Discussing the Importance of Earlier Diagnosis and Management and Reducing the Risk of Exacerbations in Patients With COPD

Moderators Guide
Indication SPIRIVA HandiHaler is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, and for reducing COPD exacerbations. Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

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Important Safety Information

Spiriva HandiHaler (tiotropium bromide inhalation powder) is contraindicated in patients with a history of hypersensitivity to tiotropium, ipratropium (atropine derivatives), or any components of SPIRIVA capsules. SPIRIVA HandiHaler is not indicated for the initial treatment of acute episodes of bronchospasm, i.e., rescue therapy. Immediate hypersensitivity reactions, including urticaria, angioedema (swelling of lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of SPIRIVA. Additionally, inhaled medicines, including SPIRIVA, may cause paradoxical bronchospasm. If any of these occurs, treatment with SPIRIVA should be stopped and other treatments considered. Patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to SPIRIVA. Use with caution in patients with severe hypersensitivity to milk proteins. SPIRIVA HandiHaler should be used with caution in patients with narrow-angle glaucoma or urinary retention. Prescribers should instruct patients to consult a physician immediately should any signs or symptoms of narrowangle glaucoma, or prostatic hyperplasia or bladder-neck obstruction occur. Since dizziness and blurred vision may occur with the use of SPIRIVA HandiHaler, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery. As SPIRIVA is a predominantly renally excreted drug, SPIRIVA use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of 50 mL/min). SPIRIVA HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions. SPIRIVA may interact additively with concomitantly used anticholinergic medications. Avoid coadministration with other anticholinergic-containing drugs. The most common adverse reactions in the 1-year placebocontrolled trials were dry mouth, upper respiratory tract infection, sinusitis, pharyngitis, non-specific chest pain, and urinary tract infection. In addition, the most commonly reported adverse reactions from the 4-year trial not included above were headache, constipation, depression, insomnia, and arthralgia. SPIRIVA capsules should not be swallowed and should only be inhaled through the mouth (oral inhalation) using the HandiHaler device. The HandiHaler device should not be used for administering other medications. SPIRIVA capsules should always be stored in the sealed blisters, and only removed immediately before use, or else its effectiveness may be reduced.

Thank you for attending todays discussion, which will focus on the role of Spiriva HandiHaler for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD)including chronic bronchitis and emphysemaand for reducing COPD exacerbations. This program was created on behalf of Boehringer Ingelheim Pharmaceuticals, Inc. and Pzer Inc. The companies have provided nancial support for this program. The information presented has been reviewed for consistency with US Food and Drug Administration guidelines.

Introductions
Program Description
This promotional program utilizes a workbook to guide discussion on the use of SPIRIVA for patients with COPD. The program includes a moderators guide for the speaker and a workbook for the participants. The workbook contains information about key current issues in COPD, as well as data on the efcacy and safety of SPIRIVA HandiHaler. This moderators guide is intended to facilitate interactive discussion between the speaker and participants by posing clinically relevant questions to the audience. Speakers are required to cover all the information within the workbook during each presentation. Please allow sufcient time to review the Important Safety Information for SPIRIVA. Important Safety Information must be reviewed at the end of this program.

Program Outline
Emphasize the importance and benets of earlier diagnosis and management for your patients with COPD Highlight why addressing exacerbations is an important component in the management of COPD Underscore the signicance of appropriate treatment and guideline recommendations for maintenance therapy to reduce risk of exacerbations Review SPIRIVA data UPLIFT study design and population UPLIFT lung function data UPLIFT exacerbations data UPLIFT hospitalizations and VA study Established long-term safety prole Examine patient proles across all COPD groups, including patients with milder disease who are appropriate candidates for maintenance therapy Important Safety Information

Indication
SPIRIVA HandiHaler is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema, and for reducing COPD exacerbations.
COPD=chronic obstructive pulmonary disease; UPLIFT=Understanding Potential Long-Term Impacts on Function with Tiotropium; VA=Veterans Affairs.

FOR MODERATOR USE ONLY. DO NOT SHARE.

Please see Important Safety Information on this page and accompanying full Prescribing Information and Instructions for Use.

The Importance of Early Recognition and Diagnosis of COPD

COPD: Rationale for Early Recognition and Diagnosis
Experts believe up to 50% of lung function may be already lost when symptoms are noticed or acknowledged1,2 Lung function (airow limitation) is affected even in GOLD grade 1 or 2 patients3 Smoking cessation is the only way to slow the progression of COPD4

OBJECTIVE
Describe the impact of COPD and related reduction in physiological capacity as the disease progresses. The goal is to stress the importance of early recognition and diagnosis of COPD.

DISCUSSION POINTS
When talking to your patients about COPD, what reasons do you provide to emphasize the importance of earlier recognition and diagnosis? In your practice What proactive steps do you take to ensure that you are recognizing and diagnosing as early as possible in your patients with COPD? What is the most challenging aspect of addressing loss of lung function and exacerbations in your patients with COPD?

The Majority of Patients With COPD Are Working Age and Female5,6
Nearly 70% of patients with COPD are <65 years old5 In 2010, 8.6 million women in the US had COPD compared with 5.7 million men5 Women had greater increases in COPD-related hospitalizations than men from 1998-20096

Exacerbations Signicantly Impact Patients With COPD

Exacerbations occur even in patients with moderate COPD (GOLD 2)7,8 Some patients may not return to baseline after an exacerbation9,10 Patients with COPD who have a high number of exacerbations will continue to have frequent exacerbations8

DATA
COPD: Rationale for Early Recognition and Diagnosis 1-4 Key message: Experts believe up to 50% of lung function may be already lost when symptoms are noticed or acknowledged, and lung function (airflow limitation) is affected even in GOLD grade 1 or 2 patients Smoking cessation is the only way to slow the progression of COPD The Majority of Patients With COPD Are Working Age and Female5,6 Key message: Based on the most recently available epidemiologic data, the majority of patients with COPD are working age. In addition, COPD has become more prevalent in women as have COPD-related hospitalizations Nearly 70% of patients with COPD are under the age of 65 In 2010, 8.6 million women in the US had COPD compared with 5.7 million men In the last decade or so, there were greater increases in COPD-related hospitalizations among women than among men Exacerbations Significantly Impact Patients With COPD7-10 Key message: All patients with COPD are at risk for an exacerbation, and once they experience an exacerbation, they may not return to baseline Exacerbations occur even in patients with moderate COPD (GOLD 2) Some patients may not return to baseline after an exacerbation Exacerbation Frequency Is an Indicator of Exacerbation Risk8,* Key message: Patients with COPD who have a high number of exacerbations may continue to have frequent exacerbations

Exacerbation Frequency Is an Indicator of Exacerbation Risk8,* Exacerbation frequency in patients with COPD
80 60 40 Predictive Value (%) 20 Infrequent 0 -20 -40 -60 -80 -100 Frequent Year 1 Year 2 Year 3

Year 1 Sensitivity Specicity 43% 87%

Year 2 60% 83%

Data from Hurst JR, et al. 8

*Frequent exacerbations were dened as 2 or more exacerbations per year.

GOLD=Global Initiative for Chronic Obstructive Lung Disease.

1. Doherty DE, Belfer MH, Brunton SA, Fromer L, Morris CM, Snader TC. Chronic obstructive pulmonary disease: consensus recommendations for early diagnosis and treatment. J Fam Pract. 2006;55(suppl [Nov]):S1-S8; 2. Barbarito N, Vaghi A, De Mattia E. Prevalence of airow obstruction according to GOLD, ATS and ERS criteria in symptomatic ever-smokers referring to a pulmonary rehabilitation department. Monaldi Arch Chest Dis. 2011;75(3):157-161; 3. Jones R, strem A. Optimising pharmacological maintenance treatment for COPD in primary care. Prim Care Respir J. 2011;20(1):33-45; 4. Fletcher C, Peto R. The natural history of chronic airow obstruction. Br Med J. 1977;1(6077):1645-1648; 5. Schiller JS, Lucas JW, Ward BW, Peregoy, JA. Summary health statistics for U.S. adults: National Health Interview Survey, 2010. Vital Health Stat 10. 2011;(252):1-227; 6. Akinbami L, Liu X. Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998-2000. NCHS Data Brief No. 63. http://www.cdc.gov/nchs/data/databriefs/db63.pdf. Published June 2011. Accessed March 2, 2012; 7. Jones PW, Willits LR, Burge PS, Calverley PM; Inhaled Steroids in Obstructive Lung Disease in Europe study investigators. Disease severity and the effect of uticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J. 2003;21(1):68-73; 8. Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138; 9. Seemungal TA, Donaldson GC, Bhownick A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-1613; 10. Parker CM, Voduc N, Aaron SD, Webb KA, ODonnell DE. Physiological changes during symptom recovery from moderate exacerbations of COPD. Eur Respir J. 2005;26(3):420-428.

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OBJECTIVE
Discuss the signicant undertreatment of COPD by reviewing data from a recently published retrospective analysis of medical and pharmacy claims involving 51,000 patients with COPD. This published study by Make et al found that the majority of patients with COPD in commercial- or Medicare-based plans were untreated with respiratory medications.

Goals of Treatment of COPD Include Reducing Symptoms and Risk of Exacerbations

Suboptimal Management of COPD Remains a Challenge
Unawareness of recommended treatments can result in suboptimal management of patients with COPD COPD is a chronic illness with symptoms that worsen over time Proactive and timely prescription of appropriate therapies and ongoing case management may help patients cope with their COPD and improve their health status

DISCUSSION POINT
Are these observations consistent with your clinical experience?

DATA
Suboptimal management of COPD remains a challenge Key message: Unawareness of recommended treatments can result in suboptimal management of patients with COPD COPD is a chronic illness with symptoms that worsen over time Proactive and timely prescription of appropriate therapies and ongoing case management may help patients cope with their COPD and improve their health status COPD is a disease that is significantly undertreated Key message: Many patients diagnosed with COPD receive no medication or treatment. Moreover, some patients were prescribed short-term pharmacotherapy when a prescription for long-term maintenance therapy may have been more appropriate A recently completed retrospective analysis of medical and pharmacy claims from 7.79 million members of 19 US health plans evaluated more than 51,000 patients with COPD and reported significant undertreatment of COPD: Nearly 60% of patients received no pharmacotherapy or treatment, and the majority did not receive long-term maintenance pharmacotherapy for COPD In addition, less than half of patients with COPD were prescribed bronchodilator therapy within 45 days following their hospital stay

COPD Is a Disease That Is Signicantly Undertreated*

Nearly 60% of patients with diagnosed COPD receive no pharmacotherapy The majority of patients in one study did not receive a maintenance pharmacotherapy for COPD 66.3% of commercial-based patients received no maintenance pharmacotherapy 70.9% of Medicare-based patients received no long-term pharmacotherapy Fewer than half of patients with COPD were prescribed bronchodilator therapy within 45 days following their hospital stay

COPD Is Undertreated in Both Commercial and Medicare Patients

SABA alone SAAC ICS LAAC SAAC + ICS LABA + ICS Ach + LABA + ICS Other combinations No medication or treatment
Commercial-based patients N=42,565 5.0% 59.1% 12.5% 4.0% Medicare-based patients N=8507 66.3% no long-term pharmacotherapy 70.9% no long-term pharmacotherapy

7.2%

7.4%

1.6% 2.3% 1.7% 8.7%

4.9%

8.9%

1.6% 1.3% 2.9% 4.2% 9.7%

66.0%

Majority of patients did not receive a maintenance pharmacotherapy or inuenza vaccination

Percentages add up to >100% (105.5% [commercial-based] and 103.5% [Medicare-based]) most likely due to use of more than 1 treatment regimen in the course of the study.

* A recently completed retrospective analysis of medical and pharmacy claims from 7.79 million members in 19 health plans across the United States evaluated the records of more than 51,000 patients with COPD and found signicant undertreatment of the disease. Individual medication groups are mutually exclusive.

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Ach=anticholinergics; COPD=chronic obstructive pulmonary disease; ICS=inhaled corticosteroids; LAAC=long-acting anticholinergic agent; LABA=long-acting beta2-agonist; SAAC=short-acting anticholinergic agent; SABA=short-acting beta2-agonist.
Make B, Dutro MP, Paulose-Ram R, Marton JP, Mapel DW. Undertreatment of COPD: a retrospective analysis of US managed care and Medicare patients. Int J Chron Obstruct Pulmon Dis. 2012;7:1-9.

GOLD Guidelines
Major COPD treatment guidelines describe maintenance therapy as having a key role in the treatment of COPD, including reducing the risk of exacerbations Goals for treatment of stable COPD include reducing the frequency and severity of exacerbations2

OBJECTIVE
Review the new GOLD guidelines Model of Symptom/Risk matrix for healthcare providers for more accurate individualized patient assessment.

DISCUSSION POINTS
How closely does your management approach resemble the one in the updated GOLD guidelines? In which Patient Group (A, B, C, and/or D), as shown in the grid, do you initiate maintenance therapy with a long-acting bronchodilator?

COPD Assessment Utilizes Reported Symptoms and Exacerbation Risk, Which Is Dened by Airow Limitation or Exacerbation History
GROUP C High Risk, Less Symptoms
4 3
Exacerbation history GOLD Classification of Airflow Limitation

DATA
Guidelines Recommend Maintenance Therapy to Reduce Risk Key message: Maintenance therapy is a key component of treating COPD, which includes reducing the risk of exacerbations Major COPD treatment guidelines recommend maintenance therapy as a key component of COPD management Goals for treatment of stable COPD include reducing the frequency and severity of exacerbations COPD Assessment Utilizes Reported Symptoms and Exacerbation Risk, Which Is Defined by Airflow Limitation or Exacerbation History Key message: Treatment strategies in the management of stable COPD should take into account a patients specic symptoms, as well as exacerbation risk In earlier versions of the GOLD guidelines, spirometry provided the basis for COPD treatment recommendations The majority of data from clinical trials regarding the efcacy of COPD treatment are centered on baseline FEV1, however, FEV1 alone is not the optimal indicator of disease status Treatment strategies for stable COPD should take into account the patients specic symptoms, as well as exacerbation risk The Model of Symptom/Risk Evaluation of COPD based on the individualized assessment strategy is shown Steps for using the matrix: Assess risk using GOLD classication of airow limitation and the history of exacerbations; this determines the horizontal row for your patient in the grid Note: When assessing risk, choose the highest risk according to GOLD grade or exacerbation history Next, evaluate the mMRC and/or CAT scores to determine the vertical row for your patient Combining these items in a matrix approach allows you to choose patient group A, B, C, or D to guide treatment strategy Guidelines recommend long-acting anticholinergics for patient groups A (second choice), B, C, and D*

GROUP D High Risk, More Symptoms

(C)

(D)

Risk

(A)
1

(B)
0

Risk

GROUP A Low Risk, Less Symptoms

mMRC 0-1 CAT 10

mMRC 2 CAT 10

Symptoms (mMRC or CAT score)

GROUP B Low Risk, More Symptoms

When Assessing Risk, Choose the Highest Risk According to GOLD Grade or Exacerbation History
Patient Groups A B C D Characteristics Low risk, less symptoms Low risk, more symptoms High risk, less symptoms High risk, more symptoms Spirometric Classication GOLD 1-2 GOLD 1-2 GOLD 3-4 GOLD 3-4 Exacerbations per Year 1 1 2 2 mMRC 0-1 2 0-1 2 CAT <10 10 <10 10

Long-acting anticholinergics are an appropriate maintenance treatment option across all COPD groups, including your milder patients (Groups A and B). For Group A patients, long-acting anticholinergics are recommended as a second choice*

* Per GOLD, the rst-choice treatment option for Group A patients is a short-acting bronchodilator. CAT=COPD Assessment Test; mMRC=modied Medical Research Council scale.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease [GOLD report]. http://www.goldcopd.org/uploads/users/les/GOLD_Report_2011_Feb21.pdf. Updated 2011. Accessed April 30, 2012.

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OBJECTIVE
Present the UPLIFT trial study design, key patient population characteristics, and efcacy data for both the overall and moderate populations.

SPIRIVA: UPLIFT Study Design and Population

UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) Clinical Study Design1
Run-in (2 weeks) Treatment period (48 months) SPIRIVA, n=2986 Screening Control, n=3006 Secondary endpoints included: Yearly rate of decline in pre- and postbronchodilator FEV1, FVC, and SVC from Day 1 until 1 month after end of study drug administration Yearly rate of decline in pre- and postbronchodilator FVC and SVC from Day 30 until completion of study Exacerbations and related hospitalizations 48 49 Coprimary endpoints: Yearly rate of decline in mean FEV1 (prebronchodilator) Yearly rate of decline in mean FEV1 (postbronchodilator) Follow-up (30 days)

DISCUSSION POINTS
How does the patient population represented in the UPLIFT trial compare to patients with COPD in your practice? What important COPD treatment goals are addressed by the UPLIFT clinical trial design? Describe your use of SPIRIVA as an initial maintenance treatment for patients with moderate COPD

GOLD Stage Subgroup Analysis

Stage II (%) SPIRIVA (n=2986) Stage III (%) Stage IV (%)

DATA
UPLIFT Clinical Study Design1 Key message: This published trial was the longest study conducted to date that included the largest overall patient population as well as the largest subpopulation of patients with GOLD Stage II disease SPIRIVA was compared with control in a 4-year, multinational, multicenter, randomized, double-blind trial named UPLIFT (Understanding Potential LongTerm Impacts on Function with Tiotropium) UPLIFT assessed the rate of decline of lung function in patients with COPD who were taking 18 micrograms of SPIRIVA in an inhalation capsule once daily 3006 Patients were randomized to control and 2986 to SPIRIVA Patients were permitted to use all respiratory medications except inhaled anticholinergic drugs At baseline, 60% of patients used a long-acting beta-agonist and 62% used an inhaled steroid. Inhaled anticholinergics were the only medications discontinued at baseline More than 45% of patients had moderate COPD (GOLD Stage II), which is important considering this is the earliest stage that patients usually seek medical attention UPLIFT 4-Year Lung Function Data1 Key message: SPIRIVA did not slow the yearly rate of decline in pre- and postbronchodilator FEV1 versus control, the coprimary endpoints of the study (P =NS) However, SPIRIVA demonstrated improvements versus control in mean values for FEV1 and FVC pre- and postbronchodilation at all time points after randomization, and the difference was sustained over 4 years UPLIFT GOLD Stage II Lung Function Data2,* Key message: At all time points, the mean pre- and postbronchodilator FEV1 were greater in the SPIRIVA group than the control group (P<.0001 at all time points [prebronchodilator change in FEV1 was 101-119 mL and postbronchodilator change in FEV1 was 52-82 mL]) This prespecified subgroup analysis of the UPLIFT trial examined change in FEV1 in GOLD Stage II COPD patients (mean postbronchodilator FEV1 1.63 L [59% of predicted]) Data from the subgroup analysis showed that: The rate of decline in mean postbronchodilator FEV1 in GOLD Stage II patients (SPIRIVA n=1218; control n=1157) was lower for SPIRIVA compared to the control group The rate of decline in prebronchodilator FEV1 did not differ between groups (SPIRIVA n=1221; control n=1158)

45

44

Control (n=3006)

46

44

Months

Randomization 0.5

SVC=slow vital capacity.

SPIRIVA: UPLIFT Lung Function Data

SPIRIVA Improved FEV1 vs Control and Sustained the Difference Over 4 Years1
SPIRIVA did not slow the yearly rate of decline in pre- and postbronchodilator FEV1 vs control, which were the coprimary endpoints of the study (P=NS).
1.50

Subgroup Analysis: SPIRIVA Improved FEV1 in Moderate COPD (GOLD Stage II)2,*
1.80

SPIRIVA (n=1384) Control (n=1355)

SPIRIVA Control
1.60

1.40

SPIRIVA (n=2516) Baseline Control (n=2374) SPIRIVA (n=2494) After bronchodilation = 47-65 mL Baseline Before bronchodilation = 87-103 mL
48

FEV1 (L)

1.30

1.40

After bronchodilation = 52-82 mL Before bronchodilation = 101-119 mL

FEV1 (L)

1.20

1.10

1.20

1.00

Control (n=2363)

0 0 6 12 18 24 30 36 42 48

0 0 6 12 18 24 30 36 42

Day 30
(steady state)

Time (mo)

Day 30
(steady state)

Time (mo)
P<.0001 at all time points for SPIRIVA as compared with control. *Ns reflect the patients in UPLIFT with GOLD stage II disease at randomization.

NS=not signicant.

1. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554; 2. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT Investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecied subgroup analysis of a randomised controlled trial. Lancet. 2009;374(9696):1171-1178.

FOR MODERATOR USE ONLY. DO NOT SHARE.

Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

SPIRIVA: UPLIFT Exacerbations Data

SPIRIVA Signicantly Reduced the Risk of COPD Exacerbations and Delayed the Time to First COPD Exacerbation vs Control1,*
Secondary Endpoint Risk of Exacerbations SPIRIVA vs Control

OBJECTIVE
Describe and discuss the outcomes for 2 of the secondary endpoints in the UPLIFT trialrisk of exacerbations and median time to first exacerbation.

DISCUSSION POINTS
How do the exacerbations data from the UPLIFT trial aid you in selecting a long-term maintenance therapy for your patients with COPD? How do the exacerbations data in GOLD Stage II patients aid you in selecting a long-term maintenance therapy for your patients with COPD? Discuss the role of SPIRIVA in reducing the risk of exacerbations in your patients and the appropriate time to initiate maintenance treatment

Reduced the risk of exacerbations versus control by 14%

Mean number of exacerbations per patient-year was 0.73 vs 0.85, respectively (HR 0.86; CI, 0.81-0.91, P<.001)

Median Time to First Exacerbation

Delayed median time to rst COPD exacerbation versus control by 33% (4.2 months)
Median time to rst COPD exacerbation for SPIRIVA was 16.7 months (95% CI, 14.9-17.9) vs 12.5 months for control (95% CI, 11.5-13.8)

DATA
UPLIFT EXACERBATIONS DATA1 Key message: SPIRIVA significantly reduced the risk of and median time to first COPD exacerbation vs control In the UPLIFT trial, exacerbations were defined as an increase in or the new onset of more than 1 respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic and/or a systemic corticosteroid Risk of exacerbations and median time to first exacerbation were secondary endpoints in the UPLIFT trial SPIRIVA reduced the risk of exacerbations vs control by 14%; mean number of exacerbations per patient-year were 0.73 vs 0.85, respectively (HR 0.86; 95% CI, 0.81-0.91, P<.001) SPIRIVA also delayed median time to first COPD exacerbation vs control by 33% (4.2 months). Median time to first COPD exacerbation for SPIRIVA was 16.7 months (95% CI, 14.9-17.9) vs 12.5 months for the control group (95% CI, 11.5-13.8) Subgroup Analysis by GOLD Staging2 Key message: SPIRIVA signicantly reduced the risk of and median time to rst COPD exacerbation vs control in patients with moderate COPD (GOLD Stage II) Prespecied subgroup analysis for exacerbations was evaluated in GOLD Stage II, III, and IV patients Examination of the secondary endpoints showed: SPIRIVA HandiHaler reduced the risk of exacerbations in GOLD Stage II patients vs control by 20%. Mean number of exacerbations per patient-year were 0.56 vs 0.70, respectively ( P<.0001) The mean number of exacerbations was also signicantly reduced by 12% ( P =.003) in GOLD Stage III patients; however, this trend did not hold true for Stage IV patients ( P =.397) SPIRIVA also delayed median time to rst COPD exacerbation vs control by 32% (5.6 months) in GOLD Stage II patients. Median time to rst COPD exacerbation for SPIRIVA was 23.1 months vs 17.5 months for the control group ( P<.001) SPIRIVA also delayed median time to rst COPD exacerbation in GOLD Stage III patients by 3.4 months vs control ( P =.002), but not for Stage IV patients ( P =.956)

SPIRIVA did not slow the yearly rate of decline in pre- and postbronchodilator FEV1 vs control, which were the coprimary endpoints of the study ( P =NS).

UPLIFT Trial: GOLD Stage II Subgroup Analysis

SPIRIVA Signicantly Reduced the Risk of COPD Exacerbations and Delayed the Time to First Exacerbation vs Control in Moderate Stage COPD (GOLD Stage II)2
Secondary Endpoint SPIRIVA vs Control

Signicantly reduced the risk of exacerbations vs control by 20%

Risk of Exacerbations*
Mean number of exacerbations per patient-year was 0.56 vs 0.70, respectively ( P =.0001) Mean number of exacerbations was also signicantly reduced by 12% ( P =.003) for GOLD Stage III patients but not for Stage IV patients ( P =.397)

Median Time to First Exacerbation*

Delayed time to rst exacerbation vs control by 32% (5.6 months)

Median time to rst exacerbation was 23.1 months vs 17.5 months. respectively ( P<.0001) Median time to rst exacerbation was also delayed by 3.4 months ( P<.002) for GOLD Stage III patients but not for Stage IV patients ( P<.956)

* Exacerbations were dened as an increase in or the new onset of more than 1 respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic and/or a systemic corticosteroid. This prespecied subgroup analysis of the UPLIFT trial examined change in FEV1 in patients with GOLD Stage II COPD (mean postbronchodilator FEV1 1.63 L [59% of predicted]). Exacerbations were evaluated as a secondary outcome in the UPLIFT trial. This prespecied subgroup analysis included data in GOLD Stages II, III, and IV. CI=condence interval; HR=hazard ratio; NS=not signicant. 1. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554; 2. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT Investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecied subgroup analysis of a randomised controlled trial. Lancet. 2009;374(9696):1171-1178.

Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

FOR MODERATOR USE ONLY. DO NOT SHARE.

DISCUSSION POINTS
In your practice, how often are patients with COPD hospitalized for an exacerbation? How important is reducing the risk of exacerbations leading to hospitalization for the patient types seen in your practice? How does the risk of hospitalizations impact your decision to initiate maintenance therapy for your patients with COPD?

SPIRIVA: UPLIFT Hospitalizations and VA Study

UPLIFT Trial: SPIRIVA Reduced the Risk of COPD Exacerbations Leading to Hospitalization vs Control1
40 Probability of exacerbation* leading to hospitalization (%) Control (n=3006) SPIRIVA (n=2986)

DATA
UPLIFT Exacerbations and Hospitalizations Data1 Key message: Patients receiving SPIRIVA had a reduced risk of an exacerbation leading to a hospitalization (hazard ratio=0.86; 95% CI, 0.78-0.95; P =.002) However, there were no statistically significant differences in the absolute number of exacerbations leading to hospitalizations (0.15 vs 0.16 per patientyear in the SPIRIVA and control group, respectively) It should be noted that the overall rate of hospitalizations was low Risk of an exacerbation leading to a hospitalization was a secondary endpoint in the UPLIFT trial VA Study2 Key messages: SPIRIVA significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% versus 32.3%, respectively; difference=4.4 percentage points [14% decrease]; P =.037) SPIRIVA reduced the number of hospitalizations for patients with a COPD exacerbation compared with placebo (7.0% versus 9.5%, respectively; difference=2.5 percentage points [26% reduction]; P =.056) This randomized, parallel-group, double-blind, placebo-controlled study was designed to prospectively evaluate the effectiveness of SPIRIVA in reducing COPD exacerbations and hospitalizations for COPD exacerbations in 1829 patients with moderate to severe COPD (mean baseline FEV1, 36% predicted) from Veterans Affairs medical centers Eligibility criteria included an age of 40 years or older, a cigarette-smoking history of 10 pack-years or more, a clinical diagnosis of COPD, and an FEV1 of 60% predicted or less and 70% or less of the FVC. Exclusion criteria included the use of systemic corticosteroids at unstable doses or in regular daily doses of 20 mg or more of prednisone (or equivalent), or an incomplete recovery from an exacerbation for at least 30 days before the first study visit Approximately 99% of the patients randomized in the study were male Exacerbations were defined as an increase in or the new onset of more than 1 respiratory symptom of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both Coprimary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation

30

20

14% reduction in risk

10 Hazard ratio, 0.86; 95% CI, 0.78-0.95; P =.002 0 0 6 12 18 24 Time (mo) 30 36 42 48

* Exacerbations were de ned as an increase in or the new onset of more than 1 respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic and/or a systemic corticosteroid.

VA Study: SPIRIVA Reduced the Proportion of Patients With COPD Exacerbations2 P=.037 14%
35 30 Patients (%) 25 20 15 10 5 0 Patients with 1 exacerbation* Patients with 1 hospitalization for exacerbations 9.5 7.0 32.3 27.9 Placebo (n=915) SPIRIVA (n=914)

P=.056 26%

Coprimary endpoints were to evaluate the effectiveness of SPIRIVA in reducing COPD exacerbations and hospitalizations for COPD exacerbations. * Exacerbations were de ned as an increase in or the new onset of more than 1 respiratory symptom of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both. Prospective, randomized, double-blind, placebo-controlled study enrolling 1829 patients with moderate to severe COPD (mean baseline FEV 1, 36% predicted) from VA medical centers. VA=Veterans Affairs.

1. Tashkin DP, Celli B, Senn S, et al; for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Eng J Med. 2008;359(15):1543-1554; 2. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143(5)317-326.

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Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

SPIRIVA: Established Safety Prole

Adverse Events Across 1-Year Clinical Registrational Trials vs Placebo and Ipratropium
Placebo-Controlled Trial Patients With Frequency 5% and Where Rate Exceeded Placebo by 1% Body as a whole Chest pain (nonspecic) Edema, dependent Gastrointestinal system disorders Abdominal pain Dry mouth Dyspepsia Respiratory system (upper) Pharyngitis Rhinitis Sinusitis Upper respiratory tract infection Urinary system Urinary tract infection 7 5 4 2 9 6 11 41 7 5 9 37 7 3 3 43 3 2 2 35 5 16 6 3 3 5 6 12 1 6 6 1 7 5 5 4 5 3 2 5 SPIRIVA, % (n=550) Placebo, % (n=371) Ipratropium-Controlled Trial SPIRIVA, % (n=356) Ipratropium, % (n=179)

OBJECTIVE
Discuss key safety data for SPIRIVA in the registrational trials.

DISCUSSION POINTS
What are your thoughts on the safety prole of SPIRIVA? How do you explain the potential for adverse events to your patients?

DATA
SPIRIVA Safety Data Key message: SPIRIVA has an established long-term safety profile. The most commonly reported adverse drug reaction with SPIRIVA was dry mouth, which was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, increased heart rate, blurred vision, glaucoma, urinary difficulty, and urinary retention Common adverse events (frequency 5% and where rate exceeded placebo by 1%) with SPIRIVA HandiHaler occurring in placebo-controlled and ipratropium-controlled trials are described in the table Common adverse events associated with the: Body as a whole included chest pain (nonspecific) and dependent edema Gastrointestinal system included abdominal pain, dry mouth, and dyspepsia Respiratory system (upper) included pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection Urinary system included urinary tract infection In the 4-year UPLIFT study, adverse reactions (with a frequency of 3% in the SPIRIVA group where the rates exceeded control by 1%) included pharyngitis, sinusitis, headache, constipation, dry mouth, depression, insomnia, and arthralgia

The most commonly reported adverse drug reaction with SPIRIVA was dry mouth, which was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, increased heart rate, blurred vision, glaucoma, urinary difculty, and urinary retention. In the 4-year UPLIFT study, adverse reactions (with a frequency of 3% in the SPIRIVA group where the rates exceeded control by 1%) included pharyngitis, sinusitis, headache, constipation, dry mouth, depression, insomnia, and arthralgia.

Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

FOR MODERATOR USE ONLY. DO NOT SHARE.

OBJECTIVE
Review the individual patient proles and discuss when a long-acting anticholinergic such as SPIRIVA may be helpful to recommend as an initial maintenance therapy option.

DISCUSSION POINTS
Based on your clinical experience, what are the typical characteristics of a patient with COPD for whom you would initiate maintenance pharmacotherapy? What are the typical characteristics of a patient for COPD for whom you would initiate maintenance pharmacotherapy with a long-acting anticholinergic, specically SPIRIVA? Discuss the effectiveness of SPIRIVA as a maintenance therapy in your patients with milder COPD (GOLD A & B)

Long-Acting Anticholinergics Are Recommended as an Initial Maintenance Therapy Option Across All COPD Groups, Including Your Milder Patients (Groups A and B)*

DATA
Key message: Long-acting anticholinergics are
recommended as an initial maintenance therapy option across all COPD groups, including your patients with milder COPD (Groups A and B). Long-acting anticholinergics are recommended as a second-choice treatment option for Group A patients

Review and discuss the individual patient profiles for Eric, Mary, Cheryl, and Jim (Groups A, B, C, and D, respectively) and what type of maintenance pharmacotherapy, if any, you would recommend for each Discuss the patients with milder COPD, Eric and Mary (Group A and B, respectively), and what type of maintenance pharmacotherapy, if any, you would recommend for each

COPD Group A*
ERIC 1 Exacerbation FEV1 70% predicted CAT Symptom Score: 4

COPD Group B
MARY 1 Exacerbation FEV1 60% predicted CAT Symptom Score: 12

COPD Group C
CHERYL 2 Exacerbations FEV1 48% predicted CAT Symptom Score: 9

COPD Group D
JIM 2 Exacerbations FEV1 45% predicted CAT Symptom Score: 16

Exacerbations and airow limitation were assessed during SPIRIVA clinical trials.

* Per GOLD, the rst-choice treatment option for Group A patients is a short-acting bronchodilator. The COPD Assessment Test is an 8-item unidimensional measure of health status impairment in COPD, with a score range from 0-40.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease [GOLD report]. http://www.goldcopd.org/uploads/users/les/GOLD_Report_2011_Feb21.pdf. Updated 2011. Accessed April 30, 2012.

FOR MODERATOR USE ONLY. DO NOT SHARE.

Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

SPOT GLUE PI 3.75 X 4.25

Please see Important Safety Information on the inside front cover and accompanying full Prescribing Information and Instructions for Use.

Summary of SPIRIVA for COPD

Lung function In the UPLIFT trial, SPIRIVA: Did not slow the yearly rate of FEV1 decline pre- and postbronchodilator, which were the coprimary endpoints Improved FEV1 vs control over the 4-year trial In the subgroup analysis of UPLIFT in GOLD Stage II patients, SPIRIVA: Sustained improvement in FEV1 vs control Exacerbations In the UPLIFT trial, SPIRIVA: Signicantly reduced the risk of COPD exacerbations by 14% ( P<.001) Signicantly delayed median time to rst COPD exacerbations by 33% (4.2 months) In the subgroup analysis of UPLIFT in GOLD Stage II patients, SPIRIVA: Reduced the mean number of exacerbations per patient-year ( P<.001) Reduced hospitalization risk due to exacerbation by 14% vs control In the 6-month VA study: 14% fewer patients on SPIRIVA experienced 1 or more exacerbations vs placebo ( P =.037) Hospitalization due to COPD exacerbations was 7.0% vs 9.5% for SPIRIVA- and placebo-treated patients, respectively ( P =.056)

Important Safety Information

Spiriva HandiHaler (tiotropium bromide inhalation powder) is contraindicated in patients with a history of hypersensitivity to tiotropium, ipratropium (atropine derivatives), or any components of SPIRIVA capsules SPIRIVA HandiHaler is not indicated for the initial treatment of acute episodes of bronchospasm, i.e., rescue therapy Immediate hypersensitivity reactions, including urticaria, angioedema (swelling of lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of SPIRIVA. Additionally, inhaled medicines, including SPIRIVA, may cause paradoxical bronchospasm. If any of these occurs, treatment with SPIRIVA should be stopped and other treatments considered Patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to SPIRIVA Use with caution in patients with severe hypersensitivity to milk proteins SPIRIVA HandiHaler should be used with caution in patients with narrow-angle glaucoma or urinary retention. Prescribers should instruct patients to consult a physician immediately should any signs or symptoms of narrow-angle glaucoma, or prostatic hyperplasia or bladder-neck obstruction occur Since dizziness and blurred vision may occur with the use of SPIRIVA HandiHaler, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery As SPIRIVA is a predominantly renally excreted drug, SPIRIVA use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of 50 mL/min) SPIRIVA HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions SPIRIVA may interact additively with concomitantly used anticholinergic medications. Avoid coadministration with other anticholinergic-containing drugs The most common adverse reactions in the 1-year placebo-controlled trials were dry mouth, upper respiratory tract infection, sinusitis, pharyngitis, non-specic chest pain, and urinary tract infection. In addition, the most commonly reported adverse reactions from the 4-year trial not included above were headache, constipation, depression, insomnia, and arthralgia SPIRIVA capsules should not be swallowed and should only be inhaled through the mouth (oral inhalation) using the HandiHaler device. The HandiHaler device should not be used for administering other medications SPIRIVA capsules should always be stored in the sealed blisters, and only removed immediately before use, or else its effectiveness may be reduced

PLEASE SEE ACCOMPANYING FULL PRESCRIBING INFORMATION AND INSTRUCTIONS FOR USE.
SPIRIVA was developed by Boehringer Ingelheim Pharmaceuticals, Inc. and is being copromoted by Boehringer Ingelheim Pharmaceuticals, Inc. and Pzer Inc.

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SAR00941A

Printed on recycled paper in the U.S.A.

Copyright 2012 Boehringer Ingelheim Pharmaceuticals, Inc.

All rights reserved.

(06/12)

SV238900PROF

Product Characteristics

SPIRIVA Is a Once-Daily Maintenance Treatment for Bronchospasm and Reducing Exacerbations in Patients With COPD
There are no head-to-head data between SPIRIVA and Tudorza Pressair (aclidinium bromide inhalation powder)
SPIRIVA1 TUDORZA3-5

Long-acting bronchodilator Indicated for chronic bronchitis and emphysema Indicated to reduce COPD exacerbations Once-daily dosing

1. SPIRIVA [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2012; 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.; 3. Tudorza Pressair NDA #202450. Pulmonary-Allergy Drugs Advisory Meeting. February 23, 2012; 4. Kerwin EM et al. COPD. 2012;2:90-101; 5. Jones PW et al. Eur Respir J. 2012 (Epub ahead of print).

Please see full Prescribing Information and Important Safety Information available at this presentation.