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David Young, Pharm.D.

There are no relationships to disclose related to this presentation.

David Young, Pharm.D. Professor of Pharmacotherapy L.S. Skaggs Pharmacy Institute Rm 4916 581-8510 [email protected]

¡ Differentiate between the stages of ¡ Define asthma and copd and copd based on current guidelines ¡ Identify which medications are classified as ¡ Recognize the current therapeutic options to long-term control and quick-relief treat patients with asthma and copd medications ¡ Identify an appropriate stepwise approach to ¡ Identify potential adverse effects from long- treat patients with asthma and copd term control and quick-relief medications ¡ Recognize the importance of correct inhaler ¡ Recognize the importance of correct inhaler technique technique

¡ Affects 8% of US population § 25.7 million in 2010 § 1:11 children § 1:12 adults § 8.9 million office visits in 2009 § 1.9 million emergency room visits in 2009 § 479,00 hospitalizations in 2009 § 14.2 million missed work in 2006 David Young, Pharm.D. Professor of Pharmacotherapy L.S. Skaggs Pharmacy Institute Rm 4916 581-8510 [email protected] http://www.cdc.gov/asthma/impacts_nation/AsthmaFactSheet.pdf accessed 5/18

1 ¡ High cost Asthma is a chronic inflammatory disorder of § $56 billion/year the airways where the obstruction is: § $3,300/person/year a) reversible ¡ Mortality b) irreversible § 3388 deaths in the US in 2009 c) untreatable d) permanent

http://www.cdc.gov/asthma/impacts_nation/AsthmaFactSheet.pdf accessed 12/17

¡ “Asthma is a CHRONIC INFLAMMATORY disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this INFLAMMATION is associated with recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable airflow obstruction within the lung that is often REVERSIBLE either spontaneously or with treatment. ”

EPR 3, 2007

histamine, , mast cell é Vascular permeability prostaglandins, bradykinin é Mucus production IL-5 IgE Cytokines VCAM-1 (TLSP) eosinophils macrophage Antigen IL-4 B lymphocyte

IL-4 IL-13 IL-3, IL-5,

GM-CSF T lymphocyte IL-8 neutrophils

Chemokines Inflammation:

LTB-4 1. Acute sx 2. Subacute sx 3. Chronic sx 4. Airway

Adapted from EPR 2, 1997 remodeling

2 ¡ Etiology / Triggers ¡ Reduce impairment ¡ Reduce risk § Prevent chronic and § Prevent recurrent § Allergens troublesome symptoms exacerbations of asthma § Require infrequent use and minimize the need for § Exercise (<2 day/week) of inhaled emergency department SABA (ED) visits or § Infections § Maintain (near) normal hospitalizations § Occupational pulmonary function § Prevent progressive loss § Maintain normal activity of lung function; for § Environmental levels (including exercise) children, prevent reduced lung growth § Meet patients’ and § Drugs / Foods families’ expectations of § Provide optimal satisfaction with asthma pharmacotherapy with care minimal or no adverse effects

EPR 3, 2007 EPR 3, 2007

AB is at your clinic with a 4-week history of coughing and shortness of breath (SOB) three times/week that awakens him at night 1 time/week. He also reports that he feels that his asthma has impacted his ability to exercise. His current medications include: albuterol prn, lisinopril/hctz, atorvastatin, metformin. Based on the above case, how would you classify AB’s asthma control according to the GINA guidelines?

a) Controlled b) Partially controlled c) Uncontrolled d) Persistent

A. Symptom control 1. Well- Partly Uncontrolled Asthma control - two domains In the past 4 weeks, has the patient had: controlled controlled § Assess symptom CONTROL over the last 4 weeks • Daytime asthma symptoms more § Assess RISK FACTORS for poor outcomes, including low lung than twice a week? function Yesq Noq 2. Treatment issues • Any night waking due to asthma? § Check inhaler technique and adherence § Ask about side-effects Yesq Noq None of 1-2 of 3-4 of • Reliever needed for symptoms* these these these § Does the patient have a written asthma action plan? more than twice a week? § What are the patient’s attitudes and goals for their asthma? Yesq Noq 3. Comorbidities • Any activity limitation due to asthma? § Think of rhinosinusitis, GERD, obesity, obstructive sleep apnea, depression, anxiety Yesq Noq § These may contribute to symptoms and poor quality of life B. Risk factors for poor asthma outcomes • Assess risk factors at diagnosis and periodically • Measure FEV at start of treatment, after 3 to 6 months of treatment to record the patient’s GINA, 2017 1 Adapted from GINA, 2017 personal best, then periodically for ongoing risk assessment GINA 2017, Box 2-1 GINA 2017,ASSESS PATIENT’S RISKS FOR: Box 2-1 • Exacerbations • Fixed airflow limitation • Medication side-effects

3 ¡ Risk factors for exacerbations include: How? § • Ever intubated for asthma Asthma severity is assessed retrospectively from the level of • Uncontrolled asthma symptoms treatment required to control symptoms and exacerbations • Having ≥1 exacerbation in last 12 months ¡ When? • Low FEV1 (measure lung function at start of treatment, at 3-6 months to assess personal best, and § Assess asthma severity after patient has been on controller treatment periodically thereafter) for several months • Incorrect inhaler technique and/or poor adherence • Smoking § Severity is not static – it may change over months or years, or as • Elevated FeNO in adults with allergic asthma different treatments become available • Obesity, pregnancy, blood eosinophilia ¡ Categories of asthma severity Risk factors for fixed airflow limitation include: § Mild asthma: well-controlled with Steps 1 or 2 (as-needed SABA or low • No ICS treatment, smoking, occupational exposure, mucus hypersecretion, blood eosinophilia dose ICS) Risk factors for medication side-effects include: § Moderate asthma: well-controlled with Step 3 (low-dose ICS/LABA) • Frequent oral steroids, high dose/potent ICS, P450 inhibitors § Severe asthma: requires Step 4/5 (moderate or high dose ICS/LABA ± add-on), or remains uncontrolled despite this treatment

GINA, 2017 Adapted from GINA, 2017 GINA 2017, Box 2-1 GINA 2017

¡ Severity based on treatment required to Which of the following asthma medications is a control symptoms and exacerbations reliever? ¡ Follow up regularly to assess effectiveness of a) fluticasone therapy b) ¡ Step up / down based on response to therapy c) d) levalbuterol

¡ Short-acting beta-2 agonist (SABA) § Albuterol ▪ MDI (Albuterol HFA, Proventil HFA, Ventolin HFA, ProAir HFA) ▪ DPI (ProAir RespiClick) ▪ Nebulized ▪ Oral tablets & syrup § Levalbuterol ▪ MDI (Xopenex HFA) ▪ Nebulized (Xopenex) § Epinephrine (Asthmanefrine) ▪ Approved >4yrs ▪ 0.5ml (11.25mg epinephrine) via EZ Breathe Atomizer 1-3 inhalations every 3 hours prn (maximum 12 inhalations/24hr) ▪ Seek medical help if no relief in 20 minutes ¡ Short-acting (SAMA) § MDI (Atrovent HFA) § Nebulized (Ipratropium)

4 ¡ Albuterol, Levalbuterol ¡ Clinical Use ¡ Ipratropium § Relief of acute symptoms / attacks ¡ Clinical use: § Prevention of exercise-induced bronchospasm (EIB) § Off label use for asthma in combination with § Frequency of use = good monitoring tool SABA for acute exacerbations (Combivent, ▪ SABA <1 MDI/month ¡ Adverse effects Duoneb) § Anxiety, insomnia, tremor, and palpitations § DOES NOT PRECLUDE THE USE OF ▪ MDI

GINA, 2017 GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

¡ Albuterol/Ipratropium ¡ Inhaled corticosteroid ¡ ICS + LABA (Long-acting (ICS) beta-2 agonist) § § Combivent Respimat (100mcg/20mcg) § Beclomethasone (Qvar; Qvar proprionate/ Redihaler) (Advair diskus, ▪ 1 inhalation QID (max 6/24hr) Advair HFA, Airduo) § Budesonide (Pulmicort Flexhaler, Pulmicort Respules) § Budesonide/ § Duoneb (2.5mg/0.5mg) (Symbicort HFA) § (Alvesco) ▪ 3ml neb QID § /Formoterol § Fluticasone (Flovent HFA, (Dulera) Flovent Diskus, Arnuity Ellipta) ¡ Combination more effective than individual § Fluticasone furorate/ § (Aerospan) (Breo Ellipta) agents for acute asthma exacerbation § Mometasone (Asmanex ¡ Long-acting muscarinic Twisthaler, Asmanex HFA) agonist (LAMA) § Tiotropium

EPR 3, 2007

¡ ¡ Clinical use: ¡ modifiers § Inhaled route preferred for chronic use § Start controller treatment early § Montelukast ▪ For best outcomes, initiate controller treatment as early as possible after § Zafirlukast making the diagnosis of asthma § Indications for regular low-dose ICS - any of: § Zileuton ▪ Asthma symptoms more than twice a month ¡ Cromolyn ▪ Waking due to asthma more than once a month ¡ Biologics ▪ Any asthma symptoms plus any risk factors for exacerbations § ¡ Adverse effects § Oropharyngeal candidiasis § Mepolizumab § Dysphonia § Reslizumab § Cough

GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

5 Inhaled steroid Total daily dose (mcg) Low Medium High 200–500 >500–1000 >1000 ¡ Salmeterol (Serevent diskus): dipropionate (CFC) Beclometasone ▪ Indicated for asthma (in combination w/ICS) and 100–200 >200–400 >400 dipropiona11te (HFA) exercise induced bronchospasm Budesonide (DPI) 200–400 >400–800 >800 ¡ Adverse effects: similar to short-acting Ciclesonide (HFA) 80–160 >160–320 >320 Fluticasone furoate beta-2 agonists 100 n.a. 200 (DPI) ¡ BLACK BOX WARNING: (DPI or 100–250 >250–500 >500 § DO NOT use as MONOTHERAPY for long- HFA) term asthma control due to increased risk of Mometasone furoate 110–220 >220–440 >440 death 400–1000 >1000–2000 >2000 acetonide GINA, 2017 GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

1° Endpoint RR (95% CI) SAL n PLA n Respiratory 1.40 (0.91-2.14) 50 36 ¡ Death or Life 28-week, multi-center, randomized, double-blind, placebo- Threatening 1.05 (0.62-1.76) 29 28 controlled, observational surveillance trial initiated in July Experience 4.10 (1.54-10.90) 20 5 1996 2° Endpoints 2.16 (1.06-4.41) 24 11 2.29 (0.94-5.56) 16 7 ¡ Respiratory 6163 US sites; 1316 investigators Death 3.88 (0.83-18.26) 8 2 ¡ N=26355 (Target enrollment: 60,000) Asthma 1.71 (1.01-2.89) 37 22 ¡ Death or Life >12 yrs with asthma currently using prescription asthma Threatening 1.08 (0.55-2.14) 17 16 medications Experience 4.92 (1.68-14.45) 19 4 § no history of previous salmeterol/formoterol use 4.37 (1.25-15.34) 13 3 Asthma Death 5.82 (0.70-48.37) 6 1 ¡ Treatment 7.26 (0.89-58.94) 7 1

§ USUAL Care + blinded salmeterol MDI (42mcg) BID or Total N=13176 N=13179 .031 .062 .125 .25 .5 1 2 4 8 16 32 64 128 Caucasian N=9281 N=9361 placebo African American N=2366 N=2319

Nelson H et al. Chest. 2006 Jan;129(1):15-26. Nelson H et al. Chest. 2006 Jan;129(1):15-26.

1° Endpoint RR (95% CI) SAL n PLA n Caucasian African American Respiratory 0.88 (0.42-1.84) 13 15 (n=18,642) (n=4683) Death or Life 1.25 (0.60-2.60) 16 13 Age (yrs), mean 40.3 36.5 Threatening 3.02 (0.82-11.11) 9 3 Experience Sex, n (%) 5.61 (1.25-25.26) 11 2 Female 11,718 (64) 3086 (67) 2° Endpoints 2.31 (0.60-8.93) 7 3 Male 6733 (36) 1545 (33) 2.29 (0.70-7.42) 9 4 Respiratory PEF % Predicted 85.3 78.1 3.12 (0.33-29.92) 3 1 Death Baseline ICS Use 49% 38% 4.43 (0.52-37.89) 5 1

≥1 ER visit in last 12 mths 22% 41% Asthma 0.68 (0.24-1.90) 6 9 Death or Life 1.62 (0.63-4.17) 11 7 Threatening ≥1 ER visit in lifetime 59% 72% 3.02 (0.82-11.11) 9 3 Experience 10.46 (1.34-81.58) 10 1 ≥1 hospitalization in last 12 6% 15% mths 0.96 (0.06-15.35) 1 1 ≥1 hospitalization in lifetime 30% 45% Asthma Death 5 0 3.12 (0.33-29.92) 3 1 ≥1 intubation for asthma in 4% 8% 4 0 lifetime .031 .062 .125 .25 .5 1 2 4 8 16 32 64 128 Nocturnal symptoms present 59% 67% Cauc. ICS (SAL N=4586, PLA N=4637) African American ICS (SAL N=906, PLA N=785) Cauc. Non-ICS (SAL N=4695, PLA N=4724) African American Non-ICS (SAL N=1460, PLA N=1444) Nelson H et al. Chest. 2006 Jan;129(1):15-26. Nelson H et al. Chest. 2006 Jan;129(1):15-26.

6 ¡ Total Population ¡ Use of a LABA alone without use of a long-term asthma § No significant differences in the primary endpoint control medication, such as an inhaled corticosteroid, is § A significant increase (?), in secondary endpoint of asthma-related deaths was observed in patients receiving salmeterol contraindicated (absolutely advised against) in the ▪ 13 vs. 3 pts treatment of asthma. ¡ African Americans ¡ LABAs should not be used in patients whose asthma is § Statistically significant increase in combined respiratory and asthma-related adequately controlled on low or medium dose inhaled deaths corticosteroids. ▪ Worse asthma at baseline ¡ ▪ NO baseline ICS led to increased risk LABAs should only be used as additional therapy for patients § No difference in asthma-related death alone with asthma who are currently taking but are not adequately ¡ Caucasians controlled on a long-term asthma control medication, such § No significant increase in primary or secondary endpoints as an inhaled corticosteroid.

Nelson H et al. Chest. 2006 Jan;129(1):15-26. hps://wayback.archive-it.org/7993/20170112130425/hp://www.fda.gov/Safety/MedWatch/SafetyInformaon/SafetyAlertsforHumanMedicalProducts/ucm201003.htm

ICS/LABA ICS ICS/LABA vs. (n = 17,537) (n = 17,552) ICS ¡ FDA removed black box warning regarding asthma related Hazard Ratio (95% CI) deaths in products that contain an ICS + LABA Serious asthma-related 116 105 1.10 (0.85, 1.44) § https://www.fda.gov/Drugs/DrugSafety/ucm589587.htm? eventc utm_campaign=New%20FDA%20Drug%20Safety %20Communication%20update%20on%20long-acting%20beta Asthma-related death 2 0 %20agonists%20%28LABAs %29&utm_medium=email&utm_source=Eloqua. Asthma-related 1 2 intubation (endotracheal) Asthma-related 115 105 hospitalization (≥24- hour stay)

Advair HFA, Advair Diskus, Airduo, Breo Ellipta, Dulera, Symbicort [package insert] FDA, 2017

¡ Clinical use: ¡ Clinical use: § Considered 2nd or 3rd line for chronic asthma (after beta-2 § Optional controller agonist, inhaled steroids, and cromolyn) § Used alone: ¡ Adverse effects ▪ less effective than low dose ICS § G.I. upset § Added to ICS § Nausea/ ▪ less effective than ICS/LABA. § Anxiety ¡ Adverse effects § Insomnia § Well tolerated § Arrhythmia ¡ Hepatotoxicity (except montelukast) ¡ Multiple drug-drug interactions ¡ Drug interactions (except montelukast) ¡ Must monitor levels GINA, 2017 GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

7 ¡ (Spiriva respimat) ¡ Clinical use: ▪ 2 (1.25mcg) puffs daily § Optional controller ¡ Clinical use § Limited role due to weak anti-inflammatory effect § Add-on treatment for step 3-4 patients with a history § Less effective than low dose ICS of exacerbations ¡ Adverse effects ¡ Adverse effects § Cough, wheezing § Dry mouth, Headache, pharyngitis, URI, ¡ May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

GINA, 2017 GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

histamine, leukotrienes, Bronchospasm mast cell ¡ Clinical use: é Vascular permeability prostaglandins, bradykinin é Mucus production § add-on option for patients ≥6 years with severe allergic asthma IL-5 uncontrolled on Step 4 treatment IgE Cytokines ¡ Adverse effects: VCAM-1 (TLSP) eosinophils macrophage Antigen IL-4 B lymphocyte § ANAPHYLAXIS (Black box warning)

IL-4 § Injection site reactions IL-13 IL-3, IL-5, § Viral infections GM-CSF T lymphocyte § URI IL-8 neutrophils § Sinusitis Chemokines Inflammation: § Headache 1. Acute sx LTB-4 § Pharyngitis 2. Subacute sx 3. Chronic sx 4. Airway remodeling GINA, 2017 Adapted from EPR 2, 1997 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2018

¡ Clinical use: ¡ Clinical use: § add-on option for patients aged ≥12 yrs with severe § add-on option for patients aged >18 yrs with severe eosinophilic asthma (>400u/L) uncontrolled on Step 4 eosinophilic asthma (blood eosinophil >150U/L) treatment uncontrolled on Step 4 treatment ¡ Adverse effects: ¡ Adverse effects: § Headache § ANAPHYLAXIS (Black box warning) § Injection site reactions § Transient increase in CPK § Oropharyngeal pain § Fatigue § Myalgia § Eczema/pruritus § Abdominal pain § Anaphylaxis

GINA, 2017 GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2018

8 ¡ Clinical use: AB is at your clinic with a 4-week history of coughing and shortness of breath (SOB) three times/week that awakens him at § add-on option for patients aged >12yrs with night 1 time/week. He also reports that he feels that his asthma severe eosinophilic asthma (blood eosinophil has impacted his ability to exercise. His current medications >150U/L) uncontrolled on Step 4 treatment include: albuterol prn, beclomethasone low dose, lisinopril/hctz, ¡ Adverse effects similar to those treated with placebo: atorvastatin, metformin. According to current guidelines, what § Headache would you recommend to treat AB’s asthma? a) § Pharyngitis Montelukast b) Mometasone low dose § Fever c) Budesonide/Formoterol low dose § Anaphylaxis d) Fluticasone/Salmeterol medium dose § Injection site reactions

GINA, 2017 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2018

¡ Start controller treatment early § For best outcomes, initiate controller treatment as early as possible after making the diagnosis of asthma ¡ Indications for regular low-dose ICS - any of: § Asthma symptoms more than twice a month § Waking due to asthma more than once a month § Any asthma symptoms plus any risk factors for exacerbations ¡ Consider starting at a higher step if: § Troublesome asthma symptoms on most days § Waking from asthma once or more a week, especially if any risk factors for exacerbations ¡ If initial asthma presentation is with an exacerbation: § Give a short course of oral steroids and start regular controller treatment (e.g. high dose ICS or medium dose ICS/LABA, then step down)

GINA, 2017 GINA 2017, Box 3-4 (1/2)

Step 1 Step 2 Step 3 Step 4 Step 5 Notes Preferred Low dose ICS Low dose Med/high Refer for add-on *Not for Controller ICS/LABA** ICS/LABA treatment children <12 e.g. years FEV-1 PEF Asthma SABA use Exacerbation Rate tiotropium,*+ **For children AM/PM symptoms anti-IgE, 6-11 years, the Ç Ç È È anti-IL5* preferred Step 3 VanNoord 1999 Daytime & ~ treatment is FP/SLM vs FP nightime medium dose Optional Consider LTRA, Low dose Med/high dose Add Add low ICS Baraniuk 1999 Ç Ç È È n/a controller low dose theophylline* ICS, tiotropium*+, dose OCS #For patients FP/SLM vs FP vs TAA ICS Low dose ICS High dose ICS prescribed BDP/ +LTRA + LTRA formoterol or (or + theoph*) (or + theoph*) BUD/ Woolcock 1996 Ç Ç È n/a ~

formoterol BDP/SALM vs maintenance BDP and reliever therapy Greening 1994 n/a Ç È È ~ +Tiotropium by BDP/SALM vs mist inhaler is an add-on BDP treatment for Rabe2006 Ç Ç È È È patients ≥12 years with a BUD/FORM history of vs BUD (2x) exacerbations O'Byrne 2005 Ç Ç È È È Reliever As-needed short-acting beta2- As-needed SABA or agonist (SABA) low dose ICS/formoterol# BUD/FORM vs BUD GINAAdapted from GINA, 2017 2017, Box 3-5 (2/8) (upper part)

9 FEV-1 PEF Asthma SABA use Exacerbation AM/PM symptoms Rate ¡ Review adherence, inhaler technique, Peters et al. 2010 Ç Ç È Asthma n/a n/a environmental control, co morbid conditions BP/Tio vs BP/Salm control days vs BP(2x) ¡ Consider stepping up if poorly or uncontrolled

Kerstjens et al. Ç Ç No difference n/a n/a symptoms, exacerbations, or risk factors 2011 ¡ Sustained step-up ICS/LABA+Tio vs ICS/LABA § 2-3 months Kerstjens et al. Ç Ç No difference n/a È ¡ Short-term step-up (e.g. viral infection, allergen) 2012 ICS/LABA+Tio vs § 1-2 weeks ICS/LABA

GINA, 2017

Current Step Current dose Step Down options

Step 5 High dose ICS/LABA + • Continue high dose ICS/LABA and reduce OCS dose oral corticosteroids (OCS) • Use sputum-guided approach to reducing OCS • Alternate-day OCS treatment High dose ICS/LABA plus • Replace OCS with high dose ICS other add-on agents • Refer for expert advice

Step 4 Moderate-High dose • Continue combination ICS/LABA with 50% reduction in ICS component, ICS/LABA maintenance by using available formulations ¡ Select agent based on classification of • Discontinuing LABA may lead to deterioration

Medium dose ICS/formoterol* • Reduce maintenance ICS/formoterol* to low dose, and continue as needed low dose ICS/ severity as maintenance + reliever formoterol* reliever

High dose ICS + second • Reduce ICS dose by 50% and continue second controller Controller § Each medication class has unique MOA

Step 3 Low dose ICS/LABA • Reduce ICS/LABA to once daily maintenance • Discontinuing LABA may lead to deterioration § MOA can help predict adverse effects

Low dose ICS/formoterol* as • Reduce maintenance ICS/formoterol* dose to once daily and continue maintenance + relief as-needed low dose ICS/formoterol* reliever ¡ Adjust therapy based on level of control

Moderate-High dose ICS • Reduce ICS dose by 50% ¡ Also consider adverse effects, adherence, Step 2 Low dose ICS • Once-daily dosing • Adding LTRA may allow ICS dose to be stepped down • Insufficient evidence to support step-down to as-needed ICS with dosing frequency, route of administration, SABA

Low dose ICS or LTRA • Consider stopping controller treatment only if there have been no interactions with other medications symptoms for 6–12 months, and patient has no risk factors • Complete cessation of ICS in adults is not advised as the risk of exacerbations is increased

Adapted from GINA, 2018

¡ Tezepelumab (thymic stromal lymphopoietine antagonist) ¡ Dupilumab (IL-4 & IL-13 antagonist)

David Young, Pharm.D. Professor of Pharmacotherapy L.S. Skaggs Pharmacy Institute Rm 4916 581-8510 [email protected]

10 ¡ 4th leading cause of death in the world ¡ $29.5 billion (direct) ¡ 3rd leading cause of death in the U.S. ¡ Cost of COPD in U.S. was ~$50 billion in 2010 § Hospital visits ¡ Since 2000, the number of COPD deaths in women ¡ $8 billion (morbidity) has exceeded those in men ¡ COPD is the only disease for which prevalence and § Loss of work mortality rates continue to rise ¡ $12.4 billion (mortality) ¡ Estimated 24 million affected ¡ § 71.7% of population have FEV1/FVC <70% without a diagnosis $49.9 BILLION TOTAL COSTS IN of COLD 2010 http://www.lung.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html Accessed 9/17 http://www.lung.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html Accessed 9/17

“Chronic Obstructive Pulmonary Disease (COPD) is a common, Smoking, Pollutants, Host factors preventable and treatable disease that is characterized by PERSISTENT respiratory symptoms and AIRFLOW Airway Inflammation and Fibrosis LIMITATION that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or Increased Airway Resistance gases” Decrease in Elastic Recoil

Luminal Plugs

PERSISTANT AIRFLOW LIMITATION

GOLD 2018 GOLD 2018

1. Chronic dyspnea ▪ Progressive Severe COPD: ▪ Persistent • Fatigue ▪ Worse with exercise • Weight loss 2. Chronic cough • Cough syncope ▪ May be intermittent at first • Depression ▪ May be unproductive • Anxiety 3. Chronic sputum production ▪ May vary from day to day 4. Recurrent lower resp tract infections

GOLD 2018

11 ¡ Reduce Symptoms ¡ SMOKING § Relieve symptoms ¡ Occupation § Improve exercise tolerance ¡ Indoor & outdoor pollution § Improve health status ¡ Genetic ¡ Reduce Risk § Alpha-1-antitrypsin deficiency § Prevent disease progression ¡ Infection § Prevent and treat exacerbation’s ¡ Socioeconomic status § Reduce mortality

GOLD 2018 GOLD 2018

EF is a 68 year old female who presents to clinic. She has a past medical history of HTN. FEV1 is 82% of predicted and CAT score of 20 and has had 1 exacerbation requiring prednisone last year. Her current medications include: albuterol, lisinopril. According to current guidelines, what category of COPD does EF have?

a) Group A b) Group B c) Group C d) Group D

Score I never cough 1,2,3,4,5 I cough all of the time Severity of Airflow Limitation Based on Post- FEV1 (Only for patients with FEV1/FVC <0.70) I have no phlegm (mucus) in my 1,2,3,4,5 My chest is completely full of phlegm chest at all (mucus) My chest does not feel tight at all 1,2,3,4,5 My chest feels very tight

GOLD 1 Mild FEV1 ≥ 80% predicted When I walk up a hill or one flight 1,2,3,4,5 When I walk up a hill or one flight of of stairs I am not breathless stairs I am very breathless I am not limited doing any 1,2,3,4,5 I am very limited doing activities at GOLD 2 Moderate 50% ≤ FEV1 < 80% predicted activities at home home I am confident leaving my home 1,2,3,4,5 I am not confident leaving my home despite my lung condition because of my lung condition GOLD 3 Severe 30% ≤ FEV1 < 50% predicted I sleep soundly 1,2,3,4,5 I don’t sleep soundly because of my lung condition I have lots of energy 1,2,3,4,5 I have no energy at all GOLD 4 Very Severe FEV1 < 30% predicted Total score

Adapted from GOLD 2018 Adapted from GOLD 2018

12 Spirometrically Assessment of Patient Group Essential Recommended Local Assessment of sx/ confirmed airflow risk of exacerbations Guidelines diagnosis limitation A Smoking Physical Flu & Exacerbation history cessation activity Pneumococcal Post- FEV1 % predicted >2 or >1 Vaccine leading to bronchodilator GOLD 1 >80% hospital C D FEV1/FVC<70 admission GOLD 2 50-79 0 or 1 (not B-D Smoking Physical Flu & GOLD 3 30-49 leading to hospital cessation, activity Pneumococcal GOLD 4 <30 A B admission) Pulmonary Vaccine rehab mMRC0-1 mMRC >2 CAT<10 CAT >10

Adapted from GOLD 2018 Adapted from GOLD 2018 Symptoms

¡ >18yrs currently smoking (2013) § 17.8% of all adults (42.1 million people) ¡ > 18yrs who currently smoke cigarettes was ▪ 20.5% of males, 15.3% of females st ¡ <18yrs (2013) 11.8% in 2011 (1 in US) § >3200 smoke 1st cigarette ¡ >18yr who currently use smokeless tobacco § ~2100 occasional smokers become daily smokers th § >250,000 middle school and high school students never smoked was 3.0% in 2011 (14 in US) regular cigarettes but had used e-cigarettes three times as many as ¡ Grades 9–12 who currently smoke cigarettes 2011 st ¡ 2011 was 5.9% in 2011 (1 in US) § Nearly 7 in 10 (68.9%) adult cigarette smokers wanted to stop ¡ Grades 9-12 who currently use smokeless smoking. nd § More than 4 in 10 (42.7%) adult cigarette smokers had made a quit tobacco was 3.7% in 2011 (2 is US) attempt in the past year.

http://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm#use. Accessed 1/2018 http://www.cdc.gov/tobacco/data_statistics/state_data/state_highlights/2012/states/utah/index.htm. Accessed 1/2018

¡ Resources Which of the following COPD medications is a § 1-800-QUIT-NOW controller?

§ www.tobaccofreeutah.org a) albuterol

§ www.quitnow.net/utah b) levalbuterol

§ 1-888-567-TRUTH (8788) c) ipratropium d) glycopyrrolate

USPHS

13 ¡ Short-acting beta-2 agonist (SABA) § Albuterol ▪ MDI (Albuterol HFA, Proventil HFA, Ventolin HFA, ProAir HFA) ▪ DPI (ProAir RespiClick) ▪ Nebulized (Accuneb, Proventil) ▪ Oral tablets & syrup (Proventil, Proventil Repetab, VoSpire ER) § Levalbuterol ▪ MDI (Xopenex HFA) ▪ Nebulized (Xopenex) § Epinephrine (Asthmanefrine) ▪ Approved >4yrs ▪ 0.5ml (11.25mg epinephrine) via EZ Breathe Atomizer 1-3 inhalations every 3 hours prn (maximum 12 inhalations/24hr) ▪ Seek medical help if no relief in 20 minutes ¡ Short-acting muscarinic antagonist (SAMA) § MDI (Atrovent HFA) § Nebulized (Ipratropium)

¡ LABA + LAMA ¡ LABA ¡ Long-acting muscarinic § Anoro Ellipta (vilanterol/umeclidinium) § Salmeterol (Serevent agonist (LAMA) § Bevespi Aerosphere (glycopyrrolate/formoterol) Diskus) § Tiotropium (Spiriva § Stiolto Respimat (olodatero/tiotropium) Handihaler, Spiriva § Formoterol § Utibron neohaler (/glycopyrrolate) Respimat) (Perforomist) 20mcg ¡ ICS + LABA (Long-acting beta-2 agonist) § Aclidinium (Tudorza § Fluticasone proprionate/Salmeterol (Advair diskus, Advair HFA) § Aformoterol (Brovana) pressair) § Budesonide/Formoterol (Symbicort HFA) § Indacaterol (Arcapta) § Umeclidinium (Incruse § Fluticasone furorate/Vilanterol (Breo Ellipta) § (Striverdi Ellipta) ¡ ICS+ LAMA + LABA Respimat) § Glycopyrrolate (Seebri § Fluticasone furoate/umeclidinium/vilanterol (Trelegy Ellipta) Neohaler; Lonhala ¡ Theophylline Magnair) ¡ Roflumilast

¡ Ipratropium ¡ Albuterol, Levalbuterol ¡ Clinical use: ¡ Clinical Use: § Regular and PRN use Èsymptoms § Regular and PRN use È symptoms § Ipratropium>Albuterol ¡ Adverse effects ▪ ÇFEV-1 § Anxiety, insomnia, tremor, and palpitations ▪ ÇHealth status ▪ MDI

GOLD, 2018 GOLD, 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

14 Medication Device Dose Frequency ¡ Albuterol/Ipratropium Aclidinium (Tudorza Pressair) DPI 400mcg 1 INH BID § 1 CAP Combivent Respimat (100mcg/20mcg) Glycopyrrolate (Seebri Neohaler; DPI; 15.6mcg; 25mcg BID; 1 ▪ 1 inhalation QID (max 6/24hr) Lonhala Magnair) NEB VIAL BID § Duoneb (2.5mg/0.5mg) 1 CAP Tiotropium (Spiriva Handihaler; DPI; 18mcg; 2.5mcg daily; 2 ▪ 3ml neb QID Spiriva Respimat ) MDI INH daily ¡ Combination more effective than individual 1 INH Umeclidinium (Incruse Ellipta) DPI 62.5 mcg agents daily

§ ÇFEV-1 Do not use in conjunction with other Anti-ACH § Èsymptoms GOLD, 2018 GOLD, 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

¡ Clinical use § Group B ¡ Wise RA, et al. NEJM 2013 ▪ ÇFEV-1 § RDBPC Tiotropium Respimat® (2.5, 5mcg) vs ▪ ÇHealth status ▪ ÈDyspnea Handihaler® (18mcg) ▪ ÈExacerbations & hospitalizations § n=17,135 § Preferred Group C vs LABA § mean follow-up 2.3 years ▪ ÈExacerbations ¡ Adverse effects § Risk of Death HR 0.96 (95% CI, 0.84 to 1.09) § Dry mouth, Headache, pharyngitis, URI, sinusitis § Non-superior with respect to risk of 1st ¡ May enhance the anticholinergic effect of exacerbation 0.98 (95% CI, 0.87 to 1.14) Anticholinergic Agents. Risk X: Avoid combination

GOLD, 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

Which of the following is an adverse effect associated with a LABA? a) dysphonia b) dry mouth c) palpitations d) immunosuppression

15 Medication Device Dose Frequency ¡ Salmeterol, Formoterol, Aformoterol, Indacaterol, Anoro Ellipta (vilanterol/umeclidinium) DPI 25/62.5 mcg 1 INH daily Olodaterol Stiolto Respimat (olodatero/tiotropium) MDI 2.5/2.5mcg 2 INH daily ¡ Clinical Use: Bevespi (glycopyrrolate/formoterol) MDI 9/4.5mcg 2 INH BID Utibron (glycopyrrolate/indacaterol) DPI 27.5/15.6mcg 1 INH BID § Group B ▪ ÇFEV-1 ¡ LABA + LAMA ▪ ÇHealth status § ÇFEV-1, ÈExacerbations & hospitalizations vs ▪ ÈDyspnea monotherapy ▪ ÈExacerbations & hospitalizations § ÇFEV-1, ÈExacerbations & hospitalizations vs ICS + LABA ¡ Adverse effects: similar to short-acting beta-2 § Preferred Group D agonists

GOLD, 2018 GOLD, 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

Medication Device Dose Frequency Medication Device Dose Frequency Advair Diskus (fluticasone/salmeterol) DPI 250/50, 500/50 mcg 1 INH BID Trelegy Ellipta (Fluticasone furoate/ DPI 25/62.5 mcg 1 INH daily umeclidinium/vilanterol) Symbicort (budesonide/formoterol) MDI 160/4.5 mcg 2 INH BID Breo Ellipta (fluticasone furoate/ DPI 100/25 mcg 1 INH daily vilanterol) ¡ ICS + LAMA + LABA ¡ ICS + LABA § ÇFEV-1, ÈExacerbations & hospitalizations vs tiotropium § History of asthma-copd overlap § ÇFEV-1, ÈExacerbations & hospitalizations vs ICS + LABA § High blood eosinophil counts(?) § Group D if experiencing exacerbations

GOLD, 2018 GOLD, 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018 Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; January 2018

¡ Roflumilast (Daliresp) ¡ Not recommended due to significant adverse ¡ Clinical use: effects § Consider if FEV-1<50% predicted and patient has ¡ Must monitor levels and numerous drug chronic bronchitis or history of hospitalizations interactions may limit its use ¡ Adverse effects § GI (diarrhea, wt loss, nausea) § Headache, dizziness, insomnia ¡ Drug interactions § CYP 3A4 inhibitors (cimetidine) increase effects § CYP 3A4 inducers (rifampin) decrease effects GOLD, 2018 GOLD, 2018

16 ¡ Inhaled steroids may be useful in ¡ Annual seasonal & H1N1 influenza Group C & Group D ¡ Pneumococcal vaccination § È exacerbations § PCV-23 (1 dose <65yrs; 1 dose >65yrs; 5-year § Ç symptoms, lung function, & QOL minimum interval) § Ç risk of pneumonia § PCV-13 (1 dose >65yrs) ¡ Combination therapy with LABA is more effective than individual agents

GOLD 2018; Calverley PM, et al. NEJM 2007; Crim C, et al. Eu Respir J 2009 GOLD, 2018

EF is a 68 year old female who presents to clinic. She has a past medical history of HTN. FEV1 is 82% of predicted and CAT score of 20 and has had 1 exacerbation requiring prednisone last year. Her current medications include: albuterol, lisinopril. According to current guidelines which medication would you recommend for EF to start at this time?

a) Umeclindinium b) Mometasone c) Theophylline d) Ipratropium

Exacerbation Group C Group D history Consider Consider if macrolide if LAMA + LABA ICS + FEV150% + chronic former ¡ Glycopyrrolate (Lonhala Magnair) >2 or >1 LABA bronchitis smoker leading to Further LAMA+ Persistent symptoms/ § Approved 12/7/17; LAMA neb soln hospital excerbations LABA+ICS Further admission excerbations Further ¡ Biologics excerbations

LAMA LAMA LAMA + LABA LAMA + ICS § Mepolizumab Group A Group B

0 or 1 (not Continue, stop or try leading to alternative class of hospital bronchodilator LAMA + LABA admission) Evaluate Persistent effect symptoms Bronchodilator A long-acting bronchodilator (LABA or LAMA)

mMRC0-1 mMRC >2 Adapted from GOLD 2018 CAT<10 Symptoms CAT >10

17 ¡ Select agent based on classification of group Which of the following is a common error when § Each medication class has unique MOA using an MDI? § MOA can help predict adverse effects ¡ Adjust therapy based on exacerbation and a) Shaking the inhaler prior to use health status b) Waiting 1 minute between puffs ¡ Also consider adverse effects, adherence, c) Rinse mouth with water after each use dosing frequency, route of administration, d) Failure to coordinate actuation with interactions with other medications inspiration

¡ House https://www.youtube.com/watch? v=bDHEEV0M62Y

¡ Utah Department of Health https://www.youtube.com/watch? v=Rdb3p9RZoR4

¡ Lindgren et al. Eur J Resp Dis 1987;70:93-98. § 56% of patients made errors in MDI-technique “There are well designed studies that which resulted in a 30% decrease in bronchodilation versus control (p<0.01) demonstrate that you have to take your ¡ Giraud et al. Eur Resp J 2002;19:246-251 medication for it to be effective!” § 71% of patients misused MDI’s ▪ 47% due to poor coordination Dr. Wayne Samuelson, MD § Asthma less stable in misusers (p<0.001) Professor of Medicine University of Utah § Among misusers, asthma less stable in poor University of Utah Asthma Center Director coordinators (p<0.001)

18 ¡ 50% of adults and children do not perform all steps ¡ Shim et al. Am J Med 1980;69:891-894. correctly (Crompton GK. Lung 1990;Suppl 168:658-662) § 50% of patients reverted back to incorrect ¡ Reasons for noncompliance § Not taking off cap technique after one to 30 days after instruction. § Not shaking ¡ Epstein et al. Can Med Assoc J § Failure to coordinate actuation with inspiration 1979;120:813-816. § Inhale through nose and not mouth § Only 10.8% of patients performed all steps § Inhale too fast required for proper MDI-technique. § Failure to breath-hold after dose § “Cold freon” effect § Holding MDI upside down

¡ 1) Stand or sit upright with your head and neck straight or tilted slightly back. Plaza et al. Resp 1998;65:195-198 2) Hold the canister upright and shake the inhaler well. Remove the § 9% of patients, 15% of nurses, and 28% of mouthpiece cap. 3) Breathe out normally through your mouth. physicians showed correct MDI-technique. 4) With the canister upright, position inhaler either 1-2 inches away from ¡ Interiano et al. Arch Intern Med “open mouth” or in the mouth with lips closed tightly around the inhaler mouthpiece “closed mouth” 1993;153:81-85 5) As you start to breathe in slowly, press down on the top of the inhaler firmly once. Continue to breathe in slowly (over 3-5 seconds) and deeply § 65% of patients, 39% of housestaff, 82% of until your lungs are full of air. nurses were categorized as having “poor” MDI- 6) Hold your breath for 5-10 seconds or as long as you can and exhale slowly. 7) If more than one puff is needed, wait 1 minute before taking your next puff technique. and repeat step 1-7. 8) Rinse your mouth out with water and spit. 9) Replace the mouthpiece cap after you are finished.

1) Remove the cover. 2) Load a single dose according to the specific device used. 3) Breathe out normally through your mouth. 4) Put the inhaler mouthpiece into your mouth, closing your lips tightly around it. 5) Inhale deeply and forcefully. 6) Hold your breath for 5-10 seconds or as long as you can and then exhale slowly. 7) If more than one dose is needed, wait 1 minute before taking your next dose and repeat steps 2-7. 8) Rinse your mouth out with water and spit. 9) Replace the mouthpiece cap after you are finished.

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