PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 17 DOSAGE AND ADMINISTRATION 17 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY 23 SPECIAL HANDLING INSTRUCTIONS 24 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 25

PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 26 DETAILED PHARMACOLOGY 31 TOXICOLOGY 34 REFERENCES 36

PART III: CONSUMER INFORMATION. 37

Pr (r)

SPIRIVA

Tiotropium Bromide Monohydrate Capsules for Oral Inhalation Capsules to be used only with the supplied Handihaler(r) inhalation device 18 ug tiotropium per capsule Bronchodilator

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

SPIRIVA (tiotropium bromide monohydrate) is contraindicated in: patients with a history of hypersensitivity to atropine or its derivatives (e.g. ipratropium or oxitropium), or to the excipient lactose monohydrate (see PHARMACEUTICAL INFORMATION - COMPOSITION).

WARNINGS AND PRECAUTIONS

General

SPIRIVA (tiotropium bromide monohydrate) should not be used more frequently than once daily. SPIRIVA, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy. Immediate hypersensitivity reactions such as skin rash, urticaria, angioedema of the lip, tongue and face, bronchospasm, and oropharyngeal edema may occur after adminsitration of SPIRIVA. As with other anticholinergic drugs, SPIRIVA should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery. This product contains 5.5 mg of lactose monohydrate per capsule.

Carcinogenesis and Mutagenesis

Animal data only. (See TOXICOLOGY section.)

Ophthalmologic

Patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these symptoms develop, they should consult a doctor immediately. Miotic drops alone are not considered to be effective treatment.

Renal

As plasma concentration increases with decreased renal function in patients with moderately to severe renal impairment (creatinine clearance # 50 mL/min), SPIRIVA should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment (see PHARMACOKINETICS).

Respiratory

Inhaled medicines may cause inhalation-induced bronchospasm. If this occurs, treatment with SPIRIVA should be discontinued immediately.

Special Populations

Pregnant Women:

There are no studies of SPIRIVA in pregnant women. Because animal reproduction studies are not always predictive of human response, SPIRIVA should be used during pregnancy only if the benefits outweigh any possible risk to the unborn child.

Oral reproduction studies with tiotropium were performed at doses up to 500 mg/kg in rats and 100 mg/kg in rabbits. These doses correspond, in each species, to about 215,000 and 86,000 times the Maximum Recommended Human Dose (MRHD) respectively, on a mg/m2 basis. Inhalation reproduction studies with tiotropium were conducted in rats and rabbits at doses of 2.0 and 0.5 mg/kg/day (about 860 and 430 times the MRHD on a mg/m2 basis). These studies demonstrated no evidence of teratogenic effects as a result of tiotropium administration.

Labour and Delivery:

The safety and effectiveness of SPIRIVA have not been studied during labor and delivery.

Nursing Women:

Based on lactating rodent studies, a small amount of tiotropium (1.9%) is excreted in milk over two days. Clinical data from nursing women exposed to SPIRIVA are not available. SPIRIVA should not be used in nursing women unless the expected benefit outweighs any possible risk to the infant.

Pediatrics

(< 18 years of age): Safety and effectiveness of SPIRIVA in patients less than 18 years of age were not studied.

DRUG INTERACTIONS

Overview

Although no formal drug interaction studies have been performed, SPIRIVA has been used concomitantly with other drugs without additional adverse drug reactions. These include sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids commonly used in the treatment of COPD. The co-administration of SPIRIVA with other anticholinergic containing drugs has not been studied and is, therefore, not recommended. Tiotropium does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 even in supratherapeutic concentrations of 1 uMol/L (= 0.4 ug/mL), which makes clinically relevant metabolic interactions by tiotropium extremely unlikely.

Drug-Drug Interactions

Interactions with drugs administered concomitantly with tiotropium are not expected due to the low dose and low steady state plasma concentration of tiotropium (18 ug, Css 2 - 20 pg/mL) and the lack of cytochrome P450 inhibition by tiotropium. Similarly, effects of concomitantly administered drugs on tiotropium metabolism are not expected due to the minor contribution of enzymatic metabolism of tiotropium.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• Counselling by doctors on smoking cessation should be the first step in treating patients with COPD, who smoke, independent of the clinical presentation i.e. chronic bronchitis

(with or without airflow limitation) or emphysema. Cessation of smoking produces dramatic symptomatic benefits and has been shown to confer a survival advantage. Elderly patients, hepatically impaired patients, and renally impaired patients can use SPIRIVA at the recommended dose. However, as with all renally excreted drugs, SPIRIVA use should be monitored closely in patients with moderate to severe renal impairment. There is no experience with SPIRIVA in infants and children and therefore should not be used in the age group.

Recommended Dose and Dosage Adjustment

The recommended dosage of SPIRIVA (tiotropium bromide monohydrate) is inhalation of the contents of one capsule (18 ug) once daily. The capsule must not be swallowed.

Missed Dose

Patients should be advised that if they forget to take a dose, they should take one as soon as they remember but do not take two doses at the same time or on the same day. Then take the next dose as usual. Patients should be advised that if they take more SPIRIVA 18 microgram than they should - talk to their doctor immediately.

Administration

SPIRIVA should be administered once daily, at the same time of day, by inhalation only through the HandiHaler inhalation device. To ensure proper administration of SPIRIVA, the doctor or other qualified health care professional should teach the patient how to operate the HandiHaler inhalation device (see Part III CONSUMER INFORMATION).

OVERDOSAGE

Acute intoxication by inadvertent oral ingestion of SPIRIVA (tiotropium bromide monohydrate) capsules is unlikely since the drug has a low oral bioavailability. Should signs of serious anticholinergic toxicity appear, vital signs should be carefully monitored and appropriate therapy should be initiated. There were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 ug tiotropium in healthy volunteers. Additionally, no relevant adverse effects, beyond bilateral conjunctivitis and dry mouth were observed following 7 day dosing with up to 141 ug tiotropium/day in healthy volunteers, (which resolved while still under treatment). In a multiple dose study in COPD patients with a maximum daily dose of 36 ug tiotropium over four weeks, dry mouth was the only observed adverse event attributable to tiotropium.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

SPIRIVA (tiotropium bromide monohydrate) is a long acting, muscarinic receptor antagonist that is used as a once-daily inhaled bronchodilator for the treatment of bronchospasm associated with Chronic Obstructive Pulmonary Disease (COPD). SPIRIVA is a quaternary ammonium molecule with a duration of action sufficient to provide 24 hours of bronchoprotection with once- a-day inhalational administration. In vitro studies using recombinant human receptors as well as animal and human tissue preparations, showed that tiotropium is a potent, reversible, M3- selective muscarinic receptor antagonist, with no other receptor interactions detected at clinically relevant concentrations. Muscarinic acetylcholine receptors are widely distributed throughout the body and serve a variety of important functions. Stimulation of muscarinic receptors in response to the activation of the parasympathetic nervous system is the dominant neural bronchoconstrictor pathway in all mammals, including humans. In fact, the reversal of chronic obstructive disease with antimuscarinic agents is a well established therapeutic approach. There are five subtypes (M1-M5) of muscarinic receptors which exhibit distinct pharmacology and tissue distribution. M3 receptors predominate in visceral smooth muscles and typically mediate the direct contractile effects of acetylcholine. In addition, M3, as well as M1 receptors, are also found in the central nervous system and autonomic ganglia. M2 receptors predominate in the heart and mediate the bradycardic effects of acetylcholine. They are also found on parasympathetic nerve terminals where their activation inhibits the release of acetylcholine. The physiological roles of M4 and M5 receptors are still uncertain. The long duration of action of tiotropium is thought to be due to its high affinity to, and slow dissociation kinetics from, the muscarinic M3-receptor subtype. Tiotropium has a higher affinity for human muscarinic 3 (hM3)-receptors (KD value: 8.89 pmol/L) than for hM2-receptors (KD value: 31.96 pmol/L). In addition, and most importantly, tiotropium dissociates very slowly from hM3-receptors. Dissociation half-lives of the receptor-ligand complex are 27.1 hours for hM3-receptors and 3.6 hours for hM2-receptors. For comparison, dissociation half-lives of ipratropium are 0.22 and 0.04 hours for hM3- and hM2-receptors, respectively. As an N- quaternary anticholinergic, tiotropium is broncho-selective when administered by inhalation, demonstrating an acceptable therapeutic range before giving rise to systemic anticholinergic effects.

Pharmacodynamics

The clinical pharmacology studies confirmed the intended pharmacodynamic effect of bronchodilation in subjects with COPD. The bronchodilation following inhalation of tiotropium is primarily a site-specific effect, rather than a systemic effect. Trough forced expiratory volume in one second (FEV1), 24 hours after a previous dose, (i.e. prior to subsequent dosing) remained significantly increased over baseline relative to placebo; the majority of the maintenance bronchodilation was achieved within a few days of treatment. Pharmacodynamic steady state was attained within the first week of once-daily dosing. Repeated inhalation of SPIRIVA has not been linked with tolerance towards bronchodilatory effects of the drug. Bronchodilatory effects gradually returned to baseline levels upon cessation of treatment with no evidence of rebound. Multiple dose studies supported the once daily dosing regimen for tiotropium administered by inhalation of a dry powder formulation. Studies with supratherapeutic doses have confirmed that reduced salivation is among the most sensitive effects. This clinical physiologic effect is mirrored by reports of dry mouth. The clinical development program included four one-year and two six-month randomized, double-blind studies in 2663 patients, 1308 receiving SPIRIVA. The one-year program consisted of two placebo-controlled and two ipratropium-controlled trials. The six-month trials were salmeterol and placebo-controlled. All studies included measurements of lung function as well as health outcome measures of dyspnea, exacerbations and health-related quality of life. SPIRIVA administered once daily provided significant improvement in lung function (forced expiratory volume in one second, FEV1; and forced vital capacity, FVC) within 30 minutes following the first dose and was maintained for 24 hours whether SPIRIVA was administered in the morning or in the evening. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. The bronchodilator effects of SPIRIVA were maintained throughout the one-year period of administration with no evidence of tolerance.

Pharmacokinetics

Absorption:

The pharmacokinetic profile of SPIRIVA (tiotropium bromide monohydrate) supports that plasma concentrations are very low following inhalation of an 18 ug dose; although the terminal elimination half life is between 5 - 7 days, there is only moderate accumulation upon repeated once daily dosing.

Absorption and Bioavailability

For tiotropium, absolute bioavailability was most reliably estimated from the total urinary excretion values in healthy volunteers rather than plasma concentrations. The absolute oral bioavailability of tiotropium is 2 - 3% for a 64 ug dose. The low extent of absorption and low oral bioavailability is expected based on animal experiments with radiolabeled drug. The absolute bioavailability of tiotropium after an inhaled dose of 108 ug (three 36 ug inhalation capsules) is 19.5%. Low oral bioavailability is a definite advantage in limiting systemic absorption following obligate ingestion of a portion of an orally-inhaled drug.

Pharmacokinetics After Inhalation

After chronic, once-daily inhalation of tiotropium (18 ug) by COPD patients, pharmacokinetic steady state was reached after 2 - 3 weeks with no accumulation thereafter. Maximum steady state tiotropium plasma concentrations (17 - 19 pg/mL) were observed 5 minutes after inhalation and decreased to approximately 3 - 4 pg/mL at trough. At steady state, urinary excretion of unchanged tiotropium during the first 4 hours following administration accounted for 1.42% (88.7% gCV) and 1.97% (74.4% gCV) in older and younger patients, respectively.

Onset of Pharmacodynamic Steady State

Study results supported that pharmacodynamic steady state was attained within the first week of dosing; additionally, the multiple dose studies supported the once daily dosing regimen for tiotropium administered by inhalation of a dry powder formulation.

Distribution:

The absolute bioavailability of SPIRIVA after dry powder inhalation is 19.5% and is negligible after oral administration (2-3%). The apparent volume of distribution is 32 L/kg suggesting extensive tissue binding.

Tiotropium is moderately bound to human plasma proteins (72%). This binding is not of the restrictive type considering the high renal clearance of 669 mL/min.

Metabolism:

The drug is not metabolized to a great extent; the majority of the drug is excreted as the parent compound.

Tiotropium is predominantly eliminated via renal secretion of unchanged drug. Seventy-four percent of an intravenous dose was recovered in urine (Ae0-4) after intravenous infusion in healthy young male subjects. The indication of active renal secretion is based on a renal clearance of 669 mL/min after intravenous infusion and 486 mL/min after inhalation, while calculated creatinine clearance was 118 mL/min and 113 mL/min, respectively. The tiotropium ester was shown to be non-enzymatically cleaved and enzymatically metabolized in animals. In humans, a small part (up to 20%) might also be metabolized in the liver. Tiotropium does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 even in supratherapeutic concentrations of 1 uMol/L (= 0.4 ug/mL), which makes clinically relevant metabolic interactions by tiotropium extremely unlikely.

Excretion

Urinary data in healthy subjects demonstrate that tiotropium was excreted with a geometric mean elimination half-life of 5.7 days (3.2 - 7.3 days) after intravenous, and 4.8 days (3.6 - 6.2 days) after inhalation. The long elimination half-life indicates a slow redistribution process, and it is likely that the slow dissociation from muscarinic receptors contributes to the slow redistribution. Indication of active renal secretion is based on a renal clearance of 669 mL/min after intravenous infusion and 486 mL/min after inhalation, while calculated creatinine clearance was 118 mL/min and 113 mL/min, respectively. Urinary recovery was approximately 74% as unchanged substance. Total clearance was 880 mL/min.

Special Populations and Conditions

Pediatrics:

Pharmacokinetics in children were not investigated as tiotropium development is currently restricted to therapy for COPD in adults.

Geriatrics: As expected for all predominantly renally excreted drugs, advanced age ($ 65 years) was associated with a decrease of tiotropium renal clearance which may be explained by decreased renal function. Tiotropium excretion in urine after inhalation decreased from 14% in young healthy volunteers to about 7% in the older COPD patients. However, plasma concentrations did not change significantly with advancing age within COPD patients ($ 69 years vs. # 58 years) if compared to inter- and intra-individual variability (43% increase in AUC0-4 after dry powder inhalation). Consequently, geriatric patients can use tiotropium at the recommended dose. The high renal clearance of tiotropium suggests the possibility of a decreased renal elimination in the elderly ($ 69 years) as a result of decreased renal function with age. To investigate this, pharmacokinetic parameters were determined for different age groups. Although highly variable, the results suggested that tiotropium plasma concentrations were moderately increased in the elderly COPD patients for both C5min and C2hr. There is an age dependent decrease in the fraction of tiotropium excreted in the urine. Total urinary excretion decreases from about 14% in young healthy volunteers to about 7% in the older COPD patients, corresponding to decreased renal clearance with age from 326 mL/min to 163 mL/min, respectively. This decrease in tiotropium renal clearance with advanced age exceeded the change in creatinine clearance; creatinine clearance was approximately 113 mL/min in young healthy volunteers and 61 mL/min in elderly COPD patients. This suggested that the renal secretion of tiotropium was more sensitive to age than glomerular filtration.

Gender:

To assess potential sex-related effects on tiotropium pharmacokinetics, plasma and urine samples were collected from a subset of COPD patients at selected centres for assessment of tiotropium concentrations. Although there was a slight trend to higher plasma concentrations in females, it is considered that male and female COPD patients showed no significant differences in drug plasma concentrations or urinary excretion of tiotropium.

Hepatic Insufficiency:

Impaired liver function is not expected to have any clinically relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and by simple non-enzymatic ester cleavage to products that do not bind to muscarinic receptors.

Renal Insufficiency: In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with reduced renal drug clearance and increased plasma drug concentrations. Mild renal impairment (CLCR 50-80 mL/min) which is often seen in elderly patients did not lead to a clinically significant change in tiotropium pharmacokinetics. However, in COPD patients with moderate to severe renal impairment (CLCR < 50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations seen in patients with normal renal function (82% increase in AUC0-4h), which was confirmed by plasma concentrations after dry powder inhalation. In a study conducted to investigate the pharmacokinetics of tiotropium in patients with varying degrees of renal impairment in comparison to healthy volunteers, a single dose of tiotropium (4.8 ug) was administered as an intravenous infusion over 15 minutes. The results indicate that renal tiotropium clearance decreased with creatinine clearance. Tiotropium plasma concentrations (AUC0-4h) were 39, 81 and 94% higher in mild, moderate and severe renal impairment when compared to control subjects. SPIRIVA should be used in patients with moderate to severe renal impairment only if the expected benefit outweighs the potential risk.

STORAGE AND STABILITY

After opening a strip, the in-use shelf life of the remaining capsules in the strip is 5 days. If more than one capsule is exposed to air inadvertently, the exposed unused capsules must be discarded.

SPECIAL HANDLING INSTRUCTIONS

Temperature Store capsules and HandiHaler device between 15-25degC. Do not freeze. Moisture Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

SPIRIVA capsules, containing 18 ug tiotropium (equivalent to 22.5 ug tiotropium bromide monohydrate), are light green, with TI 01 printed on one side of the capsule and the Boehringer Ingelheim company logo on the other side. SPIRIVA capsules also contain lactose monohydrate as a "carrier". The dry powder within the capsule is intended for oral inhalation only. SPIRIVA capsules are partially filled but contain exact amount of medication as declared on the label. Ten SPIRIVA capsules are packaged in an aluminum / PVC / aluminum blister card. One blister card consists of two 5-cavity strips joined along a perforated line. The following pack types are available:

• Carton of 30 SPIRIVA capsules (3 blister cards) and one HandiHaler device.

• Carton of 10 SPIRIVA capsules (1 blister card) and one HandiHaler device.

Refill packs: Carton of 30 SPIRIVA capsules (3 blister cards)

INHALATION DEVICE

The HandiHaler inhalation device is a reusable plastic device used for the administration of SPIRIVA capsules. It is gray colored with "HandiHaler", "Boehringer Ingelheim", and the Boehringer Ingelheim company logo, printed on the front face. The HandiHaler operates with flow rates as low as 20 L/min. All patients, regardless of their disease severity, achieved sufficient flows through the HandiHaler. To use the delivery system, a SPIRIVA capsule is placed in the center chamber of the HandiHaler inhalation device and the capsule is pierced by pressing and releasing the green piercing button on the side of the device. The tiotropium formulation is dispersed into the air stream when the patient inhales slowly and deeply through the mouthpiece. The HandiHaler inhalation devices are available individually.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: tiotropium bromide monohydrate Chemical name: (1a,2b,4b,5a,7b)-7-[Hydroxydi-2-thienylacetyl)oxy]-9,9dimethyl-3- oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate Molecular formula and molecular mass: C19H22NO4S2Br * H2O Structural formula: Physicochemical properties: Description: white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. Polymorphism: three crystalline forms are possible, the monohydrate and two anhydrous forms Melting Point: between 225o C and 235o C pH (1% aqueous solution): 5.0 - 5.6 Apparent Partition Coefficient: log Papp = -2.28

CLINICAL TRIALS

Study demographics and trial design

The efficacy of SPIRIVA was evaluated in six (6) pivotal studies involving over 2600 COPD patients with moderate to severe airways obstruction. All studies were randomized, double- blind, (double-dummy-active control), controlled, parallel group studies which followed nearly identical protocols with identical patient inclusion and exclusion criteria. In all studies, tiotropium was administered as a once-daily inhaled dose of 18 ug via the HandiHaler inhalation device.

TABLE 7- SUMMARY OF PATIENT DEMOGRAPHICS FOR CLINICAL TRIALS IN SPECIFIC INDICATION

The main inclusion criteria were patients 40 years of age or older, diagnosis of relatively stable COPD with screening of FEV1 equal or smaller than 65% of predicted normal, and a history of smoking of 10-pack years or more. The main exclusion criterion was significant disease other than COPD which in the opinion of the investigator, precluded the patient's participation in this study. For all 6 pivotal clinical trials, the primary efficacy parameter was trough FEV1 as an index of bronchodilator efficacy, and TDI as a secondary variable as an index of dyspnea. The four one- year studies were designed and conducted to include TDI as a secondary efficacy variable. The protocols of the two six-month studies were amended to include TDI as a co-primary variable after the trials were completed, but before the blind was broken. In all studies, a single 18 ug dose of SPIRIVA provided significant improvement in pulmonary function (mean FEV1 increase of 11% or more) within 30 minutes following administration; the response reached a peak within 3 hours and was maintained for 24 hours. Following one year treatment, SPIRIVA induced a sustained increase (> 120 mL) over baseline in trough FEV1 (23 - 24 hrs post dose) with no evidence of tolerance. The difference in trough FEV1 at the end of one year with SPIRIVA was 150 mL (p < 0.001). In the two six-month studies, SPIRIVA performed consistently better than salmeterol in trough response over the 24 weeks of the study. The difference between SPIRIVA and salmeterol for trough response was not statistically significant in one of the six-month studies while in the other the difference was statistically significant. A similar pattern of response was observed for FVC over the six-month and one-year treatment periods. SPIRIVA improved morning and evening peak expiratory flow rate (PEFR) as measured by patients' daily recordings. In addition to improvement of lung function, improvement in dyspnea as measured by the Baseline and Transition Dyspnea Index occurred within the first 8 days of treatment and was sustained over the one-year treatment period. In both the one-year and six-month trials, the proportion of patients achieving a clinically meaningful response (TDI focal score >= 1 was considered to be clinically significant and such patients were considered responders) was 46.0% and 43.1% for SPIRIVA, and 28.6% and 29.8% for placebo, respectively. Improvement in disease-specific quality of life was assessed using the St. George's Respiratory Questionnaire. SPIRIVA improved health-related quality of life which was maintained over the treatment period. The time course of the effect of SPIRIVA was determined in a randomized, placebo-controlled 6-week clinical study that included spirometry measurements every 3 hours in 105 COPD patients. The studies demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether SPIRIVA was administered in the morning or in the evening. Use of SPIRIVA was associated with a reduced requirement for rescue bronchodilator medications. No age or sex-related differences in efficacy were observed.

Tiotropium vs. Placebo

FEV1 (liters)

Time Post-Treatment (hours)

Tiotropium vs. Ipratropium

1.55

1.50

1.45

FEV1 (liters)

1.40

1.35

1.30

1.25

Tiotropium - Day 1 Tiotropium - Day 364 Ipratropium - Day 1 Ipratropium - Day 364

1.20

1.15

1.10

-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0

Time Post-Treatment (hours)

FEV1 (liters)

Time Post-Treatment (hours)

Exercise Tolerance

TABLE 8- SUMMARY OF PATIENT DEMOGRAPHICS FOR CLINICAL TRIALS IN EXERCISE TOLERANCE PROGRAMME

Two multicentre, double-blind, placebo-controlled trials were conducted to evaluate the efficacy and safety of 6 weeks of treatment with SPIRIVA in 459 patients with COPD. The primary efficacy endpoint was submaximal exercise tolerance as measured by endurance time (ET) to symptom limitation during constant work rate cycle exercise at 75% of maximal work capacity on day 42 of the randomized treatment phase.

Study results

The results of these trials showed that SPIRIVA significantly improved symptom-limited exercise tolerance by 102 seconds (geometric mean ET compared with placebo adjusted for baseline , p=0.0012) in Trial 205.131, and 100 seconds (median ET change from baseline compared with placebo, p=0.0003) in Trial 205.223. The increased endurance time was associated with a reduction in lung hyperinflation and dyspnea during exercise.

Exacerbations

The effect of SPIRIVA on COPD exacerbations was investigated in a randomized, double-blind, placebo-controlled trial of 1,829 patients with COPD over a 6 month period. The study enrolled patients from one health care system (US Veterans Affairs). The mean age of these patients was 68 years and about 98.5% were male. At baseline, the mean FEV1 was 1.04L and the mean predicted FEV1 was 35.6%. About 29% of patients were using home oxygen at the entry of this study. In this six month trial, a COPD exacerbation was defined as a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea or chest tightness with a duration of at least three days requiring treatment with antibiotics and/or systemic steroids and/or hospital admission (including ER visits greater than 24 hours). Although there is no consensus with respect to a definition of COPD exacerbation and its classification, the definition used in this trial has been used in a number of large clinical trials.

TABLE 9 - DEMOGRAPHICS AND BASELINE CHARACTERISTICS FOR TRIAL 205.266

Study results

The results of this trial showed that SPIRIVA reduced the proportion of patients who experienced at least one COPD exacerbation (27.9% vs. 32.3%, p=0.0368) and reduced the number of exacerbations by 18.8% (0.853 vs. 1.051 events per patient year of exposure, p=0.0028) compared to placebo. Seven percent of patients in the SPIRIVA group and 9.5% of patients in the placebo group were hospitalized due to a COPD exacerbation (p=0.056).

TABLE 10 - EFFICACY ENDPOINT FROM TRIAL 205.266

QT Interval

In a QT study involving 53 healthy volunteers, SPIRIVA 18 ug and 54ug (i.e. three times the therapeutic dose) over 12 days did not prolong QT intervals of the ECG.

DETAILED PHARMACOLOGY

Animal Pharmacology

In vitro studies have shown that tiotropium is a potent, reversible, M3-selective muscarinic receptor antagonist. Tiotropium's long duration of action is thought to be due to its high affinity and slow dissociation kinetics from the muscarinic M3-receptor subtype. The M3-receptor is the main muscarinic receptor subtype involved in the bronchoconstriction induced by acetylcholine. Among the other muscarinic receptor subtypes of known physiological relevance, M2-receptors are responsible for the effects of parasympathetic inhibition of heart rate. Tiotropium has a higher affinity for human muscarinic 3 (hm3)-receptors (KD value: 8.89 pmol/L) than for hm2- receptors. In addition, and most importantly, tiotropium dissociates only very slowly from hm3- receptors. The high potency and long duration of action of tiotropium, suggested by the in vitro studies, has been confirmed in vivo in various animal models. Following single inhaled doses in guinea pigs and dogs, tiotropium was shown to be at least as potent as ipratropium with a significantly longer duration of action. In conscious guinea pigs, a concentration dependent protective effect against bronchospastic collapse induced by acetylcholine challenge was shown for both tiotropium and ipratropium. Systemic effects of tiotropium are very limited. A conventional battery of safety pharmacology studies has been conducted. Tiotropium induced, after parenteral administration (s.c. or i.v. ), typical systemic peripheral anticholinergic effects: inhibition of salivary, lacrimal and gastric acid excretions, mydriasis, tachycardia and delayed intestinal transit. This was expected since most of the affected functions are controlled through muscarinic M3- (salivary and lacrimal secretions, intestinal transit), and/or M1- (gastric acid secretion, pupillary diameter) or M2- (heart rate) receptor subtypes. At the parenteral dosages used, sufficient plasma concentrations of tiotropium are obtained that can block all three subtypes of muscarinic receptors. After inhalation administration, however, pharmacologically effective doses were shown to be devoid of systemic anticholinergic effects in both guinea pigs and dogs. The therapeutic window between bronchoprotection and inhibition of salivation is maintained even after repeated administration of tiotropium up to 14 days. Similar peripheral anticholinergic effects were also observed after oral administration of tiotropium although equipotent oral doses were approximately 100-fold higher than parenteral doses. This indicates an extremely low absorption of tiotropium from the gastrointestinal tract. The absence of CNS-related effects of tiotropium is in accordance with the assumption that this quaternary charged molecule is unable to penetrate the blood-brain barrier. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier to any relevant extent. Most importantly, a clear dissociation between bronchoprotective effects and the above mentioned systemic anticholinergic effects was observed after an administration by inhalation, demonstrating that a lung-selective cholinergic blockade can be obtained through this route of administration. Pharmacodynamic interaction studies in anesthetized dogs revealed that the treatment with glucocorticoids did not interfere with the bronchodilatory action of tiotropium. Investigations with i.v. theophylline revealed a slight enhancement of the bronchodilatory effect of tiotropium. The bronchodilatory effect of tiotropium and salbutamol were additive in anesthetized dogs. In pregnant rats, excision studies at 10 mg/kg i.v. on day 12 or day 18 of pregnancy showed that while drug-related radioactivity crossed the placenta, the tissue and organ concentrations in the fetus were lower than in maternal tissue. The radioactivity in the fetus was eliminated rapidly. A single 10 mg/kg i.v. dose of [14C] tiotropium administered to lactating rats resulted in milk : plasma radioactivity ratios of 0.4 (0.5 hour, first sampling time) to 18 at 24 hours and approximately 1.9 % of the dose was estimated to be excreted in the milk over two days. At least four metabolites were detected in milk, one of them identified as N-methylscopine. The general pharmacodynamic profile of tiotropium does not indicate any additional activity to the well-defined anticholinergic effects.

Clinical Pharmacology Pharmacodynamics

Dose-ranging - Multiple-dose

A 9 ug dose provided 75%, the 18 ug dose provided 85%, and the 36 ug dose provided 92% of the maximum effect. The data suggested that a dose of approximately 18 ug was superior to lower doses and nearly as effective as a dose of approximately 36 ug. The increased incidence of dry mouth at and above 36 ug suggested that a lower dose would be preferable; thereby supporting the proposed dose of 18 ug. The data also suggested that since the differences between the trough FEV1 and average FEV1(0-6 hr) response are minimal, a once a day dosing regimen for tiotropium appears to be appropriate.

HandiHaler Flow Rate Characteristics in Patients with COPD

Twenty-six COPD patients with disease severity ranging from 16% to 65% of predicted normal FEV1 participated in this study. Each patient used the HandiHaler device containing a placebo capsule after being given the standard instructions to inhale slowly and deeply, but at a rate rapid enough to hear the capsule vibrate. Based on in vitro observations that capsule vibration and evacuation occurs at a rate of 20 L/min or greater, this was regarded as the minimal critical flow rate for patients to achieve. All 26 patients were able to achieve this flow rate and hear the capsule vibrate. The median inspiratory flow rate for all patients was 30 L/min with a range of 20.4 - 45.6 L/min. As such, the results indicate that COPD patients with a wide range of disease severity based on FEV1, can generate the minimal required inspiratory flow rate (20 L/min) through the HandiHaler necessary to vibrate the capsule and evacuate the powder from the capsules.

Evaluation of Mucociliary Clearance

As a class, systemically absorbed anticholinergic drugs have been reported to decrease mucociliary clearance. A study was conducted to investigate the effect of three (3) weeks of once daily inhaled tiotropium 18 ug on tracheobronchial clearance (TBC) as assessed by radioaerosol technique in patients with COPD (n=37). The data showed that once daily inhaled tiotropium resulted in improved penetration of radioaerosol but did not change TBC compared to baseline; however, TBC following tiotropium was apparently delayed compared to placebo. This difference however, was within the pre- specified limit for non-inferiority of tiotropium compared to placebo. The deeper penetration of radioaerosol is attributable to the effectiveness of tiotropium as a bronchodilator in patients with COPD. The deeper penetration of the aerosol particles influenced by the increased airway patency is the likely cause of the apparent slower TBC in the tiotropium group.

Severity of COPD

In COPD patients, disease severity is likely to be confounded with age effects and seems to have no relevant influence on tiotropium absorption.

TOXICOLOGY

Acute Toxicity

The acute inhalation toxicity in mice, rats and dogs was low and independent of the formulation type used (aqueous aerosol, lactose powder). Non-lethal dosages produced clinical signs characteristic of the pharmacodynamic activity of tiotropium (mydriasis, dry mouth and nose) as well as non-specific signs of toxicity (dyspnea, tremor, ataxia, convulsions, loss of motility and body weight). In mice, deaths occurred at 131 mg/kg tiotropium when administered as an aqueous aerosol through nose only exposure (the LD50-value could not be established). No lethal dosage was achieved by the inhalation of either formulation in rats (LD50 > 334.5 mg/kg) or dogs (LD50 > 3.6 and > 0.7 mg/kg). Necropsy of decedents revealed pulmonary emphysema and/or congestion of liver and kidneys. No gross lesions were detected among survivors. The oral LD50 for mice and rats are 219,099 and 1,279,279 times respectively the maximum recommended human dose on a mg/m2 basis.

Chronic Toxicity

The repeated-dose toxicity was investigated by inhalation of tiotropium by rats and Beagle dogs for 13 and 52 weeks, by intravenous injection over 4 weeks, and by oral gavage for 13 weeks. In rats and dogs, most in-life and morphological changes were directly or indirectly attributable to the anticholinergic activity of the compound. These changes included mydriasis, increased heart rate, and dry mucous membranes due to lowered secretory activity of the lacrimal glands as well as of the glands of the digestive and upper respiratory tract. The anticholinergic activity of the compound most probably also accounted for distension of the large bowel, and for the species- specific deposition of proteinaceous material in the urinary bladder of male rats. Subsequently, secondary indirect changes developed, such as rhinitis and keratoconjunctivitis sicca, as well as decreased food consumption, body weight gain, liver lipids, serum glucose and triglycerides. Thymic involution and changes of the Harderian gland including chromodacryorrhea were regarded as non-specific responses to stress. Even low dosages induced signs characteristic of the anticholinergic activity of tiotropium; therefore, a NOTEL could only be established in a limited number of studies. In the rat, the inhalation NOTEL was < 0.013 mg/kg and the inhalation NOTEL in the dog was > 0.010 mg/kg. The few changes that were perhaps unexpected include urogenital tract changes and cataracts in rats. The urogenital changes are nevertheless considered as sequelae to pharmacological effects and as such are part of a syndrome that includes the prostate. In view of the species-specificity of the syndrome and its harmless nature, it is unlikely to have any influence on human safety assessment. Similarly, although the precise mechanism remains unknown, cataract formation appears to be specific to Wistar rats and to the mode of administration. As the method of administration to the patient avoids direct eye exposure to tiotropium, any risk to patients is negligible.

Reproductive Toxicity

The effects of tiotropium administered via inhalation on the fertility and early embryonal development (Segment I), and on the peri- and postnatal development (Segment III) were assessed in rats, and those on the embryo-fetal development (Segment II) were investigated in rats and rabbits. Dose dependent paternal and maternal toxicity was observed. Embryo-fetal toxicity, considered secondary to maternal toxicity, was observed at high doses in rats and rabbits. There was no impairment of reproductive function of the F0 generation and no effect on the postnatal development of the F1 generation. The incidence of variations was increased at dose levels above 0.01 mg/kg but they were of the types encountered in the historical controls. No teratogenicity was noted. The No Observed Toxic Effect Level (NOTEL) for maternal/paternal toxicity in the rat and rabbit was < 0.01 mg/kg Ba 679 BR and for developmental toxicity 0.01 mg/kg in all three segments when administered by inhalation.

Carcinogenicity and Mutagenicity

Inhalation carcinogenicity studies in mice and rats have revealed no carcinogenic potential at target tiotropium doses up to 2.54, 180 and 75 ug/kg/day (male mice, female mice and rats, respectively). These doses correspond to about 0.45, 92 and 27 times the maximum recommended human dose (MRHD) on a mg/m2 basis. Results of various mutagenicity studies (Ames test and E coli bacterial gene mutation test, gene mutation test in V79 Chinese hamster cells, in vitro cytogenetic study with human lymphocytes, in vitro unscheduled DNA-synthesis test, and in vivo micronucleus test) were negative.

REFERENCES

Selected Bibliography

1. Takahashi T, Belvisi MG, Patel H, Ward JK, Tadjkarimi S, Yacoub MH, Barnes PJ: Effect of Ba 679 BR, a novel Long-acting Anticholinergic Agent, on Cholinergic Neurotransmission in Guinea Pig and Human Airways. Am J Respir Crit Care Med, 150(6) 1640-1645, (1994).

2. Haddad EB, Mak JCW and Barnes PJ: Characterization of [3H] Ba 679 BR, a slow-dissociating muscarinic antagonist, in human lung: radioligand binding and autoradiographic mapping. Mol. Pharmacol. 1994; 45:899-907.

3. Disse B, Speck GA, Rominger KL, Witek TJ, Hammer R: Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 1999; 64(6/7):457-464.

4. Van Noord JA, Smeets JJ, Custers FLJ, et al: Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J, 2002; 19:639-644.

PART III: CONSUMER INFORMATION

PrSpiriva(r)

Tiotropium Bromide Monohydrate Capsules for Oral Inhalation

This leaflet is part III of a three-part "Product Monograph" published when SPIRIVA was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about SPIRIVA. Contact your doctor or pharmacist if you have any questions about the drug.

PLEASE READ THIS INFORMATION CAREFULLY AND COMPLETELY BEFORE YOU USE SPIRIVA EVEN IF YOU HAVE JUST REFILLED YOUR PRESCRIPTION, SINCE SOME INFORMATION MAY HAVE CHANGED.

ABOUT THIS MEDICATION

What the medication is used for:

SPIRIVA is a long acting bronchodilator for maintenance treatment of bronchospasm associated with Chronic Obstructive Pulmonary Disease (COPD).

What is COPD?

COPD (Chronic Obstructive Pulmonary Disease) is a type of lung disease in which there is a progressive narrowing of the airways, leading to breathing difficulties. In many patients, this narrowing of the airways may be the result of many years of cigarette smoking; others may have a genetic predisposition. Smoking cessation produces symptomatic benefits and will slow the progression of chronic bronchitis (which is a form of COPD). COPD can be helped by medication as well.

What it does:

Tiotropium bromide is one of a group of medicines called "bronchodilators".

SPIRIVA makes breathing easier by opening your narrowed airways and keeping them open for 24 hours.

When it should not be used:

SPIRIVA should not be used by patients with a history of allergy to atropine or its derivatives (ipratropium or oxitropium) or to any component of this formulation.

SPIRIVA should not be used as a rescue medication.

What the medicinal ingredient is:

Tiotropium bromide monohydrate

What the important non-medicinal ingredients are:

Lactose monohydrate

What dosage forms it comes in:

Capsules for oral inhalation. DO NOT SWALLOW. Each capsule contains a dry powder blend of 18 ug tiotropium (equivalent to 22.5 ug tiotropium bromide monohydrate) with lactose monohydrate as the carrier. SPIRIVA capsules are light green, with TI 01 printed on one side of the capsule and the Boehringer Ingelheim company logo on the other side. Ten SPIRIVA capsules are packaged in an aluminum / PVC / aluminum blister card. One blister card consists of two 5-cavity strips joined along a perforated line.

SPIRIVA capsules are partially filled but contain exact amount of medication as declared on the label.

WARNINGS AND PRECAUTIONS

BEFORE you use SPIRIVA, talk to your doctor or pharmacist if:

• You may be pregnant or wish to become pregnant;

• You are a breastfeeding mother;

• You are taking any medications including eye drops, this includes those you can buy without prescription;

• You have any other medical problems such as difficult urination or enlarged prostate;

• You have eye problems, such as glaucoma or eye pain;

• You have any allergies to food or drugs;

• You are allergic to lactose (milk sugar).

These capsules are intended for inhalation only. DO NOT SWALLOW!

SPIRIVA should not be used more frequently than once daily. Do not exceed the prescribed dose.

This medication has been prescribed for you and should not be given to other people.

Avoid getting the drug powder into your eyes. This may result in eye pain and/or discomfort, temporary blurring of vision, and/or coloured images in association with red eyes. Should any of these symptoms develop, consult a doctor immediately.

Remember to tell any other doctor, dentist or pharmacist you consult that you are taking this medication.

If you have any questions about SPIRIVA or the HandiHaler(r) device, contact your doctor or pharmacist.

INTERACTIONS WITH THIS MEDICATION

Other medications may be affected by SPIRIVA or may affect how SPIRIVA works. Tell your doctor or pharmacist if you are taking other medications.

PROPER USE OF THIS MEDICATION

SPIRIVA should be administered once daily by inhalation only through the HandiHaler(r) inhalation device. The HandiHaler(r) enables you to inhale the medicine contained in the SPIRIVA capsule that your doctor has prescribed for your breathing problems. The HandiHaler(r) is especially designed for SPIRIVA; you must not use it to take any other medication. Likewise, you should not take your SPIRIVA capsules with any device other than the HandiHaler(r). You can use your HandiHaler(r) for up to one year to take your medication before needing a replacement. Before starting treatment with SPIRIVA, be certain that you are completely familiar with the use and proper care of the HandiHaler(r) device.

If you are unable to inspire through the HandiHaler(r) to make the SPIRIVA capsule vibrate, consult your physician.

Usual dose:

One (1) SPIRIVA capsule is to be taken once daily, preferably at the same time each day, only with the HandiHaler(r) inhalation device. DO NOT SWALLOW!

Do not use another type of inhaler with the SPIRIVA capsules. Do not use other capsules in the HandiHaler(r) inhalation device.

How to Use SPIRIVA through the HandiHaler(r) Inhalation Device:

1. Become familiar with the HandiHaler(r) device.

2. To release the dust cap, press the green piercing button completely in and let go.

3. Open the dust cap completely by pulling it upwards, then open the mouthpiece by pulling it upwards.

1. Blister Handling

4A. The blister card contains two blister strips joined along a perforated line. Prior to removing the first capsule from the blister card, separate the blister strips by tearing along the perforation.

4B. Immediately before use, peel the aluminum back foil until one capsule is fully visible. After opening a strip, the in-use shelf life of the remaining capsules in the strip is 5 days.

1. Dust cap

2. Mouthpiece

3. Mouthpiece ridge

4. Base

5. Piercing button

6. Centre chamber

7. Air intake vents

4C. Remove one SPIRIVA capsule from the blister. Do not expose more than one capsule. If more than one capsule is exposed, you should discard the exposed unused capsules. Do not store the capsule in the HandiHaler(r) device.

Place the capsule in the centre chamber. It does not matter which end of the capsule is placed in the chamber.

1. Close the mouthpiece firmly until you hear a click, leaving the dust cap open.

the air intake vents. Raise the HandiHaler(r) to your mouth and close your lips tightly around the mouthpiece. Keep your head in an upright position and breathe in slowly and deeply but at a rate sufficient to hear or feel the capsule vibrate.

Breathe in until your lungs are full; then hold your breath as long as comfortable (try counting to 10) and at the same time take the HandiHaler(r) out of your mouth. Resume normal breathing.

Hold the HandiHaler(r) with the mouthpiece up- wards and press the green piercing button completely in only once, and release. This makes holes in the capsule and allows the medication to be released when you breathe in.

8.

If you feel that your chest is congested with mucus, try to cough to clear your lungs before you inhale SPIRIVA. Breathe out completely.

Important: Do not breathe into the mouthpiece at any time.

1. Hold the HandiHaler(r) by the grey base. Do not block

2. To ensure complete inhalation of capsule contents, you must repeat steps 8 and 9 once again.

3. Open the mouthpiece again. Tip out the used capsule and dispose. Do not touch the used capsules. If the dry powder gets on your hands, make

sure you wash your hands thoroughly.

Close the mouthpiece and dust cap for storage of your HandiHaler(r) device.

When and how should you clean the HandiHaler(r)?

It is important to clean the HandiHaler(r) once a month as follows:

1. Open the dust cap and mouthpiece.

2. Open the base by lifting the piercing button.

3. Rinse the complete inhaler with warm water to remove any

powder.

Dry the HandiHaler(r) thoroughly by tipping excess of water out on a paper towel and air-dry afterwards, leaving the

dust cap, mouthpiece and base open. It takes 24 hours to air

dry, so clean it right after you used it and it will be ready for your next dose. The outside of the mouthpiece may be cleaned with a moist but not wet tissue if needed.

Do not place HandiHaler(r) in the dishwasher.

• Sudden wheeziness and chest pain or tightness

• Swelling of eyelids, face, lips, tongue or throat

• Lumpy skin rash or "hives" anywhere on the body

Do not be alarmed by this list of possible side effects. You may not experience any of them.

This is not a complete list of side effects. For any unexpected effects while taking SPIRIVA, contact your doctor or pharmacist immediately, so that these effects may be properly addressed.

If you experience dry mouth or bad taste, sucking on a sour candy or rinsing your mouth may help.

Check with your doctor if the dry mouth or bad taste persist or if you experience constipation.

If you do not get the expected relief from your treatment, you should contact your doctor.

Overdose:

If you take more SPIRIVA than you should - talk to your doctor

immediately.

Missed Dose:

If you forget to take a dose, take one as soon as you remember but do not take two doses at the same time or on the same day. Then

take your next dose as usual.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

You should be aware that prescription medicines carry some risks and that all possible risks may not be known at this stage. Discuss with your doctor the risks of taking SPIRIVA against the expected benefits.

The most commonly reported undesirable effects of SPIRIVA are:

Dry mouth

Dizziness

Constipation

Cough

Irritation of mouth and/or throat

Hoarseness

Nosebleeds

Sensation of heart beat

Retention of urine

Some people can be allergic to medicines. If you have any of the following symptoms soon after taking SPIRIVA, stop taking this medicine and tell your doctor immediately or go to the nearest hospital:

This is not a complete list of side effects. For any unexpected effects while taking SPIRIVA contact your doctor or pharmacist.

HOW TO STORE IT

Keep SPIRIVA and your HandiHaler(r) inhalation device in a cool dry place at room temperature between 15-25o C. Protect from moisture. Do not freeze. The capsules should not be exposed, either in the blister pack or in the inhaler, to extreme temperatures,

i.e. they should not be exposed to sunlight or to heat and humidity. Your bathroom or car are not good choices.

Keep out of the reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

Toll-free telephone: 866-234-2345

Toll-free fax: 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.boehringer-ingelheim.ca

or by contacting the sponsor, Boehringer Ingelheim (Canada) Ltd., at:1-800-263-5103, ext. 4633 (Medical Information)

Please visit our website to see if more up-to-date information has been posted.

This leaflet was prepared by Boehringer Ingelheim (Canada) Ltd. Last revised: November 19, 2007