1. COPD (Chronic Obstructive Pulmonary Disease)
Kathleen McNamara, PharmD
PGY1 Pharmacy Resident NEIMEF & WHC
Comm, preventable, treatable dz
COPD= 3rd leading cuase of death in US

2. Overview Therapy Goals & Assessment
Non-pharmacologic & Pharmacologic Therapy
Medications
Mechanism of Action
Adverse Effects
Pricing & Usual Dose
Summary

3. Therapy Goals Reduce symptoms Reduce Risk Relieve symptoms
Improve exercise tolerance
Reduce Risk
Prevent disease progression
Prevent & treat exacerbations
Reduce mortality

4. COPD Assessment
Classification of Severity of Airflow Limitation in COPD
GOLD 1
Mild
FEV₁ ≥ 80% predicted
GOLD 2
Moderate
50% ≤ FEV₁ < 80% predicted
GOLD 3
Severe
30% ≤ FEV₁ < 50% predicted
GOLD 4
Very Severe
FEV₁ < 30% predicted
How many docs have had pts get PFT here at FPC? Cost of pre&post spirometry = $141
FEV) meas how much air a person can exhale during a forced breath
GOLD= Global Initiative for Chronic Obstructive Lung Dz
Cost of pre & post spirometry test at FPC: $141

5. These assessments are combined into a rubric that classifies the patient as stage A, B, C, or D (Figure 1). Patients who fall into category D are considered to have the highest risk of mortality and carry the most severe symptoms. The categories step down to A, where the patient is generally very stable.1

6. Non-Pharmacological Therapy
Smoking cessation
Immunizations
Influenza
Annually for all patients with COPD
Pneumococcal
All smokers & All patients < 65 years old with COPD
Anyone > 65 years of age
Regular assessment of lung function
Worldwide – the most comm risk factor for COPD is tobacco smoking

7. Pharmacologic Therapy
Bronchodilators
Beta₂-agonists
Anticholinergics
Inhaled & oral corticosteroids
Phosphodiesterase-4 (PDE-4) Inhibitor
Methylxanthine
Oxygen

8. Pharmacologic Therapy for Stable COPD
Patient Group
Recommended 1st Choice
Alternative Choice A
SA Anticholinergic PRN OR
SABA PRN (Grade 1A)
LA Anticholinergic
OR LABA
OR SABA & SA Antichoinergic B
OR LABA (Grade 1B)
LA Anticholinergic AND LABA C
ICS + LABA
&/or LA Anticholinergic
(Bronchodilator - Grade1B)
(ICS - Grade 2B)
LA Anticholinergic & LABA
OR LA Anticholinergic & PDE-4 inhibitor
OR LABA& PDE-4 inhibitor D
&/or
(Bronchodilator Grade1B)
ICS +LABA and LA Anticholinergic
OR ICS + LABA & PDE-4 inhibitor
OR LA Anticholinergic & LABA
OR LA anticholinergic & PDE-4 inhibitor
SA= Short-acting ICS= Inhaled Corticosteroid
LA= Long-acting PDE-4= phosphodiesterase-4

9. Short-acting inhaled bronchodilator for acute relief of symptoms
FEV1
Oxygen therapy
Supplemental Therapy
Pulmonary rehab
Short-acting inhaled bronchodilator for acute relief of symptoms
Combination of inhaled corticosteroid, long-acting β-agonist, and long-acting anticholinergic
Combination of anticholinergic and β-agonist bronchodilator
Stepwise Drug Therapy
Pneumococcal and annual influenza vaccination, smoking cessation and regular assessment of lung function
Health Care Maintenance
Sutherland, 2004

10. β₂-agonists
Mechanism of action: Bind to beta-2 receptors causing relaxation of bronchial smooth muscle, resulting in bronchodilation.
Short-acting
Albuterol (ProAir, Ventolin, Proventil) T ½= 4-6 hours
Levalbuterol (Xopenex) T ½= 4 hours
Long-acting
Formoterol (Foradil) T ½= 10 hours
Salmeterol (Serevent) T ½= 5.5 hours
Arformoterol (Brovana) T ½= 26 hours
Indacaterol (Arcapta) T ½= hours

11. Anticholinergics
Mechanism of action: block the action of acetylcholine & decrease cGMP (cyclic guanosine monophosphate) in bronchial smooth muscle causing bronchodilation.
Short-acting
Ipratropium (Atrovent) T ½=1.5 hours
Long-acting
Tiotropium (Spiriva) T ½= 5-6 DAYS
Aclidinium bromide (Tudorza) T ½=5-8 hours

12. Comparison of Agents
Do you choose between anticholinergic or β₂- agonist?
ProAir & Atrovent have been compared in randomized, controlled trials– on avg, both meds improve lung function to a similar degree

13. Tiotropium vs Salmeterol for Prevention of Exacerbations of COPD
1-yr, randomized, double-blind, double- dummy , parallel-group trial
7,376 patients
Tiotropium, as compared with salmeterol:
increased time to 1st exacerbation
187 vs. 145 days
17% risk reduction (hazard ratio 0.83; 95% CI
Increased time to 1st severe exacerbation
Hazard ratio 0.72; 95% CI
Reduced annual # severe exacerbations
0.09 vs 0.13, rate ratio 0.73; 95% CI
Exacerbation – def: incr in or new onset of more than 1 sx of COPD – (cough, sputum, wheezing, dyspnea or chest tightness) w/ at least 1 sx lasting ≥ 3 days and leading to patient’s physician to initiate tx w/ systemic steroids, abx or both (moderate exacerbation criteria) or to hospitalize pt (severe)

14. Tiotropium vs. long-acting β-agonists for stable chronic obstructive pulmonary disease
Review of 7 clinical studies
>12,000 patients with COPD
Spiriva has shown to be more effective at reducing exacerbations compared with LABA
OR=0.86; (95% CI )
Symptom improvement & changes in lung function were similar between the two groups
NO significant difference
FEV
Quality of life
Overall all-cause hospitalizations
Mortality
OR= odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure.

15. Inhaled Corticosteroids
Mechanism of action: Anti-inflammatory, exact mechanism is unknown
Fluticasone (Flovent)
Budesonide (Pulmicort Flexhaler)
Beclomethasone (QVAR)

16. Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD
12-month, double-blind, parallel-group study
2485 patients with history COPD exacerbation
Methods
All participants received triple therapy of Spiriva, Serevent & Flovent x 6 week run-in period
Then randomized to continue triple therapy or withdrawal Flovent in 3 steps over 12 weeks
Primary end point: time to first moderate or severe COPD exacerbation
Results
Compared with continued glucocorticoid use, withdrawal met noninferiority criteria with respect to the first moderate or severe exacerbation
Doses: Spiriva 18 micrograms, Serevent 50 mmicrograms BID & Flovent 500 micrograms BID

17. Phosphodiesterase-4 Inhibitor & Methylxanthine
PDE-4 Inhibitor
Mechanism of action: increases cAMP levels, leading to reduction in lung inflammation
Roflumilast (Daliresp)
Methylxanthine
Mechanism of action: true mechanism not fully understood, bronchodilation through smooth muscle relaxation and suppression of airway stimuli.
Theophylline
Theophylline suggested mech
Bronchodilation mediated by inhib of 2 isoenzymes PDE III (phosphodiesterase) & PDE IV
Non-bronchodilation mediated via other molecular mechanisms

18. Adverse effects
In general, effects with >10% are included in slideshow

19. Beta-agonists Adverse Effects
General
Respiratory: 5% or more: bronchitis, cough, sore throat, rhinitis 5-16%, upper respiratory infection 5-21%
GI: nausea 10%, pharyngitis 14%
Neuro: feeling nervous 7%, tremor 5-7%
Serevent:
Musculoskeletal: pain 12%
Neuro: headache 13-17%
Arcapta
Respiratory: cough 6-24%

20. Adverse Effects with Anticholinergic Medications
Atrovent
Respiratory: bronchitis 10-23%, sinusitis 14%
GI: xerostomia 4%
Spiriva
Respiratory: pharyngitis 10%, upper respiratory infection 43% (w/ powder formulation)
GI: xerostomia 4% (w/ respimat spray), 12-16% (w/ powder formulation)

21. Steroid Adverse Effects
Flovent
Respiratory: sinusitis 4-10%, throat irritation 3- 22%, upper respiratory infection 14-21%
Neuro: headache 2-16%
Pulmicort
Respiratory: respiratory tract infection 3-38%
Methylprednisone
Cardio: hypertension
Immunologic: at risk for infection

22. Adverse Effects with Alternative Treatment
Daliresp
Endocrine metabolic: decreased weight 7-20%
GI: diarrhea 10%
Theophylline
Cardio: tachycardia, arrhythmia
GI: nausea/vomiting/diarrhea
Neuro: headache
Psychiatric: irritability/restlessness/insomnia

23. Pricing $$$
As with ANY chronic condition, adherence is very important… Is the patients cost for the medication manageable???

24. What is the approximate cash price cost to a patient for ProAir
What is the approximate cash price cost to a patient for ProAir? (Without insurance)

25. Beta-agonists SA β-agonists Usual Dose Price ProAir (albuterol)
2 inhalations q4-6h prn
$59.17
Xopenex (levalbuterol)
$72.46
LA β-agonists
Foradil (formoterol)
12mcg inhaled BID
$137.78
Serevent (salmeterol)
50mcg inhaled BID
$312.73
Brovana (arformoterol)
15mcg inhaled BID
$755.26
Arcapta (indacaterol)
75mcg inhaled daily
$225.83

26. How much would you estimate Spiriva to cost a patient without insurance?

27. Anticholinergics SA Anticholinergic Usual Dose Price
Atrovent (ipratropium)
2 inhalations q6h prn
$290.04
LA Anticholinergics
Spiriva (tiotropium)
18mcg inhaled daily
$351.41
Tudorza (aclidinium bromide)
400mcg BID
$313.70

28. Steroids & Alternative Treatments
Inhaled Corticosteroids
 Usual Dose
Price
Flovent HFA (fluticasone)
1-2 inhalations BID
$216.22
Pulmicort Flexhaler (budesonide)
$156.63
QVAR (beclomethasone)
$150.00
Systemic Corticosteroids
methylprednisolone
40-80mg daily in 1-2 divided doses then taper
$27.75
Phosphodiesterase-4 Inhibitor
 Usual Dose
Price
Daliresp (roflumilast
500mcg daily
$ (#30)
Methylxanthine
Theophylline 300mg ER
300mg ER BID
$57.80 (#100)

29. Combination Products Combination Products Usual Dose Price
Combivent (albuterol/ipratropium)
1 inhalation QID
$329.44
Advair 100/50 (salmeterol/fluticasone)
1 inhalation BID
$278.46
Symbicort 160 (formoterol/budesonide)
2 inhalations BID
$306.35
Stiolto Respimat
(tiotropium/olodaterol)
2 inhalations QD $
Breo Ellipta
(fluticasone/vilanterol)
1 inhalation QD
$320.00
Oldaterol & vilanterol = LABA
Stiolto FDA approved May & Breo FDA approved April 2015

30. Chronic Antibiotic Therapy
Generally NOT indicated for majority of patients with COPD.
BUT, some antibiotics (macrolides) may have anti-inflammatory effects in addition to antibiotic effect.
May be appropriate for continued, frequent exacerbations despite optimal therapy with bronchodilators and anti-inflammatory agents.

31. Summary

32. References
Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease (Review). The Cochrane Collection. Published by John Wiley & Sons, Ltd.
Global Strategy for the Diagnosis, Management, and Prevention of COPD. Scientific information and recommendations for COPD programs. Updated 2015.
Magnussen, Disse, Rodriguez-Roisin, et al. Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD. NEJM 371;14. 2 October, 2014.
Micromedex Drug Index

33. Questions?
Thank you!