMAT inhaler

{ "type": "p", "children": [], "text": "\nHow to store your SPIRIVA RESPIMAT inhaler\n" }

{ "type": "ul", "children": [ "Store SPIRIVA RESPIMAT at room temperature between 68°F to 77°F (20°C to 25°C).", "\nDo not freeze your SPIRIVA RESPIMAT cartridge and inhaler.", "If SPIRIVA RESPIMAT has not been used for more than 3 days, release 1 puff towards the ground.", "If SPIRIVA RESPIMAT has not been used for more than 21 days, repeat steps 4 to 6 under the \"Prepare for first use\" until a mist is visible. Then repeat steps 4 to 6 three more times.", "\nKeep your SPIRIVA RESPIMAT cartridge, inhaler, and all medicines out of the reach of children.\n" ], "text": "" }

How to care for your SPIRIVA RESPIMAT inhaler Clean the mouthpiece, including the metal part inside the mouthpiece, with a damp cloth or tissue only, at least 1 time each week. Any minor discoloration in the mouthpiece does not affect your SPIRIVA RESPIMAT inhaler.

{ "type": "p", "children": [], "text": "\nHow to care for your SPIRIVA RESPIMAT inhaler\nClean the mouthpiece, including the metal part inside the mouthpiece, with a damp cloth or tissue only, at least 1 time each week. Any minor discoloration in the mouthpiece does not affect your SPIRIVA RESPIMAT inhaler." }

When to get a new SPIRIVA RESPIMAT inhaler

{ "type": "p", "children": [], "text": "\nWhen to get a new SPIRIVA RESPIMAT inhaler\n" }

{ "type": "ul", "children": [ "The scale on your inhaler shows the number of puffs in the inhaler. You should use 2 puffs 1 time each day.", "The dose indicator shows approximately how many puffs are left in the inhaler.", "When the dose indicator enters the red area of the scale you need to refill your prescription as soon as possible.", "When the dose indicator reaches the end of the red scale, your SPIRIVA RESPIMAT is empty and automatically locks. At this point, the clear base cannot be turned any further." ], "text": "" }

{ "type": "ul", "children": [ "Three months after insertion of cartridge, throw away the SPIRIVA RESPIMAT even if it has not been used, or when the inhaler is locked, or when it expires, whichever comes first." ], "text": "" }

Prepare for first use

{ "type": "p", "children": [], "text": "\nPrepare for first use\n" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"> <dl> <dt class="Bold">1.</dt> <dd> <span class="Bold">Remove clear base</span> <ul class="Disc"> <li>Keep the cap closed.</li> <li>Press the safety catch while firmly pulling off the clear base with your other hand. Be careful not to touch the piercing element.</li> <li>Write the discard by date on the label (3 months from the date the cartridge is inserted).</li> </ul> </dd> </dl> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-06.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt class="Bold">2.</dt> <dd> <span class="Bold">Insert cartridge</span> <ul class="Disc"> <li>Insert the narrow end of the cartridge into the inhaler.</li> <li>Place the inhaler on a firm surface and push down firmly until it clicks into place.</li> </ul> </dd> </dl> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-07.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt class="Bold">3.</dt> <dd> <span class="Bold">Replace clear base</span> <ul class="Disc"> <li>Put the clear base back into place until it clicks.</li> <li>Do not remove the clear base or the cartridge after it has been put together.</li> </ul> </dd> </dl> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-08.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt class="Bold">4.</dt> <dd> <span class="Bold">Turn</span> <ul class="Disc"> <li>Keep the cap closed.</li> <li>Turn the clear base in the direction of the arrows on the label until it clicks (half a turn).</li> </ul> </dd> </dl> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-09.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt class="Bold">5.</dt> <dd> <span class="Bold">Open</span> <ul class="Disc"> <li>Open the cap until it snaps fully open.</li> </ul> </dd> </dl> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-10.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule"> <dl> <dt class="Bold">6.</dt> <dd> <span class="Bold">Press</span> <ul class="Disc"> <li>Point the inhaler toward the ground.</li> <li>Press the dose-release button.</li> <li>Close the cap.</li> <li>If you do not see a mist, repeat steps 4 to 6 until a mist is seen.</li> <li> <span class="Bold">After a mist is seen, repeat steps 4 to 6 three more times.</span> </li> <li> <span class="Bold">After complete preparation of your inhaler, it will be ready to deliver the number of puffs on the label.</span> </li> </ul> </dd> </dl> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-11.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<dl>\n<dt class=\"Bold\">1.</dt>\n<dd>\n<span class=\"Bold\">Remove clear base</span>\n<ul class=\"Disc\">\n<li>Keep the cap closed.</li>\n<li>Press the safety catch while firmly pulling off the clear base with your other hand. Be careful not to touch the piercing element.</li>\n<li>Write the discard by date on the label (3 months from the date the cartridge is inserted).</li>\n</ul>\n</dd>\n</dl>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-06.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<dl>\n<dt class=\"Bold\">2.</dt>\n<dd>\n<span class=\"Bold\">Insert cartridge</span>\n<ul class=\"Disc\">\n<li>Insert the narrow end of the cartridge into the inhaler.</li>\n<li>Place the inhaler on a firm surface and push down firmly until it clicks into place.</li>\n</ul>\n</dd>\n</dl>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-07.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<dl>\n<dt class=\"Bold\">3.</dt>\n<dd>\n<span class=\"Bold\">Replace clear base</span>\n<ul class=\"Disc\">\n<li>Put the clear base back into place until it clicks.</li>\n<li>Do not remove the clear base or the cartridge after it has been put together.</li>\n</ul>\n</dd>\n</dl>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-08.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<dl>\n<dt class=\"Bold\">4.</dt>\n<dd>\n<span class=\"Bold\">Turn</span>\n<ul class=\"Disc\">\n<li>Keep the cap closed.</li>\n<li>Turn the clear base in the direction of the arrows on the label until it clicks (half a turn).</li>\n</ul>\n</dd>\n</dl>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-09.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<dl>\n<dt class=\"Bold\">5.</dt>\n<dd>\n<span class=\"Bold\">Open</span>\n<ul class=\"Disc\">\n<li>Open the cap until it snaps fully open.</li>\n</ul>\n</dd>\n</dl>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-10.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule Last\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<dl>\n<dt class=\"Bold\">6.</dt>\n<dd>\n<span class=\"Bold\">Press</span>\n<ul class=\"Disc\">\n<li>Point the inhaler toward the ground.</li>\n<li>Press the dose-release button.</li>\n<li>Close the cap.</li>\n<li>If you do not see a mist, repeat steps 4 to 6 until a mist is seen.</li>\n<li>\n<span class=\"Bold\">After a mist is seen, repeat steps 4 to 6 three more times.</span>\n</li>\n<li>\n<span class=\"Bold\">After complete preparation of your inhaler, it will be ready to deliver the number of puffs on the label.</span>\n</li>\n</ul>\n</dd>\n</dl>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-11.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Daily use (T O P)

{ "type": "p", "children": [], "text": "\nDaily use (T O P)\n" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold"><span class="Underline">T</span>urn</span> <ul class="Disc"> <li>Keep the cap closed.</li> <li> <span class="Bold">Turn</span> the clear base in the direction of the arrows on the label until it clicks (half a turn).</li> </ul> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-12.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold"><span class="Underline">O</span>pen</span> <ul class="Disc"> <li> <span class="Bold">Open</span> the cap until it snaps fully open.</li> </ul> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-13.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule"><span class="Bold"><span class="Underline">P</span>ress</span> <ul class="Disc"> <li>Breathe out slowly and fully.</li> <li>Close your lips around the mouthpiece without covering the air vents.</li> <li>Point the inhaler to the back of your throat.</li> <li>While taking a slow, deep breath through your mouth, <span class="Bold">Press</span> the dose-release button and continue to breathe in.</li> <li>Hold your breath for 10 seconds or for as long as comfortable.</li> <li>Repeat <span class="Bold"><span class="Underline">T</span>urn, <span class="Underline">O</span>pen, <span class="Underline">P</span>ress (TOP)</span> for a total of 2 puffs.</li> <li>Close the cap until you use your inhaler again.</li> </ul> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=spiriva-14.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\"><span class=\"Underline\">T</span>urn</span>\n<ul class=\"Disc\">\n<li>Keep the cap closed.</li>\n<li>\n<span class=\"Bold\">Turn</span> the clear base in the direction of the arrows on the label until it clicks (half a turn).</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-12.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\"><span class=\"Underline\">O</span>pen</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Open</span> the cap until it snaps fully open.</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-13.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n<tr class=\"Botrule Last\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\"><span class=\"Underline\">P</span>ress</span>\n<ul class=\"Disc\">\n<li>Breathe out slowly and fully.</li>\n<li>Close your lips around the mouthpiece without covering the air vents.</li>\n<li>Point the inhaler to the back of your throat.</li>\n<li>While taking a slow, deep breath through your mouth, <span class=\"Bold\">Press</span> the dose-release button and continue to breathe in.</li>\n<li>Hold your breath for 10 seconds or for as long as comfortable.</li>\n<li>Repeat <span class=\"Bold\"><span class=\"Underline\">T</span>urn, <span class=\"Underline\">O</span>pen, <span class=\"Underline\">P</span>ress (TOP)</span> for a total of 2 puffs.</li>\n<li>Close the cap until you use your inhaler again.</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=spiriva-14.jpg&amp;setid=7b656b14-fcaa-2741-f6f0-e0be48971c02\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Answers to Common Questions

{ "type": "p", "children": [], "text": "\nAnswers to Common Questions\n" }

It is difficult to insert the cartridge deep enough:

{ "type": "p", "children": [], "text": "\nIt is difficult to insert the cartridge deep enough:\n" }

Did you accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release button, then insert the cartridge.

{ "type": "p", "children": [], "text": "\nDid you accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release button, then insert the cartridge." }

Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow end first.

{ "type": "p", "children": [], "text": "\nDid you insert the cartridge with the wide end first? Insert the cartridge with the narrow end first." }

I cannot press the dose-release button:

{ "type": "p", "children": [], "text": "\nI cannot press the dose-release button:\n" }

Did you turn the clear base? If not, turn the clear base in a continuous movement until it clicks (half a turn).

{ "type": "p", "children": [], "text": "\nDid you turn the clear base? If not, turn the clear base in a continuous movement until it clicks (half a turn)." }

Is the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? The SPIRIVA RESPIMAT inhaler is locked after the labeled number of puffs have been used. Prepare and use your new SPIRIVA RESPIMAT inhaler.

{ "type": "p", "children": [], "text": "\nIs the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? The SPIRIVA RESPIMAT inhaler is locked after the labeled number of puffs have been used. Prepare and use your new SPIRIVA RESPIMAT inhaler." }

I cannot turn the clear base:

{ "type": "p", "children": [], "text": "\nI cannot turn the clear base:\n" }

Did you turn the clear base already? If the clear base has already been turned, follow steps "Open" and "Press" under "Daily use" to get your medicine.

{ "type": "p", "children": [], "text": "\nDid you turn the clear base already? If the clear base has already been turned, follow steps \"Open\" and \"Press\" under \"Daily use\" to get your medicine." }

Is the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? The SPIRIVA RESPIMAT inhaler is locked after the labeled number of puffs have been used. Prepare and use your new SPIRIVA RESPIMAT inhaler.

{ "type": "p", "children": [], "text": "\nIs the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? The SPIRIVA RESPIMAT inhaler is locked after the labeled number of puffs have been used. Prepare and use your new SPIRIVA RESPIMAT inhaler." }

The dose indicator on the SPIRIVA RESPIMAT reaches 0 (zero) too soon:

{ "type": "p", "children": [], "text": "\nThe dose indicator on the SPIRIVA RESPIMAT reaches 0 (zero) too soon:\n" }

Did you use SPIRIVA RESPIMAT as indicated (2 puffs 1 time each day)?

{ "type": "p", "children": [], "text": "\nDid you use SPIRIVA RESPIMAT as indicated (2 puffs 1 time each day)?\n" }

Did you turn the clear base before you inserted the cartridge? The dose indicator counts each turn of the clear base regardless whether a cartridge has been inserted or not.

{ "type": "p", "children": [], "text": "\nDid you turn the clear base before you inserted the cartridge? The dose indicator counts each turn of the clear base regardless whether a cartridge has been inserted or not." }

Did you spray in the air often to check whether the SPIRIVA RESPIMAT is working? After you have prepared SPIRIVA RESPIMAT, no test-spraying is required if used daily.

{ "type": "p", "children": [], "text": "\nDid you spray in the air often to check whether the SPIRIVA RESPIMAT is working? After you have prepared SPIRIVA RESPIMAT, no test-spraying is required if used daily." }

Did you insert the cartridge into a used SPIRIVA RESPIMAT? Always insert a new cartridge into a new SPIRIVA RESPIMAT.

{ "type": "p", "children": [], "text": "\nDid you insert the cartridge into a used SPIRIVA RESPIMAT? Always insert a new cartridge into a new SPIRIVA RESPIMAT." }

My SPIRIVA RESPIMAT sprays automatically:

{ "type": "p", "children": [], "text": "\nMy SPIRIVA RESPIMAT sprays automatically:\n" }

Was the cap open when you turned the clear base? Close the cap, then turn the clear base.

{ "type": "p", "children": [], "text": "\nWas the cap open when you turned the clear base? Close the cap, then turn the clear base." }

Did you press the dose-release button when turning the clear base? Close the cap, so the dose-release button is covered, then turn the clear base.

{ "type": "p", "children": [], "text": "\nDid you press the dose-release button when turning the clear base? Close the cap, so the dose-release button is covered, then turn the clear base." }

Did you stop when turning the clear base before it clicked? Turn the clear base in a continuous movement until it clicks (half a turn).

{ "type": "p", "children": [], "text": "\nDid you stop when turning the clear base before it clicked? Turn the clear base in a continuous movement until it clicks (half a turn)." }

My SPIRIVA RESPIMAT does not spray:

{ "type": "p", "children": [], "text": "\nMy SPIRIVA RESPIMAT does not spray:\n" }

Did you insert a cartridge? If not, insert a cartridge.

{ "type": "p", "children": [], "text": "\nDid you insert a cartridge? If not, insert a cartridge." }

Did you repeat Turn, Open, Press (TOP) less than 3 times after inserting the cartridge? Repeat Turn, Open, Press (TOP) 3 times after inserting the cartridge as shown in steps 4 to 6 under "Prepare for first use".

{ "type": "p", "children": [], "text": "\nDid you repeat Turn, Open, Press (TOP) less than 3 times after inserting the cartridge? Repeat Turn, Open, Press (TOP) 3 times after inserting the cartridge as shown in steps 4 to 6 under \"Prepare for first use\"." }

Is the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? You have used up all your medicine and the inhaler is locked.

{ "type": "p", "children": [], "text": "\nIs the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? You have used up all your medicine and the inhaler is locked." }

For more information about SPIRIVA RESPIMAT, including current prescribing information, a video demonstration or a Quick Start Guide on how to use SPIRIVA RESPIMAT, go to www.spiriva.com, scan the code, or call 1-800-542-6257.

{ "type": "p", "children": [], "text": "For more information about SPIRIVA RESPIMAT, including current prescribing information, a video demonstration or a Quick Start Guide on how to use SPIRIVA RESPIMAT, go to www.spiriva.com, scan the code, or call 1-800-542-6257." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA

{ "type": "p", "children": [], "text": "Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA" }

Licensed from: Boehringer Ingelheim International GmbH

{ "type": "p", "children": [], "text": "Licensed from: Boehringer Ingelheim International GmbH" }

SPIRIVA® and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH

{ "type": "p", "children": [], "text": "SPIRIVA® and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH" }

Copyright © 2025 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

{ "type": "p", "children": [], "text": "Copyright © 2025 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED" }

Revised: January 2025

{ "type": "p", "children": [], "text": "Revised: January 2025" }

COL10534BA022025SPL10536D

{ "type": "p", "children": [], "text": "COL10534BA022025SPL10536D" }

NDC 0597-0160-61

{ "type": "p", "children": [], "text": "NDC 0597-0160-61" }

Spiriva® Respimat® (tiotropium bromide inhalation spray)

{ "type": "p", "children": [], "text": "Spiriva® Respimat®\n(tiotropium bromide inhalation spray)" }

1.25 mcg/actuation*

{ "type": "p", "children": [], "text": "1.25 mcg/actuation*" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION ONLY" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

4 Grams 60 Metered Inhalations (Two inhalations equal one dose)

{ "type": "p", "children": [], "text": "4 Grams 60 Metered Inhalations (Two inhalations equal one dose)" }

Boehringer Ingelheim

{ "type": "p", "children": [], "text": "Boehringer Ingelheim" }

NDC 0597-0100-61

{ "type": "p", "children": [], "text": "NDC 0597-0100-61" }

Spiriva® Respimat® (tiotropium bromide inhalation spray)

{ "type": "p", "children": [], "text": "Spiriva® Respimat®\n(tiotropium bromide inhalation spray)" }

2.5 mcg/actuation*

{ "type": "p", "children": [], "text": "2.5 mcg/actuation*" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION ONLY" }

ATTENTION PHARMACIST:Dispense with Instructions for Use

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST:Dispense with Instructions for Use" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

4 Grams60 Metered Inhalations(Two inhalations equal one dose)

{ "type": "p", "children": [], "text": "4 Grams60 Metered Inhalations(Two inhalations equal one dose)" }

Boehringer Ingelheim

{ "type": "p", "children": [], "text": "Boehringer Ingelheim" }

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

{ "type": "p", "children": [], "text": "\nTiotropium bromide inhalation powder is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Tiotropium bromide inhalation powder is indicated to reduce exacerbations in COPD patients." }

For oral inhalation only. Do not swallow tiotropium bromide inhalation powder capsules, as the intended effects on the lungs will not be obtained. The contents of the tiotropium bromide inhalation powder capsules should only be used with the LupinHaler® device [see Overdosage (10)].

{ "type": "p", "children": [], "text": "\nFor oral inhalation only. Do not swallow tiotropium bromide inhalation powder capsules, as the intended effects on the lungs will not be obtained. The contents of the tiotropium bromide inhalation powder capsules should only be used with the LupinHaler® device [see Overdosage (10)]." }

The recommended dosage of tiotropium bromide inhalation powder is two inhalations of the powder contents of one tiotropium bromide inhalation powder capsule, once-daily, with the LupinHaler device [see Patient Counseling Information (17)]. Do not take more than one dose in 24 hours.

{ "type": "p", "children": [], "text": "The recommended dosage of tiotropium bromide inhalation powder is two inhalations of the powder contents of one tiotropium bromide inhalation powder capsule, once-daily, with the LupinHaler device [see Patient Counseling Information (17)]. Do not take more than one dose in 24 hours." }

For administration of tiotropium bromide inhalation powder, a tiotropium bromide inhalation powder capsule is placed into the center chamber of the LupinHaler device. The tiotropium bromide inhalation powder capsule is pierced by pressing and releasing the green piercing button on the side of the LupinHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [see Patient Counseling Information (17)].

{ "type": "p", "children": [], "text": "For administration of tiotropium bromide inhalation powder, a tiotropium bromide inhalation powder capsule is placed into the center chamber of the LupinHaler device. The tiotropium bromide inhalation powder capsule is pierced by pressing and releasing the green piercing button on the side of the LupinHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [see Patient Counseling Information (17)].\n" }

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given tiotropium bromide inhalation powder should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given tiotropium bromide inhalation powder should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].\n" }

Inhalation Powder: Tiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules containing tiotropium powder for oral inhalation and a LupinHaler device. Tiotropium bromide inhalation powder capsules contain 18 mcg of tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) in a hypromellose capsule with white opaque cap and white opaque body, imprinted with "LU" on cap and "T18" on body. The LupinHaler device is only intended for use with the tiotropium bromide inhalation powder capsules.

{ "type": "p", "children": [], "text": "\nInhalation Powder: Tiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules containing tiotropium powder for oral inhalation and a LupinHaler device. Tiotropium bromide inhalation powder capsules contain 18 mcg of tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) in a hypromellose capsule with white opaque cap and white opaque body, imprinted with \"LU\" on cap and \"T18\" on body. The LupinHaler device is only intended for use with the tiotropium bromide inhalation powder capsules." }

Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product [see Warnings and Precautions (5.2)]. In clinical trials and postmarketing experience with tiotropium bromide inhalation powder, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "\nTiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product [see Warnings and Precautions (5.2)]. In clinical trials and postmarketing experience with tiotropium bromide inhalation powder, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)]." }

Tiotropium bromide inhalation powder is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administration of tiotropium bromide inhalation powder. If such a reaction occurs, therapy with tiotropium bromide inhalation powder should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to tiotropium bromide inhalation powder. In addition, tiotropium bromide inhalation powder should be used with caution in patients with severe hypersensitivity to milk proteins.

Inhaled medicines, including tiotropium bromide inhalation powder, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short- acting beta2-agonist such as albuterol. Treatment with tiotropium bromide inhalation powder should be stopped and other treatments considered.

Tiotropium bromide inhalation powder should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Tiotropium bromide inhalation powder should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with tiotropium bromide inhalation powder should be monitored closely for anticholinergic side effects [see Clinical Pharmacology (12.3)].

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice.

6-Month to 1-Year Trials

The data described below reflect exposure to tiotropium bromide inhalation powder in 2,663 patients. Tiotropium bromide inhalation powder was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1,308 patients were treated with tiotropium bromide inhalation powder at the recommended dosage of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected.

The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention.

Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated tiotropium bromide inhalation powder in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the tiotropium bromide inhalation powder group in the 1-year placebo-controlled trials where the rates in the tiotropium bromide inhalation powder group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 1:      Adverse Reactions (% Patients) in One-Year COPD Clinical Trials </span> </caption> <col width="33%"/> <col width="22%"/> <col width="9%"/> <col width="22%"/> <col width="12%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Toprule" rowspan="2" valign="top"><span class="Bold"> Body System (Event)</span> <br/> </td><td align="center" class="Botrule Toprule" colspan="2" valign="top"><span class="Bold"> Placebo-Controlled Trials</span> <br/> </td><td align="center" class="Botrule Toprule" colspan="2" valign="top"><span class="Bold"> Ipratropium-Controlled Trials</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold"> Tiotropium Bromide Inhalation Powder </span> <br/> <span class="Bold"> (n = 550)</span> <br/> </td><td align="center" class="Botrule" valign="top"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> (n = 371)</span> <br/> </td><td align="center" class="Botrule" valign="top"><span class="Bold"> Tiotropium Bromide Inhalation Powder </span> <br/> <span class="Bold"> (n = 356)</span> <br/> </td><td align="center" class="Botrule" valign="top"><span class="Bold"> Ipratropium</span> <br/> <span class="Bold"> (n</span><span class="Bold"> = 179)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule"><span class="Bold"> Body as a Whole</span> <br/> Chest Pain (non-specific)<br/> </td><td align="center" class="Botrule"><span class="Bold"> 7</span> <br/> </td><td align="center" class="Botrule"><span class="Bold"> 5</span> <br/> </td><td align="center" class="Botrule"><span class="Bold"> 5</span> <br/> </td><td align="center" class="Botrule"><span class="Bold"> 2</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Edema, Dependent<br/> </td><td align="center" class="Botrule"> 5<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"><span class="Bold"> Gastrointestinal System Disorders</span> <br/> Dry Mouth<br/> </td><td align="center" class="Botrule"> 16<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 12<br/> </td><td align="center" class="Botrule"> 6<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Dyspepsia<br/> </td><td align="center" class="Botrule"> 6<br/> </td><td align="center" class="Botrule"> 5<br/> </td><td align="center" class="Botrule"> 1<br/> </td><td align="center" class="Botrule"> 1<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Abdominal Pain<br/> </td><td align="center" class="Botrule"> 5<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 6<br/> </td><td align="center" class="Botrule"> 6<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Constipation<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 2<br/> </td><td align="center" class="Botrule"> 1<br/> </td><td align="center" class="Botrule"> 1<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Vomiting<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 2<br/> </td><td align="center" class="Botrule"> 1<br/> </td><td align="center" class="Botrule"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"><span class="Bold"> Musculoskeletal System</span> <br/> Myalgia<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"><span class="Bold"> Resistance Mechanism Disorders</span> <br/> Infection<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 1<br/> </td><td align="center" class="Botrule"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Moniliasis<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 2<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"><span class="Bold"> Respiratory System (Upper)</span> <br/> Upper Respiratory Tract Infection<br/> </td><td align="center" class="Botrule"> 41<br/> </td><td align="center" class="Botrule"> 37<br/> </td><td align="center" class="Botrule"> 43<br/> </td><td align="center" class="Botrule"> 35<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Sinusitis<br/> </td><td align="center" class="Botrule"> 11<br/> </td><td align="center" class="Botrule"> 9<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Pharyngitis<br/> </td><td align="center" class="Botrule"> 9<br/> </td><td align="center" class="Botrule"> 7<br/> </td><td align="center" class="Botrule"> 7<br/> </td><td align="center" class="Botrule"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Rhinitis<br/> </td><td align="center" class="Botrule"> 6<br/> </td><td align="center" class="Botrule"> 5<br/> </td><td align="center" class="Botrule"> 3<br/> </td><td align="center" class="Botrule"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"> Epistaxis<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 2<br/> </td><td align="center" class="Botrule"> 1<br/> </td><td align="center" class="Botrule"> 1<br/> </td> </tr> <tr> <td align="left" class="Botrule" valign="top"><span class="Bold"> Skin and Appendage Disorders</span> <br/> Rash<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 2<br/> </td><td align="center" class="Botrule"> 2<br/> </td><td align="center" class="Botrule"> 2<br/> </td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top"><span class="Bold"> Urinary System</span> <br/> Urinary Tract Infection<br/> </td><td align="center" class="Botrule"> 7<br/> </td><td align="center" class="Botrule"> 5<br/> </td><td align="center" class="Botrule"> 4<br/> </td><td align="center" class="Botrule"> 2 <br/> </td> </tr> </tbody> </table></div>

Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the tiotropium bromide inhalation powder treatment group, but were <1% in excess of the placebo group.

Other reactions that occurred in the tiotropium bromide inhalation powder group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention.

In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [see Use in Specific Populations (8.5)].

Two multicenter, 6-month, controlled studies evaluated tiotropium bromide inhalation powder in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.

4-Year Trial

The data described below reflect exposure to tiotropium bromide inhalation powder in 5,992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2,986 patients were treated with tiotropium bromide inhalation powder at the recommended dosage of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥3% in the tiotropium bromide inhalation powder group where the rates in the tiotropium bromide inhalation powder group exceeded placebo by ≥1%, adverse reactions included (tiotropium bromide inhalation powder, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).

Additional Adverse Reactions

Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with tiotropium bromide inhalation powder than placebo include:

dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.

Adverse reactions have been identified during worldwide post-approval use of tiotropium bromide inhalation powder. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria.

Tiotropium bromide inhalation powder has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse reactions.

There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of tiotropium bromide inhalation powder with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].

Risk Summary

The limited human data with tiotropium bromide inhalation powder use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. 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.

Data

Animal Data

In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and 8 times the MRHDID, respectively (on a mcg/m2 basis at inhalation doses of 1,471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m2 basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

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 tiotropium bromide inhalation powder and any potential adverse effects on the breastfed child from tiotropium bromide inhalation powder 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.

Tiotropium bromide inhalation powder is not indicated for use in children. The safety and effectiveness of tiotropium bromide inhalation powder in pediatric patients have not been established.

Based on available data, no adjustment of tiotropium bromide inhalation powder dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

Of the total number of patients who received tiotropium bromide inhalation powder in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the tiotropium bromide inhalation powder and the comparator groups for most events. Dry mouth increased with age in the tiotropium bromide inhalation powder group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the tiotropium bromide inhalation powder group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups.

Patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with tiotropium bromide inhalation powder should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once- daily inhalation of 141 mcg of tiotropium.

{ "type": "p", "children": [], "text": "\nHigh doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once- daily inhalation of 141 mcg of tiotropium." }

Treatment of overdosage consists of discontinuation of tiotropium bromide inhalation powder together with institution of appropriate symptomatic and/or supportive therapy.

{ "type": "p", "children": [], "text": "Treatment of overdosage consists of discontinuation of tiotropium bromide inhalation powder together with institution of appropriate symptomatic and/or supportive therapy." }

Accidental Ingestion

{ "type": "p", "children": [], "text": "\nAccidental Ingestion\n" }

Acute intoxication by inadvertent oral ingestion of tiotropium bromide inhalation powder capsules is unlikely since it is not well-absorbed systemically.

{ "type": "p", "children": [], "text": "\nAcute intoxication by inadvertent oral ingestion of tiotropium bromide inhalation powder capsules is unlikely since it is not well-absorbed systemically.\n" }

A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, tiotropium bromide inhalation powder was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day.

{ "type": "p", "children": [], "text": "A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, tiotropium bromide inhalation powder was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day." }

Tiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules and a LupinHaler device. Each white opaque, hypromellose tiotropium bromide inhalation powder capsule contains a dry powder consisting of 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) blended with lactose monohydrate (which may contain milk proteins).

{ "type": "p", "children": [], "text": "\nTiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules and a LupinHaler device. Each white opaque, hypromellose tiotropium bromide inhalation powder capsule contains a dry powder consisting of 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) blended with lactose monohydrate (which may contain milk proteins)." }

The contents of tiotropium bromide inhalation powder capsules are intended for oral inhalation only, and are intended for administration only with the LupinHaler device.

{ "type": "p", "children": [], "text": "The contents of tiotropium bromide inhalation powder capsules are intended for oral inhalation only, and are intended for administration only with the LupinHaler device." }

The active component of tiotropium bromide inhalation powder is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-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.

{ "type": "p", "children": [], "text": "The active component of tiotropium bromide inhalation powder is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-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:

{ "type": "p", "children": [], "text": "The structural formula is:" }

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

{ "type": "p", "children": [], "text": "\nTiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O." }

The LupinHaler device is an inhalation device used to inhale the dry powder contained in the tiotropium bromide inhalation powder capsule. The dry powder is delivered from the LupinHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the LupinHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the LupinHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the LupinHaler device, which may vary from patient to patient, and may vary with the exposure time of the tiotropium bromide inhalation powder capsule outside the blister pack.

{ "type": "p", "children": [], "text": "The LupinHaler device is an inhalation device used to inhale the dry powder contained in the tiotropium bromide inhalation powder capsule. The dry powder is delivered from the LupinHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the LupinHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the LupinHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the LupinHaler device, which may vary from patient to patient, and may vary with the exposure time of the tiotropium bromide inhalation powder capsule outside the blister pack." }

Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

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 tiotropium bromide inhalation powder 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 studies with tiotropium bromide inhalation powder 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 dry powder for inhalation 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 dry powder for inhalation 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec.

Tiotropium is administered by dry powder inhalation. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) from the LupinHaler device resulted in a similar systemic exposure between the two products.

Absorption

Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium. Maximum tiotropium plasma concentrations were observed 7 minutes after inhalation.

Distribution

Tiotropium is 72% bound to plasma protein and had a volume of distribution of 32 L/kg after intravenous administration 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 readily penetrate the blood-brain barrier.

Elimination

The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was 880 mL/min after intravenous administration in young healthy volunteers. After chronic once-daily dry powder inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Metabolism

The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.

In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Excretion

Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation to COPD patients at steady state, urinary excretion was 7% (1.3 mcg) of the unchanged dose over 24 hours. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.

Specific Populations

Geriatric Patients

As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (365 mL/min in COPD patients <65 years to 271 mL/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values following administration via LupinHaler device.

Renal Impairment

Following 4-week tiotropium bromide inhalation powder or SPIRIVA RESPIMAT® once daily dosing in patients with COPD, mild renal impairment (creatinine clearance 60-<90 mL/min) resulted in 6-23% higher AUC0-6,ss and 6-17% higher Cmax,ss values; moderate renal impairment (creatinine clearance 30-<60 mL/min) resulted in 54-57% higher AUC0-6,ss and 15-31% higher Cmax,ss values compared to COPD patients with normal renal function (creatinine clearance ≥90 mL/min). There is insufficient data for tiotropium exposure in patients with severe renal impairment (creatinine clearance <30 mL/min) following inhalation of tiotropium bromide inhalation powder or SPIRIVA RESPIMAT®. However AUC0-4 and Cmax were 94% and 52% higher, respectively, in patients with severe renal impairment following intravenous infusion of tiotropium bromide.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

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 (long-acting beta2-adrenergic agonists (LABA), inhaled corticosteroids (ICS)) used by patients with COPD were not found to alter the exposure to tiotropium.

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 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 1,689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m2 basis).

The tiotropium bromide inhalation powder clinical development program consisted of six Phase 3 studies in 2,663 patients with COPD (1,308 receiving tiotropium bromide inhalation powder): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies 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 a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7.

{ "type": "p", "children": [], "text": "\nThe tiotropium bromide inhalation powder clinical development program consisted of six Phase 3 studies in 2,663 patients with COPD (1,308 receiving tiotropium bromide inhalation powder): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies 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 a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7." }

In these studies, tiotropium bromide inhalation powder, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose.

{ "type": "p", "children": [], "text": "In these studies, tiotropium bromide inhalation powder, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose." }

Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1,829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5,992 COPD patients. Long-term effects on lung function and other outcomes, were also evaluated in the 4-year multicenter trial.

{ "type": "p", "children": [], "text": "Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1,829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5,992 COPD patients. Long-term effects on lung function and other outcomes, were also evaluated in the 4-year multicenter trial." }

6-Month to 1-Year Effects on Lung Function

{ "type": "p", "children": [], "text": "\n6-Month to 1-Year Effects on Lung Function\n" }

In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance.

{ "type": "p", "children": [], "text": "In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance." }

In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with tiotropium bromide inhalation powder, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period.

{ "type": "p", "children": [], "text": "In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with tiotropium bromide inhalation powder, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period." }

Figure 1:         Mean FEV1 Over Time (prior to and after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*

{ "type": "p", "children": [], "text": "\nFigure 1:         Mean FEV1 Over Time (prior to and after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*\n" }

*Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the tiotropium bromide inhalation powder and placebo groups, respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.

{ "type": "p", "children": [], "text": "\n*Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the tiotropium bromide inhalation powder and placebo groups, respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward. " }

Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2.

{ "type": "p", "children": [], "text": "Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2." }

Figure 2:         Mean FEV1 Over Time (0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the Two Ipratropium-Controlled Studies*

{ "type": "p", "children": [], "text": "\nFigure 2:         Mean FEV1 Over Time (0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the Two Ipratropium-Controlled Studies*\n" }

*Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the tiotropium bromide inhalation powder and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.

{ "type": "p", "children": [], "text": "\n*Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the tiotropium bromide inhalation powder and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward." }

A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether tiotropium bromide inhalation powder was administered in the morning or in the evening.

{ "type": "p", "children": [], "text": "A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether tiotropium bromide inhalation powder was administered in the morning or in the evening." }

Throughout each week of the 1-year treatment period in the two placebo-controlled trials, patients taking tiotropium bromide inhalation powder had a reduced requirement for the use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6 -month studies.

{ "type": "p", "children": [], "text": "Throughout each week of the 1-year treatment period in the two placebo-controlled trials, patients taking tiotropium bromide inhalation powder had a reduced requirement for the use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6 -month studies." }

4-Year Effects on Lung Function

{ "type": "p", "children": [], "text": "\n4-Year Effects on Lung Function\n" }

A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving  5,992 COPD patients was conducted to evaluate the long-term effects of tiotropium bromide inhalation powder on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long- acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3).

{ "type": "p", "children": [], "text": "A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving  5,992 COPD patients was conducted to evaluate the long-term effects of tiotropium bromide inhalation powder on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long- acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3)." }

Tiotropium bromide inhalation powder maintained improvements in trough (pre-dose) FEV1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3).

{ "type": "p", "children": [], "text": "Tiotropium bromide inhalation powder maintained improvements in trough (pre-dose) FEV1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3)." }

Figure 3:         Trough (pre-dose) FEV1 Mean Values at Each Time Point

{ "type": "p", "children": [], "text": "\nFigure 3:         Trough (pre-dose) FEV1 Mean Values at Each Time Point\n" }

Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis.

{ "type": "p", "children": [], "text": "\nRepeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis." }

Exacerbations

{ "type": "p", "children": [], "text": "\nExacerbations\n" }

The effect of tiotropium bromide inhalation powder on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1,829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre -bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Tiotropium bromide inhalation powder significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs. 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used tiotropium bromide inhalation powder compared to placebo was 7.0% vs. 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056.

{ "type": "p", "children": [], "text": "The effect of tiotropium bromide inhalation powder on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1,829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre -bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Tiotropium bromide inhalation powder significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs. 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used tiotropium bromide inhalation powder compared to placebo was 7.0% vs. 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056." }

Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Tiotropium bromide inhalation powder significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the tiotropium bromide inhalation powder group.

{ "type": "p", "children": [], "text": "Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Tiotropium bromide inhalation powder significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the tiotropium bromide inhalation powder group." }

All-Cause Mortality

{ "type": "p", "children": [], "text": "\nAll-Cause Mortality\n" }

In the 4-year placebo-controlled lung-function trial described above, all-cause mortality compared to placebo was assessed. There were no significant differences in all- cause mortality rates between tiotropium bromide inhalation powder and placebo.

{ "type": "p", "children": [], "text": "In the 4-year placebo-controlled lung-function trial described above, all-cause mortality compared to placebo was assessed. There were no significant differences in all- cause mortality rates between tiotropium bromide inhalation powder and placebo." }

The all-cause mortality of tiotropium bromide inhalation powder was also compared to tiotropium inhalation spray 5 mcg (SPIRIVA RESPIMAT® 5 mcg) in an additional long-term, randomized, double-blind, double-dummy active-controlled study with an observation period up to 3 years. All-cause mortality was similar between tiotropium bromide inhalation powder and SPIRIVA RESPIMAT®.

{ "type": "p", "children": [], "text": "The all-cause mortality of tiotropium bromide inhalation powder was also compared to tiotropium inhalation spray 5 mcg (SPIRIVA RESPIMAT® 5 mcg) in an additional long-term, randomized, double-blind, double-dummy active-controlled study with an observation period up to 3 years. All-cause mortality was similar between tiotropium bromide inhalation powder and SPIRIVA RESPIMAT®." }

Tiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules and the LupinHaler device. Tiotropium bromide inhalation powder capsules contain 18 mcg of tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) in a hypromellose capsule with white opaque cap and white opaque body, imprinted with "LU" on cap and "T18" on body.

{ "type": "p", "children": [], "text": "\nTiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules and the LupinHaler device. Tiotropium bromide inhalation powder capsules contain 18 mcg of tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) in a hypromellose capsule with white opaque cap and white opaque body, imprinted with \"LU\" on cap and \"T18\" on body." }

The LupinHaler device is a white colour inhaler with a green piercing button. It is also imprinted with LupinHaler, Tiotropium Bromide Inhalation Powder and the LUPIN company Logo. It is also imprinted to indicate that Tiotropium Bromide Inhalation Powder Capsules should not be stored in the LupinHaler device and that the LupinHaler device is only to be used with Tiotropium Bromide Inhalation Powder Capsules.

{ "type": "p", "children": [], "text": "The LupinHaler device is a white colour inhaler with a green piercing button. It is also imprinted with LupinHaler, Tiotropium Bromide Inhalation Powder and the LUPIN company Logo. It is also imprinted to indicate that Tiotropium Bromide Inhalation Powder Capsules should not be stored in the LupinHaler device and that the LupinHaler device is only to be used with Tiotropium Bromide Inhalation Powder Capsules." }

Tiotropium bromide inhalation powder capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. Tiotropium bromide inhalation powder capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual tiotropium bromide inhalation powder capsule is opened.

{ "type": "p", "children": [], "text": "Tiotropium bromide inhalation powder capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. Tiotropium bromide inhalation powder capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual tiotropium bromide inhalation powder capsule is opened." }

The following packages are available:

{ "type": "p", "children": [], "text": "The following packages are available:" }

{ "type": "ul", "children": [ "carton (NDC 68180-964-12) containing 30 Tiotropium Bromide Inhalation Powder Capsules (3 unit-dose blister cards NDC 68180-964-11) and 1 LupinHaler inhalation device" ], "text": "" }

Keep out of reach of children. Do not get powder into eyes.

{ "type": "p", "children": [], "text": "\nKeep out of reach of children. Do not get powder into eyes." }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]." }

The Tiotropium Bromide Inhalation Powder Capsules should not be exposed to extreme temperature or moisture. Do not store Tiotropium Bromide Inhalation Powder Capsules in the LupinHaler device.

{ "type": "p", "children": [], "text": "The Tiotropium Bromide Inhalation Powder Capsules should not be exposed to extreme temperature or moisture. Do not store Tiotropium Bromide Inhalation Powder Capsules in the LupinHaler device." }

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "\nAdvise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)." }

Not for Acute Use:

{ "type": "p", "children": [], "text": "\nNot for Acute Use:\n" }

Instruct patients that tiotropium bromide inhalation powder is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

{ "type": "p", "children": [], "text": "Instruct patients that tiotropium bromide inhalation powder is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication)." }

Immediate Hypersensitivity Reactions:

{ "type": "p", "children": [], "text": "\nImmediate Hypersensitivity Reactions:\n" }

Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration of tiotropium bromide inhalation powder. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.

{ "type": "p", "children": [], "text": "Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration of tiotropium bromide inhalation powder. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop." }

Paradoxical Bronchospasm:

{ "type": "p", "children": [], "text": "\nParadoxical Bronchospasm:\n" }

Inform patients that tiotropium bromide inhalation powder can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue tiotropium bromide inhalation powder.

{ "type": "p", "children": [], "text": "Inform patients that tiotropium bromide inhalation powder can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue tiotropium bromide inhalation powder." }

Worsening of Narrow-Angle Glaucoma:

{ "type": "p", "children": [], "text": "\nWorsening of Narrow-Angle Glaucoma:\n" }

Instruct patients to be alert for signs and symptoms of narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs and symptoms develop.

{ "type": "p", "children": [], "text": "Instruct patients to be alert for signs and symptoms of narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs and symptoms develop." }

Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

{ "type": "p", "children": [], "text": "Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation." }

Since dizziness and blurred vision may occur with the use of tiotropium bromide inhalation powder, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

{ "type": "p", "children": [], "text": "Since dizziness and blurred vision may occur with the use of tiotropium bromide inhalation powder, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery." }

Worsening of Urinary Retention:

{ "type": "p", "children": [], "text": "\nWorsening of Urinary Retention:\n" }

Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

{ "type": "p", "children": [], "text": "Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop." }

Instructions for Administering Tiotropium Bromide Inhalation Powder:

{ "type": "p", "children": [], "text": "\nInstructions for Administering Tiotropium Bromide Inhalation Powder:\n" }

Instruct patients on how to correctly administer tiotropium bromide inhalation powder capsules using the LupinHaler device [see Patient Counseling Information (17)]. Instruct patients that tiotropium bromide inhalation powder capsules should only be administered via the LupinHaler device and the LupinHaler device should not be used for administering other medications. Remind patients that the contents of tiotropium bromide inhalation powder capsules are for oral inhalation only and must not be swallowed.

{ "type": "p", "children": [], "text": "Instruct patients on how to correctly administer tiotropium bromide inhalation powder capsules using the LupinHaler device [see Patient Counseling Information (17)]. Instruct patients that tiotropium bromide inhalation powder capsules should only be administered via the LupinHaler device and the LupinHaler device should not be used for administering other medications. Remind patients that the contents of tiotropium bromide inhalation powder capsules are for oral inhalation only and must not be swallowed.\n" }

Instruct patients always to store tiotropium bromide inhalation powder capsules in sealed blisters and to remove only one tiotropium bromide inhalation powder capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional tiotropium bromide inhalation powder capsules that are exposed to air (i.e., not intended for immediate use).

{ "type": "p", "children": [], "text": "Instruct patients always to store tiotropium bromide inhalation powder capsules in sealed blisters and to remove only one tiotropium bromide inhalation powder capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional tiotropium bromide inhalation powder capsules that are exposed to air (i.e., not intended for immediate use)." }

LupinHaler® is a registered trademark of Lupin Limited.

{ "type": "p", "children": [], "text": "\nLupinHaler® is a registered trademark of Lupin Limited." }

®The other brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.

{ "type": "p", "children": [], "text": "\n®The other brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products." }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nLupin Pharmaceuticals, Inc.\n" }

Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108" }

United States

{ "type": "p", "children": [], "text": "United States" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Lupin Limited

{ "type": "p", "children": [], "text": "\nLupin Limited\n" }

Pithampur (M.P.) - 454 775

{ "type": "p", "children": [], "text": "Pithampur (M.P.) - 454 775" }

India

{ "type": "p", "children": [], "text": "India" }

May 2025

{ "type": "p", "children": [], "text": "May 2025" }

Patient Information

{ "type": "p", "children": [], "text": "\nPatient Information\n" }

Tiotropium Bromide Inhalation Powder

{ "type": "p", "children": [], "text": "\nTiotropium Bromide Inhalation Powder\n" }

(tye-oh-TROE-pee-um BROE-mide)

{ "type": "p", "children": [], "text": "\n(tye-oh-TROE-pee-um BROE-mide)\n" }

Do NOT swallow Tiotropium Bromide Inhalation Powder Capsules.

{ "type": "p", "children": [], "text": "\nDo NOT swallow Tiotropium Bromide Inhalation Powder Capsules.\n" }

Important Information: Do not swallow tiotropium bromide inhalation powder capsules. Tiotropium bromide inhalation powder capsules should only be used with the LupinHaler® device and inhaled through your mouth (oral inhalation).

{ "type": "p", "children": [], "text": "\nImportant Information: Do not swallow tiotropium bromide inhalation powder capsules. Tiotropium bromide inhalation powder capsules should only be used with the LupinHaler® device and inhaled through your mouth (oral inhalation).\n" }

Read the information that comes with your tiotropium bromide inhalation powder before you start using it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read the information that comes with your tiotropium bromide inhalation powder before you start using it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment." }

What is tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nWhat is tiotropium bromide inhalation powder?\n" }

{ "type": "ul", "children": [ "Tiotropium bromide inhalation powder is a prescription medicine used each day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.", "Tiotropium bromide inhalation powder helps make your lungs work better for 24 hours. Tiotropium bromide inhalation powder relaxes your airways and helps keep them open. You may start to feel like it is easier to breathe on the first day, but it may take longer for you to feel the full effects of the medicine. Tiotropium bromide inhalation powder works best and may help make it easier to breathe when you use it every day.", "Tiotropium bromide inhalation powder reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD exacerbations). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine." ], "text": "" }

Tiotropium bromide inhalation powder is not a rescue medicine and should not be used for treating sudden breathing problems. Your doctor may give you other medicine to use for sudden breathing problems.

{ "type": "p", "children": [], "text": "\nTiotropium bromide inhalation powder is not a rescue medicine and should not be used for treating sudden breathing problems. Your doctor may give you other medicine to use for sudden breathing problems." }

It is not known if tiotropium bromide inhalation powder is safe and effective in children.

{ "type": "p", "children": [], "text": "It is not known if tiotropium bromide inhalation powder is safe and effective in children." }

Who should not take tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nWho should not take tiotropium bromide inhalation powder?\n" }

Do not use tiotropium bromide inhalation powder if you:

{ "type": "p", "children": [], "text": "\nDo not use tiotropium bromide inhalation powder if you:\n" }

{ "type": "ul", "children": [ "are allergic to tiotropium, ipratropium (Atrovent®), or any of the ingredients in tiotropium bromide inhalation powder. See the end of this leaflet for a complete list of ingredients in tiotropium bromide inhalation powder." ], "text": "" }

Symptoms of a serious allergic reaction to tiotropium bromide inhalation powder may include:

{ "type": "p", "children": [], "text": "\nSymptoms of a serious allergic reaction to tiotropium bromide inhalation powder may include:" }

{ "type": "ul", "children": [ "raised red patches on your skin (hives)", "itching", "rash", "swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing" ], "text": "" }

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

{ "type": "p", "children": [], "text": "\nIf you have these symptoms of an allergic reaction, stop taking tiotropium bromide inhalation powder and call your doctor right away or go to the nearest hospital emergency room." }

What should I tell my doctor before using tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before using tiotropium bromide inhalation powder?\n" }

Before taking tiotropium bromide inhalation powder, tell your doctor about all your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore taking tiotropium bromide inhalation powder, tell your doctor about all your medical conditions, including if you:\n" }

{ "type": "ul", "children": [ "have kidney problems.", "have glaucoma. Tiotropium bromide inhalation powder may make your glaucoma worse.", "have an enlarged prostate, problems passing urine, or a blockage in your bladder. Tiotropium bromide inhalation powder may make these problems worse.", "are pregnant or plan to become pregnant. It is not known if tiotropium bromide inhalation powder could harm your unborn baby.", "are breast-feeding or plan to breast-feed. It is not known if tiotropium bromide passes into breast milk. You and your doctor will decide if tiotropium bromide inhalation powder is right for you while you breast-feed.", "have a severe allergy to milk proteins. Ask your doctor if you are not sure." ], "text": "" }

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way tiotropium bromide inhalation powder works. Tiotropium bromide inhalation powder is an anticholinergic medicine. You should not take other anticholinergic medicines while using tiotropium bromide inhalation powder, including ipratropium. Ask your doctor or pharmacist if you are not sure if one of your medicines is an anticholinergic.

{ "type": "p", "children": [], "text": "\nTell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way tiotropium bromide inhalation powder works. Tiotropium bromide inhalation powder is an anticholinergic medicine. You should not take other anticholinergic medicines while using tiotropium bromide inhalation powder, including ipratropium. Ask your doctor or pharmacist if you are not sure if one of your medicines is an anticholinergic." }

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine." }

How should I take tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nHow should I take tiotropium bromide inhalation powder?\n" }

{ "type": "ul", "children": [ "Use tiotropium bromide inhalation powder exactly as prescribed. Use tiotropium bromide inhalation powder one time every day.", "Read the \"Instructions for Use\" at the end of this leaflet before you use tiotropium bromide inhalation powder. Talk with your doctor if you do not understand the instructions.", "\nDo not swallow tiotropium bromide inhalation powder capsules.\n", "\nOnly use tiotropium bromide inhalation powder capsules with the LupinHaler device\n", "\nDo not use the LupinHaler device to take any other medicine.\n", "Tiotropium bromide inhalation powder comes as a powder in a tiotropium bromide inhalation powder capsule that fits the LupinHaler device. Each tiotropium bromide inhalation powder capsule, containing only a small amount of tiotropium bromide inhalation powder, is one full dose of medicine.", "Separate one blister from the blister card. Then take out one of the tiotropium bromide inhalation powder capsules from the blister package right before you use it.", "After the capsule is pierced, take a complete dose of tiotropium bromide inhalation powder by breathing in the powder by mouth two times, using the LupinHaler device (take 2 inhalations from one tiotropium bromide inhalation powder capsule). See the \"Instructions for Use\" at the end of this leaflet.", "Throw away any tiotropium bromide inhalation powder capsule that is not used right away after it is taken out of the blister package. Do not leave the tiotropium bromide inhalation powder capsules open to air; they may not work as well.", "If you miss a dose, take it as soon as you remember. Do not use tiotropium bromide inhalation powder more than one time every 24 hours.", "If you use more than your prescribed dose of tiotropium bromide inhalation powder, call your doctor or a poison control center." ], "text": "" }

What should I avoid while using tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while using tiotropium bromide inhalation powder?\n" }

{ "type": "ul", "children": [ "Do not let the powder from the tiotropium bromide inhalation powder capsule get into your eyes. Your vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.", "Tiotropium bromide inhalation powder 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." ], "text": "" }

What are the possible side effects of tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of tiotropium bromide inhalation powder?\n" }

Tiotropium bromide inhalation powder can cause serious side effects, including: Allergic reaction. Symptoms may include:

{ "type": "p", "children": [], "text": "\nTiotropium bromide inhalation powder can cause serious side effects, including: Allergic reaction. Symptoms may include:" }

{ "type": "ul", "children": [ "raised red patches on your skin (hives)", "itching", "rash", "swelling of the lips, tongue, or throat that may cause difficulty in breathing or swallowing" ], "text": "" }

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

{ "type": "p", "children": [], "text": "\nIf you have these symptoms of an allergic reaction, stop taking tiotropium bromide inhalation powder and call your doctor right away or go to the nearest hospital emergency room." }

{ "type": "ul", "children": [ "\nSudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse." ], "text": "" }

If you have these symptoms of bronchospasm, stop taking tiotropium bromide inhalation powder and call your doctor right away or go to the nearest hospital emergency room.

{ "type": "p", "children": [], "text": "\nIf you have these symptoms of bronchospasm, stop taking tiotropium bromide inhalation powder and call your doctor right away or go to the nearest hospital emergency room." }

{ "type": "ul", "children": [ "\nNew or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-angle glaucoma may include:\neye pain\nblurred vision\nseeing halos (visual halos) or colored images along with red eyes\n\n" ], "text": "" }

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

{ "type": "p", "children": [], "text": "\nUsing only eye drops to treat these symptoms may not work. If you have these symptoms, stop taking tiotropium bromide inhalation powder and call your doctor right away." }

{ "type": "ul", "children": [ "\nNew or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: difficulty passing urine, painful urination." ], "text": "" }

If you have these symptoms of urinary retention, stop taking tiotropium bromide inhalation powder and call your doctor right away.

{ "type": "p", "children": [], "text": "\nIf you have these symptoms of urinary retention, stop taking tiotropium bromide inhalation powder and call your doctor right away." }

Other side effects with tiotropium bromide inhalation powder include:

{ "type": "p", "children": [], "text": "Other side effects with tiotropium bromide inhalation powder include: " }

{ "type": "ul", "children": [ "upper respiratory tract infection", "dry mouth", "sinus infection", "sore throat", "non-specific chest pain", "urinary tract infection", "indigestion", "runny nose", "constipation", "increased heart rate", "blurred vision" ], "text": "" }

These are not all the possible side effects with tiotropium bromide inhalation powder. Tell your doctor if you have any side effect that bothers you or that does not go away.

{ "type": "p", "children": [], "text": "\nThese are not all the possible side effects with tiotropium bromide inhalation powder. Tell your doctor if you have any side effect that bothers you or that does not go away." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How do I store tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nHow do I store tiotropium bromide inhalation powder?\n" }

{ "type": "ul", "children": [ "\nDo not store tiotropium bromide inhalation powder capsules in the LupinHaler device.\n", "Store tiotropium bromide inhalation powder capsules in the sealed blister package at room temperature between 68°F to 77°F (20°C to 25°C).", "Keep tiotropium bromide inhalation powder capsules away from heat and cold (do not freeze).", "Store tiotropium bromide inhalation powder capsules in a dry place. Throw away any unused tiotropium bromide inhalation powder capsules that have been open to air." ], "text": "" }

Ask your doctor or pharmacist if you have any questions about storing your tiotropium bromide inhalation powder capsules.

{ "type": "p", "children": [], "text": "\nAsk your doctor or pharmacist if you have any questions about storing your tiotropium bromide inhalation powder capsules." }

Keep LupinHaler, tiotropium bromide inhalation powder capsules, and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep LupinHaler, tiotropium bromide inhalation powder capsules, and all medicines out of the reach of children.\n" }

General information about tiotropium bromide inhalation powder

{ "type": "p", "children": [], "text": "\nGeneral information about tiotropium bromide inhalation powder\n" }

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use tiotropium bromide inhalation powder for a purpose for which it has not been prescribed. Do not give tiotropium bromide inhalation powder to other people even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use tiotropium bromide inhalation powder for a purpose for which it has not been prescribed. Do not give tiotropium bromide inhalation powder to other people even if they have the same symptoms that you have. It may harm them. " }

For more information about tiotropium bromide inhalation powder, talk with your doctor. You can ask your doctor or pharmacist for information about tiotropium bromide inhalation powder that is written for health professionals.

{ "type": "p", "children": [], "text": "For more information about tiotropium bromide inhalation powder, talk with your doctor. You can ask your doctor or pharmacist for information about tiotropium bromide inhalation powder that is written for health professionals. " }

For current prescribing information for tiotropium bromide inhalation powder, visit our website at www.lupin.com/US/lupinhaler/, or for additional information you may also call Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

{ "type": "p", "children": [], "text": "For current prescribing information for tiotropium bromide inhalation powder, visit our website at www.lupin.com/US/lupinhaler/, or for additional information you may also call Lupin Pharmaceuticals, Inc. at 1-800-399-2561." }

What are the ingredients in tiotropium bromide inhalation powder?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in tiotropium bromide inhalation powder?\n" }

Active ingredient: tiotropium

{ "type": "p", "children": [], "text": "Active ingredient: tiotropium " }

Inactive ingredient: lactose monohydrate

{ "type": "p", "children": [], "text": "Inactive ingredient: lactose monohydrate" }

What is COPD (Chronic Obstructive Pulmonary Disease)?

{ "type": "p", "children": [], "text": "\nWhat is COPD (Chronic Obstructive Pulmonary Disease)?\n" }

COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking. When you have COPD, your airways become narrow. So, air moves out of your lungs more slowly. This makes it hard to breathe.

{ "type": "p", "children": [], "text": "COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking. When you have COPD, your airways become narrow. So, air moves out of your lungs more slowly. This makes it hard to breathe." }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration." }

Instructions for Use

{ "type": "p", "children": [], "text": "\nInstructions for Use\n" }

Tiotropium Bromide (tye-oh-TROE-pee-um BROE-mide) Inhalation Powder LupinHaler®

{ "type": "p", "children": [], "text": "\nTiotropium Bromide (tye-oh-TROE-pee-um BROE-mide) Inhalation Powder LupinHaler®\n" }

Do NOT swallow Tiotropium Bromide Inhalation Powder Capsules.

{ "type": "p", "children": [], "text": "\nDo NOT swallow Tiotropium Bromide Inhalation Powder Capsules.\n" }

Important Information about using your tiotropium bromide inhalation powder LupinHaler

{ "type": "p", "children": [], "text": "\nImportant Information about using your tiotropium bromide inhalation powder LupinHaler \n" }

{ "type": "ul", "children": [ "\nDo not swallow tiotropium bromide inhalation powder capsules.\n", "\nTiotropium bromide inhalation powder capsules should only be used with the LupinHaler device and inhaled through your mouth (oral inhalation).\n", "\nDo not use your LupinHaler device to take any other medicine.\n" ], "text": "" }

First read the Patient Information, then read these Instructions for Use before you start to use tiotropium bromide inhalation powder LupinHaler and each time you refill your prescription. There may be new information.

{ "type": "p", "children": [], "text": "\nFirst read the Patient Information, then read these Instructions for Use before you start to use tiotropium bromide inhalation powder LupinHaler and each time you refill your prescription. There may be new information." }

Becoming familiar with your LupinHaler device and tiotropium bromide inhalation powder capsules:

{ "type": "p", "children": [], "text": "\nBecoming familiar with your LupinHaler device and tiotropium bromide inhalation powder capsules:\n" }

Your tiotropium bromide inhalation powder comes with tiotropium bromide inhalation powder capsules in blister packaging and a LupinHaler device. Use the new LupinHaler device provided with your medicine.

{ "type": "p", "children": [], "text": "Your tiotropium bromide inhalation powder comes with tiotropium bromide inhalation powder capsules in blister packaging and a LupinHaler device. Use the new LupinHaler device provided with your medicine." }

The parts of your LupinHaler device include:

{ "type": "p", "children": [], "text": "\nThe parts of your LupinHaler device include:\n" }

(See Figure A)

{ "type": "p", "children": [], "text": "(See Figure A)" }

{ "type": "", "children": [], "text": "" }

Each tiotropium bromide inhalation powder capsule is packaged in a blister. (See Figure B)

{ "type": "p", "children": [], "text": "\nEach tiotropium bromide inhalation powder capsule is packaged in a blister. (See Figure B)" }

{ "type": "ul", "children": [ "Each tiotropium bromide inhalation powder capsule contains only a small amount of powder. (See Figure C) This is 1 full dose.", "\nDo not open the tiotropium bromide inhalation powder capsule or it may not work." ], "text": "" }

Taking your full daily dose of medicine requires 4 main steps.

{ "type": "p", "children": [], "text": "\nTaking your full daily dose of medicine requires 4 main steps. \n" }

Step 1. Opening your LupinHaler device:

{ "type": "p", "children": [], "text": "\nStep 1. Opening your LupinHaler device:\n" }

After removing your LupinHaler device from the pouch:

{ "type": "p", "children": [], "text": "After removing your LupinHaler device from the pouch:" }

{ "type": "ul", "children": [ "Open the dust cap (lid) by pressing the green piercing button. (See Figure D)" ], "text": "" }

{ "type": "ul", "children": [ "Pull the dust cap (lid) upwards away from the base to expose the mouthpiece. (See Figure E)" ], "text": "" }

{ "type": "ul", "children": [ "Open the mouthpiece by pulling the mouthpiece ridge up from the base so the center chamber is showing. (See Figure F)" ], "text": "" }

Step 2. Inserting the tiotropium bromide inhalation powder capsule into your LupinHaler device:

{ "type": "p", "children": [], "text": "\nStep 2. Inserting the tiotropium bromide inhalation powder capsule into your LupinHaler device:\n" }

Each day, separate only 1 of the blisters from the blister card by tearing along the perforated line. (See Figure G)

{ "type": "p", "children": [], "text": "Each day, separate only 1 of the blisters from the blister card by tearing along the perforated line. (See Figure G)" }

Remove the tiotropium bromide inhalation powder capsule from the blister:

{ "type": "p", "children": [], "text": "\nRemove the tiotropium bromide inhalation powder capsule from the blister:\n" }

{ "type": "ul", "children": [ "\nDo not cut the foil or use sharp instruments to take out the tiotropium bromide inhalation powder capsule from the blister.", "Bend 1 of the blister corners with an arrow and separate the aluminum foil layers.", "Peel back the printed foil until you see the whole tiotropium bromide inhalation powder capsule. (See Figure H)", "If you have opened more than 1 blister to the air, the extra tiotropium bromide inhalation powder capsule should not be used and should be thrown away." ], "text": "" }

Place the tiotropium bromide inhalation powder capsule in the center chamber of your LupinHaler device. (See Figure I)

{ "type": "p", "children": [], "text": "\nPlace the tiotropium bromide inhalation powder capsule in the center chamber of your LupinHaler device. (See Figure I)" }

Close the mouthpiece firmly against the white base until you hear a click. Leave the dust cap (lid) open. (See Figure J)

{ "type": "p", "children": [], "text": "\nClose the mouthpiece firmly against the white base until you hear a click. Leave the dust cap (lid) open. (See Figure J) " }

Step 3. Piercing the tiotropium bromide inhalation powder capsule:

{ "type": "p", "children": [], "text": "\nStep 3. Piercing the tiotropium bromide inhalation powder capsule:\n" }

{ "type": "ul", "children": [ "Hold your LupinHaler device with the mouthpiece pointed up. (See Figure K)", "Press the green piercing button once until it is flat (flush) against the base, then release. This is how you make holes in the tiotropium bromide inhalation powder capsule so that you get your medicine when you breathe in.", "\nDo not press the green button more than one time.", "\nDo not shake your LupinHaler device.", "The piercing of the tiotropium bromide inhalation powder capsule may produce small pieces of the capsule. Some of these small pieces may pass through the screen of your LupinHaler device into your mouth or throat when you breathe in your medicine. This is normal.The small pieces of the capsule should not harm you." ], "text": "" }

Step 4. Taking your full daily dose (2 inhalations from the same tiotropium bromide inhalation powder capsule):

{ "type": "p", "children": [], "text": "\nStep 4. Taking your full daily dose (2 inhalations from the same tiotropium bromide inhalation powder capsule):\n" }

Breathe out completely in 1 breath, emptying your lungs of any air. (See Figure L)

{ "type": "p", "children": [], "text": "\nBreathe out completely in 1 breath, emptying your lungs of any air. (See Figure L)" }

Important: Do not breathe into your LupinHaler device.

{ "type": "p", "children": [], "text": "\nImportant: Do not breathe into your LupinHaler device." }

With your next breath, take your medicine:

{ "type": "p", "children": [], "text": "\nWith your next breath, take your medicine:\n" }

{ "type": "ul", "children": [ "\nHold your head in an upright position while you are looking straight ahead. (See Figure M)", "Raise your LupinHaler device to your mouth in a horizontal position. Do not block the air intake vents.", "Close your lips tightly around the mouthpiece.Breathe in deeply until your lungs are full. You should hear or feel the tiotropium bromide inhalation powder capsule vibrate (rattle). (See Figure M)", "Hold your breath for a few seconds and, at the same time, take your LupinHaler device out of your mouth.", "Breathe normally again." ], "text": "" }

The rattle tells you that you breathed in correctly. If you do not hear or feel a rattle, see the section, "If you do not hear or feel the tiotropium bromide inhalation powder capsule rattle as you breathe in your medicine."

{ "type": "p", "children": [], "text": "\nThe rattle tells you that you breathed in correctly. If you do not hear or feel a rattle, see the section, \"If you do not hear or feel the tiotropium bromide inhalation powder capsule rattle as you breathe in your medicine.\"" }

To get your full daily dose, you must again, breathe out completely (See Figure N) and for a second time, breathe in (See Figure O) from the same tiotropium bromide inhalation powder capsule.

{ "type": "p", "children": [], "text": "\nTo get your full daily dose, you must again, breathe out completely (See Figure N) and for a second time, breathe in (See Figure O) from the same tiotropium bromide inhalation powder capsule.\n" }

Important: Do not press the green piercing button again.

{ "type": "p", "children": [], "text": "\nImportant: Do not press the green piercing button again." }

Remember: To get your full medicine dose each day, you must breathe in 2 times from the same tiotropium bromide inhalation powder capsule. Make sure you breathe out completely each time before you breathe in from your LupinHaler device.

{ "type": "p", "children": [], "text": "\nRemember: To get your full medicine dose each day, you must breathe in 2 times from the same tiotropium bromide inhalation powder capsule. Make sure you breathe out completely each time before you breathe in from your LupinHaler device." }

Caring for and storing your tiotropium bromide inhalation powder LupinHaler:

{ "type": "p", "children": [], "text": "\nCaring for and storing your tiotropium bromide inhalation powder LupinHaler:\n" }

{ "type": "ul", "children": [ "After taking your daily dose, open the mouthpiece and tip out the used tiotropium bromide inhalation powder capsule into your trash can, without touching it.", "Remove any tiotropium bromide inhalation powder capsule pieces or tiotropium bromide inhalation powder buildup by turning your LupinHaler device upside down and gently, but firmly, tapping it. (See Figure P) Then, close the mouthpiece and dustcap for storage.", "\nDo not store your LupinHaler device and tiotropium bromide inhalation powder capsules (blisters) in a damp moist place. Always store tiotropium bromide inhalation powder capsules in the sealed blisters." ], "text": "" }

If you do not hear or feel the tiotropium bromide inhalation powder capsule rattle as you breathe in your medicine: 

{ "type": "p", "children": [], "text": "\nIf you do not hear or feel the tiotropium bromide inhalation powder capsule rattle as you breathe in your medicine: \n" }

Do not press the green piercing button again.

{ "type": "p", "children": [], "text": "\nDo not press the green piercing button again." }

Hold your LupinHaler device with the mouthpiece pointed up and tap your LupinHaler device gently on a table. (See Figure Q)

{ "type": "p", "children": [], "text": "Hold your LupinHaler device with the mouthpiece pointed up and tap your LupinHaler device gently on a table. (See Figure Q)" }

Check to see that the mouthpiece is completely closed. Breathe out completely before deeply breathing in again with the mouthpiece in your mouth. (See Figure O)

{ "type": "p", "children": [], "text": "\nCheck to see that the mouthpiece is completely closed. Breathe out completely before deeply breathing in again with the mouthpiece in your mouth. (See Figure O)" }

If you still do not hear or feel the tiotropium bromide inhalation powder capsule rattle after repeating the above steps:

{ "type": "p", "children": [], "text": "If you still do not hear or feel the tiotropium bromide inhalation powder capsule rattle after repeating the above steps:" }

{ "type": "ul", "children": [ "Throw away the tiotropium bromide inhalation powder capsule.", "Open the base by lifting the green piercing button and check the center chamber for pieces of the tiotropium bromide inhalation powder capsule. Tiotropium bromide inhalation powder capsule pieces in the center chamber can cause a tiotropium bromide inhalation powder capsule not to rattle.", "Turn your LupinHaler device upside down and gently, but firmly, tap to remove the tiotropium bromide inhalation powder capsule pieces. Call your doctor for instructions." ], "text": "" }

Cleaning your LupinHaler device:

{ "type": "p", "children": [], "text": "\nCleaning your LupinHaler device:\n" }

Clean your LupinHaler device as needed. (See Figure R)

{ "type": "p", "children": [], "text": "Clean your LupinHaler device as needed. (See Figure R)" }

{ "type": "ul", "children": [ "\nIt takes 24 hours to air dry your LupinHaler device after you clean it.", "\nDo not use cleaning agents or detergents.", "\nDo not place your LupinHaler device in the dishwasher for cleaning." ], "text": "" }

Cleaning Steps:

{ "type": "p", "children": [], "text": "\nCleaning Steps:" }

{ "type": "ul", "children": [ "Open the dust cap and mouthpiece", "Open the base by lifting the green piercing button.", "Look in the center chamber for tiotropium bromide inhalation powder capsule pieces or powder buildup. If seen, tap out.", "Rinse your LupinHaler device with warm water, pressing the green piercing button a few times so that the center chamber and the piercing needle is under the running water. Check that any powder buildup or tiotropium bromide inhalation powder capsule pieces are removed.", "Dry your LupinHaler device well by tipping the excess water out on a paper towel. Air-dry afterwards, leaving the dust cap, mouthpiece, and base open by fully spreading it out so that it dries completely.", "\nDo not use a hair dryer to dry your LupinHaler device.", "\nDo not use your LupinHaler device when it is wet. If needed, you may clean the outside of the mouthpiece with a clean damp cloth." ], "text": "" }

Helpful Hints to help ensure that you are properly taking your full daily dose of tiotropium bromide inhalation powder LupinHaler:

{ "type": "p", "children": [], "text": "\nHelpful Hints to help ensure that you are properly taking your full daily dose of tiotropium bromide inhalation powder LupinHaler:" }

{ "type": "ul", "children": [ "\nPress the green piercing button 1 time; Breathe in 2 times; Breathe out completely before each of the 2 inhalations.", "Always use the new LupinHaler device provided with your medicine.", "Keep your LupinHaler device with the mouthpiece pointed up when pressing the green piercing button.", "\nPress the green piercing button 1 time to pierce the tiotropium bromide inhalation powder capsule.", "Do not breathe out into your LupinHaler device.", "Keep your LupinHaler device in a horizontal position and keep your head upright, looking straight ahead, when breathing in.", "Check the center chamber of your LupinHaler device for tiotropium bromide inhalation powder capsule pieces or powder build-up. If pieces or powder are seen, tap out before use.", "Clean your LupinHaler as needed and dry thoroughly." ], "text": "" }

For current prescribing information for tiotropium bromide inhalation powder, visit our website at www.lupin.com/US/lupinhaler/, or for additional information you may also call Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

{ "type": "p", "children": [], "text": "\nFor current prescribing information for tiotropium bromide inhalation powder, visit our website at www.lupin.com/US/lupinhaler/, or for additional information you may also call Lupin Pharmaceuticals, Inc. at 1-800-399-2561." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration. " }

LupinHaler® is a registered trademark of Lupin Limited.

{ "type": "p", "children": [], "text": "\nLupinHaler® is a registered trademark of Lupin Limited." }

®The other brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.

{ "type": "p", "children": [], "text": "\n®The other brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products." }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for: " }

Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nLupin Pharmaceuticals, Inc. \n" }

Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108 " }

United States

{ "type": "p", "children": [], "text": "United States" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Lupin Limited

{ "type": "p", "children": [], "text": "\nLupin Limited\n" }

Pithampur (M.P.) - 454 775

{ "type": "p", "children": [], "text": "Pithampur (M.P.) - 454 775" }

India

{ "type": "p", "children": [], "text": "India" }

May 2025                                                                                  ID#:278818        

{ "type": "p", "children": [], "text": "May 2025                                                                                  ID#:278818         " }

Tiotropium Bromide Inhalation Powder Capsules

{ "type": "p", "children": [], "text": "\nTiotropium Bromide Inhalation Powder Capsules" }

Unit-dose blister card containing 10 capsules

{ "type": "p", "children": [], "text": "Unit-dose blister card containing 10 capsules" }

NDC 68180-964-11

{ "type": "p", "children": [], "text": "NDC 68180-964-11" }

{ "type": "", "children": [], "text": "" }

Tiotropium Bromide Inhalation Powder Capsules

{ "type": "p", "children": [], "text": "\nTiotropium Bromide Inhalation Powder Capsules" }

Carton containing 30 Capsules (3 unit-dose blister cards)

{ "type": "p", "children": [], "text": "Carton containing 30 Capsules (3 unit-dose blister cards)" }

NDC 68180-964-12

{ "type": "p", "children": [], "text": "NDC 68180-964-12" }

{ "type": "", "children": [], "text": "" }