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 C 19 H 22 NO 4 S 2 Br ∙ H 2 O. 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 . Chemical Structure

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 The long-term, once-daily, maintenance treatment of asthma in patients 6 years of age and older Limitation of Use: Not indicated for relief of acute bronchospasm ( 1.1 , 1.2 , 5.1 ) 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease SPIRIVA RESPIMAT (tiotropium bromide) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA RESPIMAT is indicated to reduce exacerbations in COPD patients. Important Limitation of Use: SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm

Maintenance Treatment of Asthma SPIRIVA RESPIMAT is a bronchodilator indicated for the long-term, once-daily, maintenance treatment of asthma in patients 6 years of age and older . Important Limitation of Use: SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm.

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). Inhalation spray: 1.25 mcg or 2.5 mcg tiotropium (equivalent to 1.562 mcg or 3.124 mcg, respectively, of tiotropium bromide monohydrate) per actuation with the SPIRIVA RESPIMAT inhaler. Two actuations equal one dose (2.5 mcg or 5 mcg).

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 . For oral inhalation only. To receive the full dose of medication, SPIRIVA RESPIMAT must be administered as two inhalations once-daily. Treatment of COPD: 2 inhalations of SPIRIVA RESPIMAT 2.5 mcg once-daily. Treatment of asthma patients 6 years and older: 2 inhalations of SPIRIVA RESPIMAT 1.25 mcg once-daily

Chronic Obstructive Pulmonary Disease 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

Asthma 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

Special Populations 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 .

Not for acute use, i.e., not a rescue medication. Immediate hypersensitivity reactions: Discontinue SPIRIVA RESPIMAT at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, urticaria, rash, bronchospasm, or anaphylaxis, occur. Paradoxical bronchospasm: Discontinue SPIRIVA RESPIMAT and consider other treatments if paradoxical bronchospasm occurs. 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. 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. 5.1 Not for Acute Use 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 beta 2 -agonist should be used

Immediate Hypersensitivity 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

Paradoxical Bronchospasm Inhaled medicines, including SPIRIVA RESPIMAT, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta 2 -agonist such as albuterol. Treatment with SPIRIVA RESPIMAT should be stopped and other treatments considered

Worsening of Narrow-Angle Glaucoma 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

Worsening of Urinary Retention 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

Renal Impairment 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 .

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

Concomitant Respiratory Medications 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

Anticholinergics 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 .