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1 I have no conflicts of interest or financial relationships to disclose! Timothy R. Hudd BS, PharmD, RPh, AE-C Associate Professor of Pharmacy Practice MCPHS University Boston, MA Clinical Pharmacist Primary Care of the Andovers 1. Describe the pathogenesis, associated risk factors, and clinical presentation of COPD. 2. Apply evidence-based strategies published in 215 GOLD Report to help guide therapeutic decision making. 3. Utilize strategies to monitor the efficacy of a treatment regimen, as well as, ways to avoid adverse effects. 4. Demonstrate and evaluate the proper use of various inhalation devices to support patient self-management education. Salmeterol Xinafoate (Serevent Diskus ) 2/4/1994 Budesonide Inhalation Suspension (Pulmicort Respules )..8/9/2 Formoterol Fumarate (Foradil Aerolizer )..9/25/21 Tiotropium Bromide (Spiriva Handihaler ) 1/3/24 Mometasone Furoate (Asmanex Twisthaler ).3/3/25 Budesonide (Pulmicort Flexhaler )... 7/12/26 Indacaterol (Arcapta Neohaler ) 7/1/211 Ipratropium Bromide, Albuterol (Combivent Respimat )...1/7/211 Aclidinium Bromide (Tudorza Pressair )... 7/23/212 Fluticasone Furoate, Vilanterol (Breo Ellipta )... 5/1/213 Albuterol Sulfate (ProAir RespiClick )... 3/31/215 An estimated 31 85% of health professionals show incorrect technique when tested objectively Source: Basheti IA, Armour CL, Bosnic-Anticevich SZ, Reddel HK. Evaluation of a novel educational strategy, including inhaler based reminder labels, to improve asthma inhaler technique. Patient Educ Couns 28;72:26 33 Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. Asthma COPD Onset Early in life Later in life (midlife) Usual etiology Immunologic stimuli, hereditary? Tobacco use or noxious gas exposure Course Intermittent Chronic, progressive Airflow limitation Largely reversible Partially reversible Clinical features Inflammatory Cells & Mediators Episodic wheezing, chest tightness, cough, dyspnea Eosinophils Small in macrophages CD4 & Th2 lymph Mast cell activation IL-4 & IL-5 (+others) Chronic cough/sputum, persistent dyspnea Neutrophils Large in macrophages In CD8 & T lymph LTB4, IL-8,TNF-alpha Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Kelly WH, Sorkness CA. Asthma. In: Pharmacotherapy, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 6 th ed. The McGraw-Hill Companies, Inc.;25:

2 Chronic Bronchitis Chronic productive cough for 3 months in each of 2 successive years when other causes of chronic cough have been excluded Emphysema Abnormal permanent enlargement of airspaces distal to the terminal bronchioles Source: Barnes, P. Chronic Obstructive Pulmonary Disease. N Engl J Med 2;343: Inflammatory Process in COPD activates Macrophages in respiratory tract Key Indicators in patients > 4 yrs of age Dyspnea Associated Considerations Persistent Progressive Worse with exercise/activity release Chronic Cough May be intermittent & unproductive Neutrophils Chronic Sputum Production Any chronic pattern of production may indicate COPD release Proteases result in Parenchymal Destruction History of Risk Factor Exposure Tobacco Smoke Smoke from cooking/heating fuels Occupational Exposures Family History of COPD Genetic Link? Source: Adapted with permission from NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 21(Updated 23). Barnes PJ. Chronic Obstructive Pulmonary Disease. N Engl J Med. 2;343: Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Spirometry 11 An Obstructive Disorder when ratio is 7% Liters (ATPS) FEV 1 / FVC = 3.L / 4.8L =.625 or 62.5% FVC = 4.8 L FEV 1 = 3. L/sec Predicted value Based on age, height, gender and race Healthy non-smokers Patient Results FEV1 = 3.L/sec Let s say Predicted Value is 4.6L/sec 1 Compare patient s value to predicted value How would this patient s results compare? Seconds 8 3.L/4.6L =.652 or 65.2% 2

3 GOLD Spirometric Grade GOLD 1 GOLD 2 GOLD 3 GOLD 4 Severity Mild Moderate Severe Very Severe *Post- Bronchodilator FEV1 FEV1 8% predicted FEV1 5% - 8% predicted FEV1 3% - 5% predicted FEV1 < 3% predicted * In patients with FEV1/FVC <.7 **Note: Risk estimates from placebo data from TORCH and ECLIPSE studies Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease [adapted Figures 2.5 & 2.6] (Updated 215) **Annual Hospitalization Risk Estimate????? GOLD Definition: An acute event characterized by a worsening of the patient s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medications. The rate at which exacerbations occur varies greatly between patients! Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Very poor 1 Health Status (SGRQ) Good GOLD 2 GOLD 3 FEV1 (% predicted) GOLD Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease adapted Figure 2.2 (Updated 215). R= -.23 P<.1 Upper limit of normal mmrc Grade mmrc Grade 1 mmrc Grade 2 mmrc Grade 3 mmrc Grade 4 I only get breathless with strenuous exercise I get short of breath when hurrying on the level or walking up a slight hill I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking at my own pace on the level I stop for breath after walking about 1 meters or after a few minutes on the level I am too breathless to leave the house or I am breathless when dressing or undressing Check the box that applies to you (one box only) I never cough I have no phlegm (mucus) in my chest at all My chest does not feel tight at all When I walk up a hill or 1 flight of stairs I am not breathless I am not limited doing any activities at home I am confident leaving my home despite my lung condition I sleep soundly I have lots of energy I cough all the time My chest is completely full of phlegm (mucus) My chest feels very tight When I walk up a hill or 1 flight of stairs I am very breathless I am very limited doing activities at home I am not at all confident leaving my home because of my lung condition I don t sleep soundly because of my lung condition I have no energy at all Lung Function GOLD 4 GOLD 3 GOLD 2 GOLD 1 Symptom Scores (mmrc or CAT Score) Total Score Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease adapted Figure 2.3 (Updated 215). C A mmrc -1 CAT <1 D B mmrc 2 CAT 1 1 leading to hospital admission # Exacerbations in Past Year 3

4 Please assign Mr. Peabody to the appropriate Group CAT Score of 16 FEV1 = 58% predicted Has had 2 exacerbations in the past 12 months Group Characteristics Spirometric Classification Exacerbations per year mmrc CAT A Low Risk; Less Symp GOLD <1 B Low Risk; More Symp GOLD C High Risk; Less Symp GOLD < 1 D High Risk; More Symp GOLD Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease [adapted Figure 4.2] (Updated 215). Relieve symptoms Improve exercise tolerance Improve health status And Prevent progression Prevent & treat exacerbations Reduce mortality Symptoms Risk Control comorbidities (e.g. GERD, etc) Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (Updated 215). Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Teaching Slide Deck Adapted Slide 18 (Updated 215). FEV 1 (% of value at age 25) Disability Death Age (y) Source: Fletcher C. The natural history of chronic airflow obstruction. BMJ Used with permission from BMJ Publishing Group. Never smoked or not susceptible to smoke Smoked regularly and susceptible to its effects Stopped smoking at 45 Stopped smoking at 65 Short Acting -2 Agonists Examples: Albuterol Levalbuterol Long Acting -2 Agonists Examples: Salmeterol Formoterol Arformoterol Short Acting Anticholinergics Example: Ipratropium Long Acting Anticholinergics Examples: Aclidinium Glycopyrrolate Tiotropium Umeclidinium Ultra Long Acting -2 Agonists Methylxanthines Examples: Indacaterol Example: Theophylline Olodaterol **Vilanterol ** Only commercially available in combination with other agents 4

5 Ach Bronchodilation Bronchial Tone + Muscarinic Theophylline Antagonists Bronchoconstriction Adenosine AC camp PDE ATP AMP ß2-agonist Theophylline Drugs Used in Asthma - Homer A. Boushey, MD, & Bertram G. Katzung, MD, PhD + - Cost & Coverage!!! Product availability Adverse effect profile Patient population (e.g. children, pregnancy, etc) Lifestyle Patient preference Prior experience Ability to use device Lung function Cognitive function Dexterity & strength In-Check Dial Kit Simulates inhalation through inhalers Informs users of optimum inspiratory flow rates Clemente-Clark. In-Check Dial. Accessed 5/4/15 Diskus 3-9L/min Flexhaler 6-9L/min Autohaler 3-6L/min Aerolizer 6-12L/min HandiHaler 2-45L/min Twisthaler 6-9L/min Examples How to use inhalers - interactive guidance and management. useinhalers.com National Jewish Health. Inhaled Medication Instructional Videos: Asthma and General Lung Diseases. Centers for Disease Control and Prevention (213). Know How to Use Your Asthma Inhaler. Retrieved from Allergy and Asthma Network Mothers of Asthmatics: Product manufacturer websites A B C D Randomized Controlled Trials (RCTs) Rich body of data Randomized Controlled Trials (RCTs) Limited body of data Non-Randomized Trials Observational Studies Panel Consensus Judgment Lung Function GOLD 4 GOLD 3 GOLD 2 GOLD 1 Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease adapted Figure 2.3 (Updated 215). C A D B mmrc -1 mmrc 2 CAT <1 CAT 1 Symptom Scores (mmrc or CAT Score) # Exacerbations in Past Year 5

6 Group A B Recommended First Choice SAMA PRN or SABA PRN LAMA or LABA Alternative Choice LAMA or LABA or SAMA + SABA LAMA + LABA Other Possible Treatments** Theophylline SAMA and/or SABA Theophylline Decrease symptoms Inhaled route is preferred Improve health status & exercise tolerance Reduce exacerbation frequency & severity Prescribe PRN or on a regular basis to prevent or reduce symptoms (Evidence A) ** Medications in this column can be used alone or in combination with other options SAMA = Short acting antimuscarinic SABA = Short acting beta-agonist LAMA = Long acting antimuscarinic LABA = Long acting beta-agonist Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease [adapted Figure 4.4] (Updated 215). Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Beta- 2 Agonists Rescue Products Proventil HFA (albuterol) ProAir RespiClick (albuterol) ProAir HFA (albuterol) Xopenex HFA (levalbuterol) Ventolin HFA (albuterol) FDA Approval # Doses Dose Priming Cost 4-years + 2 9mcg 1 st use & 2 weeks (4 sprays) $ years + 2 9mcg None $6.2 4-years + 2 9mcg 4-years mcg 4-years Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 Sept 3] 9mcg 1 st use & 2 weeks (3 sprays) 1st use & after 3days (4 sprays) 1 st use & 2 weeks (4 sprays) $6.2 $74.52 $54.28 RespiClick Device Indication Treatment or prevention of bronchospasm in 12 years + Prevention of exercise-induced bronchospasm in 12 years + Features Dose counter Click open ~ loads dose Expires 13 months after opening No priming or cleaning required Breath activated device (Dry Powder) Counts down by even numbers only Product Information: PROAIR(R) RESPICLICK(TM) oral inhalation powder, albuterol sulfate oral inhalation powder. Teva Respiratory, LLC, Horsham, PA, 215 Metered Dose Inhaler Steps: Hold inhaler in an L position (mouth piece down) Shake well before each use (if necessary) Remove the cap from the mouthpiece Exhale completely Seal lips around mouthpiece Breathe in deeply and depress canister to deliver dose Remove inhaler from mouth and hold breath for about 1 seconds before breathing out Wait a predefined period of time in between puffs Replace cap on mouthpiece Note: Prime inhaler according to MFR instructions (before 1 st use and/or after a pre-defined period of non-use) Product Information: Ventolin (R) HFA oral inhalation aerosol, albuterol sulfate oral inhalation aerosol. GlaxoSmithKline, Research Triangle Park 214 6

7 Combivent Respimat Respimat Components Combivent Respimat ($354.85) Dose: One puff QID (Max 6 puffs/day) Indication: COPD uncontrolled on a regular aerosol bronchodilator and require a second Features: Spring release no propellant Locking mechanism when empty Potential Issues: Frequent priming Expires 3 months after inserting the cartridge Cumbersome steps to load cartridge system into device Source: Product Information: Combivent Respimat. Boehringer Ingelheim Pharmaceuticals. Ridgefield, CT February 212 Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 September 3] Product Information: COMBIVENT(R) RESPIMAT(R) oral inhalation spray, ipratropium bromide albuterol oral inhalation spray. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 212. Respimat - Preparation With the cap closed, press the safety catch while pulling off clear base Write the discard date on the inhaler Remove the cartridge from the box. Push the narrow end of the cartridge into the inhaler The base of the cartridge will not sit flush with the inhaler base Put the clear base back into place Do not remove the clear base or cartridge again Hold the inhaler upright with the cap closed Turn the base in the direction of the white arrows on the label until it clicks (half a turn) Flip the cap until it snaps open Pointing towards the ground, press the dose-release button Repeat these steps until a spray is visible, then repeat 3 more times to ensure the inhaler is ready for use Product Information: COMBIVENT(R) RESPIMAT(R) oral inhalation spray, ipratropium bromide albuterol oral inhalation spray. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 212. Respimat - Technique Hold the inhaler upright with the cap closed Turn the clear base in the direction of the white arrows on the label until it clicks (half a turn) Flip the cap until it snaps open fully Breathe out slowly, away from the inhaler Close your lips around the end of the mouthpiece Don t cover the air vents with fingers or lips While taking in a slow, deep breath through your mouth, press the dose-release button and continue to breathe in slowly for as long as you can Hold your breath for 1 seconds Exhale slowly and close the cap Product Information: COMBIVENT(R) RESPIMAT(R) oral inhalation spray, ipratropium bromide albuterol oral inhalation spray. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 212. Serevent Diskus 5mcg Foradil Aerolizer 12mcg For both beta 2 -agonists and anticholinergics [antimuscarinics], long-acting formulations are preferred over short-acting formulations (Evidence A) Chemical Name Salmeterol Formoterol # Doses & Cost 6 doses ($336.62) 6 doses ($291.55) Onset 3 minutes 5 minutes Age Approved >4 yrs age >5 yrs age Dose 5mcg inh BID 12mcg via device Q12 h Expiration 6 weeks from opening foil pouch 4 months when stored at room temperature Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 Sept 3] 7

8 Brovana (Arformoterol) 12mcg/2ml ($ ct) Dosing: One nebulization (15mcg) Q12 hours Features/Notes Store in the refrigerator until ready to use May be stored at room temp for up to 6-weeks Do not combine with other nebulized solutions Perforomist (Formoterol Fumarate) 2mcg/2ml ($ ct) Dosing: One nebulization (2mcg) Q12 hours Features/Notes Store in the refrigerator until ready to use May be stored at room temp for up to 3 months Do not combine with other nebulized solutions Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 April 25] Indacaterol maleate (Arcapta Neohaler 75mcg) ($ ct) Approved July 211 Dose: 75mcg once daily Onset 5 min and last up to 24 hours o Whirring sound - + feedback o May require multiple inhalations Olodaterol (Striverdi Respimat 2.5 mcg) ($ ct) Approved July 214 Dose: Use 2 inhalations (5mcg) once daily Onset 5 min and last up to 24 hours o See comments related to Respimat Device Pricing Based on AWP Redbook Online. Thomson Reuters, cited 215 Sept 3] Anticholinergics [aka Antimuscarinics ] Images adapted from Arcapta Neohaler [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; September 212 Short Demonstration video - Antimuscarinic Comparison Parasympathetic Nerves M 1 CNS Cranial Nerve X M 2 Inhibits Ach Release Medication Class Estimated Onset (Inhaler) Atrovent HFA (Ipratropium) Short Acting (SAMA) Tudorza Pressair (Aclidinium bromide) Long Acting (LAMA) Spiriva (Tiotropium) Long Acting (LAMA) 15-2 minutes 5-15 minutes 3 minutes Acetylcholine M 3 RECEPTORS Acetylcholine AIRWAY SMOOTH MUSCLE CELLS MUCUS GLANDS Source: Drawing by Dennis E. Doherty, MD, University of Kentucky Medical Center. Used with permission. M 1 RECEPTORS M 2 RECEPTORS M 3 RECEPTORS Peak Effect hours 2 hours 3 hours Duration of Action (approx) 4-6 hours Up to 12 hours 24 hours (approx) # of Doses/ Device 2 actuations 6 actuations 3 blister units Inhaler Pricing $ $ $ Pricing Based on AWP Redbook Online Thomson Reuters 215 [cited 215 Sept 3] 8

9 Spiriva Handihaler 18mcg - Inhale 1 capsule once daily - Dexterity is important - Expires per MFR date Spiriva Respimat 2.5mcg - Use 2 puffs (5mcg) once daily - Initial cartridge load cumbersome - Expires 9 days after loading Spiriva HandiHaler Product Information: SPIRIVA(R) RESPIMAT(R) Boehringer Ingelheim Pharmaceuticals, Inc. (per Manufacturer), Ridgefield, CT, 214 Product Information: SPIRIVA(R) HandiHaler(R). Boehringer Ingelheim Pharmaceuticals, Inc. (per Manufacturer), Ridgefield, CT, 214. SPIRIVA and HandiHaler [package insert] Boehringer Ingelheim Pharmaceuticals, Inc. 214 Spiriva HandiHaler - Components Spiriva HandiHaler - Preparation Separate only one of the blisters from the blister card; then open the blister Open the dust cap (lid) by pressing the green piercing button Open the mouthpiece by pulling the mouthpiece ridge up and away from the base so the center chamber is showing Insert the capsule in the center chamber and close the mouthpiece firmly against the gray base until you hear a click Press the green piercing button until it is flat against the base, then release Do not press the green button more than once and do not shake the device SPIRIVA and HandiHaler [package insert] Boehringer Ingelheim Pharmaceuticals, Inc. 214 SPIRIVA and HandiHaler [package insert] Boehringer Ingelheim Pharmaceuticals, Inc. 214 Spiriva HandiHaler - Technique Hold your head in an upright position while looking straight ahead Breathe out completely. Then, with the Handihaler in your mouth, breathe in deeply until your lungs are full. You should hear or feel the capsule vibrate (rattle) Do not block the air intake vents with your fingers Take a second inhalation to ensure the contents of the capsule have been inhaled completely Remove any capsule pieces by turning your Handihaler upside down and gently tapping it Aclidinium Bromide Class: LAMA Dose: One inhalation (4mcg) twice daily Indication: Long-term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema Features - Faster onset, but shorter duration than tiotropium - No cleaning, no priming, no shaking - Expires 45 days after opening - Rapidly hydrolyzed in the plasma SPIRIVA and HandiHaler [package insert] Boehringer Ingelheim Pharmaceuticals, Inc. 214 Product Information: Tudorza Pressair ) aclidinium bromide inhalation powder. Forest Pharmaceuticals, INC. St Louis, MO

10 Tudorza Pressair Components Tudorza Pressair - Preparation Remove inhaler from pouch Remove cap by lightly squeezing the arrows marked on each side of the cap and pulling Hold the inhaler with the mouthpiece facing you. The green button should be facing straight up Before placing the inhaler in your mouth, press the green button all the way down and release Do not continue to hold the button down Check the control window to make sure the dose is ready for inhalation. This will be evident by the window turning from red to green Product Information: TUDORZA(TM) PRESSAIR(TM) oral inhalation powder, aclidinium bromide oral inhalation powder. Forest Pharmaceuticals, Inc, St Louis, MO, 212. Product Information: TUDORZA(TM) PRESSAIR(TM) oral inhalation powder, aclidinium bromide oral inhalation powder. Forest Pharmaceuticals, Inc, St Louis, MO, 212. Tudorza Pressair - Technique Breathe out completely, away from the inhaler Place your lips tightly around the mouthpiece Breathe in quickly and deeply through your mouth. Continue breathing in after you hear a click from the inhaler Remove the inhaler from your mouth and hold your breath for 1 seconds, then breathe out slowly through your nose To ensure you have received your dose correctly, check to be sure the control window has turned back to red Recap Product Information: TUDORZA(TM) PRESSAIR(TM) oral inhalation powder, aclidinium bromide oral inhalation powder. Forest Pharmaceuticals, Inc, St Louis, MO, 212. Glycopyrrolate $ Class: LAMA Dose: Inhale 1 capsule (15.6 mcg) twice daily Indication: long-term, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Features - Rapid onset of action - No cleaning, no priming, no shaking - May require multiple inhalations to clear capsule Incruse Ellipta (umeclidinium bromide inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; June Umeclidinium Bromide $ Class: LAMA Dose: One inhalation (62.5mcg) daily Indication: long-term, maintenance treatment of airflow obstruction in COPD, including chronic bronchitis and/or emphysema Features - No cleaning, no priming, no shaking - Expires 6 weeks after opening - Rapid onset and similar duration than tiotropium Incruse Ellipta (umeclidinium bromide inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; June Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 Sept 3] Hold the inhaler in the upright position Slide cover down to expose the mouth piece The click indicates dose is ready Exhale away from device Place lips around mouthpiece and take a long steady deep inhalation Do not block air vent with fingers Hold breath for 3-4 seconds Exhale slowly Close the inhaler Note: Discard 6 weeks after opening or when counter reads Incruse Ellipta (umeclidinium bromide inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; June

11 FDA recently announced that long term use of Spiriva HandiHaler (tiotropium) is NOT associated with an increased risk stroke, heart attack, or death from a cardiovascular cause. 1 Controversy stemmed from pooled data from a large meta-analysis. 2 The Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial used to support the FDA s position. 3 Lung Function GOLD 4 GOLD 3 GOLD 2 GOLD 1 1. Follow-Up to the October 28 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler). FDA s Post market Drug Safety Information for Patients and Providers. Jan.14, 21. Accessed May 7, CAT <1 CAT 1 2. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 28:3; 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. 28;359: Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease adapted Figure 2.3 (Updated 215). C A mmrc -1 D B mmrc 2 Symptom Scores (mmrc or CAT Score) # Exacerbations in Past Year Group Recommended First Choice C ICS + LABA or LAMA ICS = Inhaled corticosteroid Alternative Choice LAMA + LABA or LAMA + PDE4I or LABA + PDE4I PDE4I = Phosphodiesterase Inhibitor Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease [adapted Figure 4.4] (Updated 215). Other Possible Treatments** SAMA and/or SABA Theophylline Carbocysteine ICS + LAMA+LABA or ICS + LABA N-acetylcysteine ICS + LABA+PDE4I or D And/or SAMA and/or LAMA + LABA or LAMA SABA LAMA + PDE4I Theophylline ** Medications in this column can be used alone or in combination with other options Regular treatments with ICS improves symptoms, lung function, and quality of life, and reduces the frequency of exacerbations in COPD patients with an FEV1<6% predicted (Evidence A) An ICS + LABA regimen is more effective than the individual components in reducing exacerbations, improving health status and lung function in patients with Moderate COPD (Evidence B) to Severe COPD (Evidence A) 1. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.n Engl J Med. 27 Feb 22;356(8): NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (Updated 215). ICS+LABA Products Advair Diskus Advair HFA Symbicort HFA Dulera HFA Active Components Fluticasone+ Salmeterol Fluticasone + Salmeterol Budesonide + Formoterol Mometasone + Formoterol Dosing 1 puff BID 2 puffs BID 2 puffs BID 2 puffs BID How Supplied & Cost 1/5 $ /5 $ /5 $ /21 $ /21 $ /21$ /4.5 $ /4.5 $ /5. $ /5. $37.78 #Doses 6 doses 124 doses 12 doses 124 doses Priming (Initially &Time after non-use) Expiration N/A 1 month of opening foil wrapper 1 st use & 4 weeks (4 sprays/2after) Per date set by MFR Pricing Based on AWP Redbook Online. Thomson Reuters, 215 (cited 215 Sept 3] 1 st use & 7 days (2 sprays) 3 month of opening foil wrapper 1 st use & 5 days (4 sprays) Per date set by MFR Fluticasone furoate/vilanterol $ Class: ICS/LABA Strengths: **1mcg/25mcg & 2mcg/25mcg Dose: One inhalation once daily Indication: Maintenance treatment of airflow obstruction & reducing exacerbations in COPD Features - No cleaning, no priming, no shaking - Expires 6 weeks after opening - Vilanterol component - bronchodilation approx. 5 min ** Only strength FDA approved for COPD Breo Ellipta (fluticasone furoate/vilanterol) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; April 215 Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 Sept 3] 11

12 Steps: Diskus Hold the inhaler like a hamburger with the mouthpiece facing you Place thumb on thumb grip and slide away from you to reveal the mouthpiece To load dose: slide the lever away from you until it clicks Breathe out away from the inhaler Place the mouthpiece in your mouth and breathe in forcefully and deeply Remove the inhaler from your mouth and hold breath for about 1 seconds before breathing out Wait one minute in between doses If ICS, rinse mouth with water (do not swallow) Close mouthpiece Inhaled corticosteroid therapy is associated with a small increased risk of pneumonia. Withdrawal from treatment with inhaled corticosteroids may lead to exacerbations in some. Regular treatment with ICS does NOT modify the long term decline of FEV1, nor mortality in patients with COPD.(Evidence A) Adding a LAMA to a ICS/LABA regimen may provide an additional benefit. Advair Diskus [package insert]. Research Triangle Park, NC: GlaxoSmithKline; revised April Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (Updated 215). LAMA + LABA Combinations Product Ingredients & Strengths Image Anoro Ellipta umeclidinium/vilanterol Once Daily 62.5 mcg/25mcg $ a Stiolto Respimat Once Daily $ a Utibron Neohaler Twice Daily $ FDA Approval 12/18/13 b tiotropium/olodaterol 2.5mcg/2.5mcg FDA Approval 5/21/15 b glycopyrrolate/indacaterol 15.6mcg/27.5mcg FDA Approval 1/29/15 b Theophylline Advantages: Reduce pulmonary vascular resistance Reduce pulmonary inflammation Low dose theophylline reduces exacerbations in patients with COPD but does not increase post-bronchodilator lung function. (Evidence B) Disadvantages Narrow Therapeutic Index SE s and Toxicity especially in elderly Multiple drug-drug interactions (i.e. smoking) Limited role in COPD- cause mild bronchodilation a) Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 Nov 6] b) Drugs@FDA Roflumilast (Daliresp ) ($39.46 Qty #3) Once daily add-on option in patients not controlled on a bronchodilator Pros Oral capsule Weight loss May decrease exacerbation frequency Cons Psychiatric disturbances?? Metabolized mostly via CYP3A4 and CYP1A2 Nausea is the most common adverse effect Combination Products Fluticasone furoate/umeclidinium/vilanterol (ICS+ LAMA+LABA) (GlaxoSmithKline/Theravance) GSK Bifunctional molecule (muscarinic antagonism/beta2-agonist) (GlaxoSmithKline/Theravance) Broad-spectrum anti-inflammatory drugs Phase II studies AZD Inhaled P38 inhibitor MEDI Anti-interleukin-5 Receptor Alpha Monoclonal Antibody Soluble epoxide hydrolase (seh) inhibitor Intracellular phosphoinositide-3-kinase (PI3K) inhibitor Danirixin - Chemokine receptor antagonist (CXCR2) Pricing Based on AWP Redbook Online. Thomson Reuters, 215 [cited 215 Sept 3s] Source - Accessed Sept 3,

13 Mucolytics & Antioxidants - (e.g. N-acetylcysteine) Widespread use not recommended at this time (Evidence D) Antitussives Regular use not recommended (Evidence D) Leukotriene Modifiers Not been adequately tested Anti-TNF alpha antibody (e.g. infliximab) No benefit when tested in Mod-severe COPD. Harm? Alternative Therapies Not been adequately tested Vitamin D Not recommended at this time mixed results Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215). Multidisciplinary program of care Exercise training Education Psychological counseling Nutritional counseling Patients at any stage of COPD can benefit particularly Groups B, C, and D Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. Executive Summary (Updated 215) Influenza 1 Trivalent or quadrivalent inactivated influenza vaccine annually Newer abbreviations IIV3 and IIV4 Pneumococcal 2 Frequency Depends on severity Spirometry recommended annually Assess the following at every visit QOL Medication adherence Inhalation technique Patient related concerns COPD control/symptom Changes Trigger Management 1 CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, influenza season. August 7, (Accessed Sept 3, 215). 2. CDC. CDC. Intervals Between PCV13 and PPSV23 Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 9/4/15;64(34); Available: 1. FEV1/FVC < 7% 2. FEV1/FVC < 6% 3. FEV1 < 8% 4. FEV1 < 7% 5. Not sure 1. Ipratropium 2. Tiotropium 3. Smoking cessation 4. Influenza vaccination 5. Not sure 13

14 1. Salmeterol Long acting antimuscarinic (LAMA) 2. Aclidinium Bromide Long acting beta agonist (LABA) 3. Ipratropium Short acting antimuscarinic (SAMA) 4. Indacaterol Inhaled corticosteroid (ICS) 5. Not sure Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur Respir J 29;34: Cazzola M, Calzetta L, Matera MG. Beta-2 adrenoceptor agonists: current and future direction. British Journal of Pharmacology 211;163: Accessed March 9, 212. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.n Engl J Med. 27 Feb 22;356(8): Drummond MB, Dasenbrook EC, Pitz MW, et.al. Inhaled Corticosteroids in patients with stable chronic obstructive pulmonary disease. JAMA. 28;3(2): Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease. JAMA. 28;3(12): Ogale SS, Lee TA, Au DH, et.al.cardiovascular events associated with ipratropium bromide in COPD. Chest 21;137; Tashkin DP, Celli B, Senn S, et.al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 28;359: Wedzicha1 JA, Calverley PA, Seemungal TA, et.al. The Prevention of Chronic Obstructive Pulmonary Disease Exacerbations by Salmeterol/Fluticasone Propionate or Tiotropium Bromide. Am J Respir Crit Care Med Vol 177. pp 19 26, 28 Tudorza Pressair [package insert]. St. Louis, MO: Forest Laboratories, Inc.; 212. Additional References Product Information: PROAIR HFA(R) inhalation aerosol, albuterol sulfate inhalation aerosol. Teva Specialty Pharmaceuticals,LLC, Horsham, PA, 28. Product Information: PROVENTIL(R) HFA oral inhalation aerosol, albuterol sulfate oral inhalation aerosol. Schering Corporation, Kenilworth, NJ, 27 Product Information: VENTOLIN(R) HFA inhalation aerosol, albuterol sulfate HFA inhalation aerosol. GlaxoSmithKline, Research Triangle Park, NC, 28 Product Information: XOPENEX HFA(TM) oral inhalation aerosol, levalbuterol tartrate oral inhalation aerosol. Sepracor Inc., Marlborough, MA, 25. Product Information: Advair Diskus(R), fluticasone propionate and salmeterol inhalation powder. GlaxoSmithKline, Research Triangle Park, NC, 22. Product Information: SYMBICORT(R) oral inhalation, budesonide formoterol fumarate dihydrate oral inhalation. Astra Zeneca, Wilington, DE, 21 Product Information: DULERA(R) inhalation aerosol, mometasone furoate formoterol fumarate dihydrate inhalation aerosol. Schering Corporation, Whitehouse Station, NJ,

15 DPI = Dry powder inhaler MDI = Metered dose inhaler SMI = Soft mist inhaler Inhaled Therapeutic Options for COPD Medication Brand Name & Strength (per inhalation) Chemical Name Device # of Doses a /Device or Box Short Acting Beta-2 Agonists ProAir HFA 9mcg, Proventil HFA 9mcg, Ventolin HFA 9mcg Albuterol MDI 2 b ProAir RespiClick 9mcg Albuterol DPI 2 AccuNeb.63mg/3ml, 1.25mg/3ml Albuterol Nebulizer varies Proventil 2.5mg/3ml (.83%), **5mg/ml (.5%) concentrate Xopenex HFA 45mcg Levalbuterol MDI 2 b Xopenex.31mg/3ml,.63mg/3ml, 1.25mg/3ml, **1.25mg/.5ml concentrate Levalbuterol Nebulizer varies Short Acting Anticholinergic Atrovent HFA 17mcg Ipratropium MDI 2 b Atrovent.2% (.5mg/2.5ml) vial Ipratropium Nebulizer 25ct, 3ct, 6ct Short Acting Anticholinergic + Beta-2 Agonist Combination Combivent Respimat 2-1mcg Ipratropium + Albuterol SMI 12 b DuoNeb.5mg-2.5mg/3ml vial Ipratropium + Albuterol Nebulizer 3ct, 6ct Long Acting Beta-2 Agonists Serevent Diskus 5mcg Salmeterol DPI 6 Foradil Aerolizer 12mcg Formoterol DPI 6 blister units Brovana 15mcg/2ml vial Arformoterol Nebulizer 3ct, 6ct Perforomist 2mcg/2ml vial Formoterol Nebulizer 3ct, 6ct Long Acting Beta-2 Agonists (Once Daily) Arcapta Neohaler 75mcg Indacaterol maleate DPI 3 blister units Striverdi Respimat 2.5mcg Olodaterol SMI 6 b a) Institutional sizes not included b) Number of doses after initial priming * Only FDA approved strength for COPD other strengths may be commercially available Nebulized solutions marked.5 ml concentrate should be diluted with.9% Sodium Chloride Solution Last Revised 11/15 Authors: Timothy R. Hudd, BS, Pharm.D. and Kathy Zaiken, Pharm.D.

16 DPI = Dry powder inhaler Inhaled Therapeutic Options for COPD - continued Long Acting Anticholinergics Spiriva HandiHaler 18mcg Tiotropium DPI 3 blister units Spiriva Respimat 2.5mcg Tiotropium SMI 6 b Tudorza Pressair 4mcg Aclidinium bromide DPI 6 Incruse Ellipta 62.5mcg Umeclidinium DPI 3 blister units Seebri Neohaler 15.6mcg Glycopyrrolate DPI 6 blister units Inhaled Corticosteroid + Long Acting Beta-2 Agonist Combination *Advair Diskus 25/5mcg Fluticasone + Salmeterol DPI 6 *Symbicort HFA 16mcg/4.5mcg Budesonide + Formoterol MDI 12 b *Breo Ellipta 1-25mcg Fluticasone + Vilanterol DPI 6 blister units Long Acting Anticholinergic + Beta-2 Agonist Combination Anoro Ellipta mcg Umeclidinium + Vilanterol DPI 6 blister units Stiolto Respimat mcg Tiotropium + Olodaterol SMI 6 b Utibron Neohaler mcg Glycopyrrolate + Indacaterol DPI 6 blister units MDI = Metered dose inhaler SMI = Soft mist inhaler a) Institutional sizes not included b) Number of doses after initial priming * Only FDA approved strength for COPD other strengths may be commercially available Nebulized solutions marked.5 ml concentrate should be diluted with.9% Sodium Chloride Solution Last Revised 11/15 Authors: Timothy R. Hudd, BS, Pharm.D. and Kathy Zaiken, Pharm.D.