Spiriva Respimat

Important Limitation of Use:

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

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.

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)].

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.

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.

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[3.3.1.0^2,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol.

The structural formula is:

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

The drug product, SPIRIVA RESPIMAT, is composed of a sterile, aqueous solution of tiotropium bromide filled into a 4.5 mL plastic container crimped into an aluminum cylinder (SPIRIVA RESPIMAT cartridge) for use with the SPIRIVA RESPIMAT inhaler. Excipients include 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).

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)].

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)].

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.

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)].

The following adverse reactions are described, or described in greater detail, in other sections:

• Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Paradoxical bronchospasm [see Warnings and Precautions (5.3)]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)]
• Worsening of urinary retention [see Warnings and Precautions (5.5)]

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.

Since the same active ingredient (tiotropium bromide) is administered to COPD and asthma patients, prescribers and patients should take into account that the observed adverse reactions could be relevant for both patient populations independent of dosage strength.

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SPIRIVA RESPIMAT with other anticholinergic-containing drugs. (7.2)

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)].

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)].

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)].

SPIRIVA^® RESPIMAT^® (speh REE vah - RES peh mat)

(tiotropium bromide inhalation spray), for oral inhalation use

For oral inhalation only

Do not spray SPIRIVA RESPIMAT into your eyes.

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.

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.

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.

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

Do not turn the clear base before inserting the cartridge.

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.

How to store your SPIRIVA RESPIMAT inhaler

• Store SPIRIVA RESPIMAT at room temperature between 68°F to 77°F (20°C to 25°C).
• Do 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.
• Keep your SPIRIVA RESPIMAT cartridge, inhaler, and all medicines out of the reach of children.

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.

When to get a new SPIRIVA RESPIMAT inhaler

• 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.

• 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.

Prepare for first use

Daily use (T O P)

Answers to Common Questions

It is difficult to insert the cartridge deep enough:

Did 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.

I cannot press the dose-release button:

Did 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.

I cannot turn the clear base:

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.

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.

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

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

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.

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.

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

My SPIRIVA RESPIMAT sprays automatically:

Was 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.

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).

My SPIRIVA RESPIMAT does not spray:

Did 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".

Is 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.

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

Licensed from:

Boehringer Ingelheim International GmbH

SPIRIVA^® 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

Revised: January 2025

COL10534BA022025

SPL10536D

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.

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.

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

SPIRIVA RESPIMAT is an anticholinergic indicated for:

• The long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations (1.1)
• The long-term, once-daily, maintenance treatment of asthma in patients 6 years of age and older (1.2)

Limitation of Use:

• Not indicated for relief of acute bronchospasm (1.1, 1.2, 5.1)

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)].

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.

• Not for acute use, i.e., not a rescue medication. (5.1)
• Immediate hypersensitivity reactions: Discontinue SPIRIVA RESPIMAT at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, urticaria, rash, bronchospasm, or anaphylaxis, occur. (5.2)
• Paradoxical bronchospasm: Discontinue SPIRIVA RESPIMAT and consider other treatments if paradoxical bronchospasm occurs. (5.3)
• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.4)
• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patient to consult a physician immediately if this occurs. (5.5)

To receive the full dosage of medication, SPIRIVA RESPIMAT must be administered as two inhalations once-daily. Do not take more than one dose (2 inhalations) in 24 hours.

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)].

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).

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.

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.

• Glaucoma, intraocular pressure increased, vision blurred,
• Atrial fibrillation, tachycardia, supraventricular tachycardia,
• Bronchospasm,
• Glossitis, stomatitis,
• Dehydration,
• Insomnia,
• Hypersensitivity (including immediate reactions), and urticaria.

Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects. (2, 8.6)

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

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.

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

SPIRIVA RESPIMAT Inhalation Spray is supplied in a carton containing one SPIRIVA RESPIMAT cartridge and one SPIRIVA RESPIMAT inhaler.

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

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

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

To deliver the recommended dosage for COPD:

To deliver the recommended dosage for asthma:

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

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

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

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

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 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.

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.

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 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).

NDC 0597-0100-61

Spiriva^® Respimat^®

(tiotropium bromide inhalation spray)

2.5 mcg/actuation*

FOR ORAL INHALATION ONLY

ATTENTION PHARMACIST:

Dispense with Instructions for Use

Rx only

4 Grams

60 Metered Inhalations

(Two inhalations equal one dose)

Boehringer

Ingelheim

NDC 0597-0160-61

Spiriva^® Respimat^®

(tiotropium bromide inhalation spray)

1.25 mcg/actuation*

FOR ORAL INHALATION ONLY

ATTENTION PHARMACIST:

Dispense with Instructions for Use

Rx only

4 Grams

60 Metered Inhalations

(Two inhalations equal one dose)

Boehringer

Ingelheim

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).

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.

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.

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.

Important Limitation of Use:

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

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.

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)].

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.

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.

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[3.3.1.0^2,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol.

The structural formula is:

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

The drug product, SPIRIVA RESPIMAT, is composed of a sterile, aqueous solution of tiotropium bromide filled into a 4.5 mL plastic container crimped into an aluminum cylinder (SPIRIVA RESPIMAT cartridge) for use with the SPIRIVA RESPIMAT inhaler. Excipients include 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).

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)].

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)].

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.

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)].

The following adverse reactions are described, or described in greater detail, in other sections:

• Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Paradoxical bronchospasm [see Warnings and Precautions (5.3)]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)]
• Worsening of urinary retention [see Warnings and Precautions (5.5)]

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.

Since the same active ingredient (tiotropium bromide) is administered to COPD and asthma patients, prescribers and patients should take into account that the observed adverse reactions could be relevant for both patient populations independent of dosage strength.

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SPIRIVA RESPIMAT with other anticholinergic-containing drugs. (7.2)

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)].

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)].

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)].

SPIRIVA^® RESPIMAT^® (speh REE vah - RES peh mat)

(tiotropium bromide inhalation spray), for oral inhalation use

For oral inhalation only

Do not spray SPIRIVA RESPIMAT into your eyes.

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.

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.

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.

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

Do not turn the clear base before inserting the cartridge.

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.

How to store your SPIRIVA RESPIMAT inhaler

• Store SPIRIVA RESPIMAT at room temperature between 68°F to 77°F (20°C to 25°C).
• Do 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.
• Keep your SPIRIVA RESPIMAT cartridge, inhaler, and all medicines out of the reach of children.

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.

When to get a new SPIRIVA RESPIMAT inhaler

• 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.

• 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.

Prepare for first use

Daily use (T O P)

Answers to Common Questions

It is difficult to insert the cartridge deep enough:

Did 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.

I cannot press the dose-release button:

Did 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.

I cannot turn the clear base:

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.

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.

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

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

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.

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.

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

My SPIRIVA RESPIMAT sprays automatically:

Was 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.

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).

My SPIRIVA RESPIMAT does not spray:

Did 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".

Is 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.

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

Licensed from:

Boehringer Ingelheim International GmbH

SPIRIVA^® 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

Revised: January 2025

COL10534BA022025

SPL10536D

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.

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.

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

SPIRIVA RESPIMAT is an anticholinergic indicated for:

• The long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations (1.1)
• The long-term, once-daily, maintenance treatment of asthma in patients 6 years of age and older (1.2)

Limitation of Use:

• Not indicated for relief of acute bronchospasm (1.1, 1.2, 5.1)

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)].

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.

• Not for acute use, i.e., not a rescue medication. (5.1)
• Immediate hypersensitivity reactions: Discontinue SPIRIVA RESPIMAT at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, urticaria, rash, bronchospasm, or anaphylaxis, occur. (5.2)
• Paradoxical bronchospasm: Discontinue SPIRIVA RESPIMAT and consider other treatments if paradoxical bronchospasm occurs. (5.3)
• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.4)
• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patient to consult a physician immediately if this occurs. (5.5)

To receive the full dosage of medication, SPIRIVA RESPIMAT must be administered as two inhalations once-daily. Do not take more than one dose (2 inhalations) in 24 hours.

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)].

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).

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.

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.

• Glaucoma, intraocular pressure increased, vision blurred,
• Atrial fibrillation, tachycardia, supraventricular tachycardia,
• Bronchospasm,
• Glossitis, stomatitis,
• Dehydration,
• Insomnia,
• Hypersensitivity (including immediate reactions), and urticaria.

Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects. (2, 8.6)

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

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.

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

SPIRIVA RESPIMAT Inhalation Spray is supplied in a carton containing one SPIRIVA RESPIMAT cartridge and one SPIRIVA RESPIMAT inhaler.

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

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

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

To deliver the recommended dosage for COPD:

To deliver the recommended dosage for asthma:

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

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

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

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

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 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.

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.

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 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).

NDC 0597-0100-61

Spiriva^® Respimat^®

(tiotropium bromide inhalation spray)

2.5 mcg/actuation*

FOR ORAL INHALATION ONLY

ATTENTION PHARMACIST:

Dispense with Instructions for Use

Rx only

4 Grams

60 Metered Inhalations

(Two inhalations equal one dose)

Boehringer

Ingelheim

NDC 0597-0160-61

Spiriva^® Respimat^®

(tiotropium bromide inhalation spray)

1.25 mcg/actuation*

FOR ORAL INHALATION ONLY

ATTENTION PHARMACIST:

Dispense with Instructions for Use

Rx only

4 Grams

60 Metered Inhalations

(Two inhalations equal one dose)

Boehringer

Ingelheim

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).

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.

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.

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.