COPD (Chronic Obstructive Pulmonary Disease)

Kathleen McNamara, PharmDPGY1 Pharmacy Resident 2015-2016 NEIMEF & WHC

Therapy Goals & Assessment Non-pharmacologic & Pharmacologic

Therapy◦ Medications◦ Mechanism of Action

Adverse Effects Pricing & Usual Dose Summary

Overview

Reduce symptoms◦ Relieve symptoms◦ Improve exercise tolerance

Reduce Risk◦ Prevent disease progression◦ Prevent & treat exacerbations◦ Reduce mortality

Therapy Goals

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

COPD Assessment

Cost of pre & post spirometry test at FPC: $141

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

Non-Pharmacological Therapy

Bronchodilators◦ Beta₂-agonists◦ Anticholinergics

Inhaled & oral corticosteroids Phosphodiesterase-4 (PDE-4) Inhibitor Methylxanthine Oxygen

Pharmacologic Therapy

Patient Group

Recommended 1st Choice

Alternative Choice

A SA Anticholinergic PRNORSABA PRN (Grade 1A)

LA AnticholinergicOR LABAOR SABA & SA Antichoinergic

B LA Anticholinergic OR LABA (Grade 1B)

LA Anticholinergic AND LABA

C ICS + LABA&/or LA Anticholinergic (Bronchodilator - Grade1B) (ICS - Grade 2B)

LA Anticholinergic & LABAOR LA Anticholinergic & PDE-4 inhibitorOR LABA& PDE-4 inhibitor

D ICS + LABA&/orLA Anticholinergic(Bronchodilator Grade1B) (ICS - Grade 2B)

ICS +LABA and LA AnticholinergicOR ICS + LABA & PDE-4 inhibitorOR LA Anticholinergic & LABAOR LA anticholinergic & PDE-4 inhibitor

Pharmacologic Therapy for Stable COPD

SA= Short-acting ICS= Inhaled CorticosteroidLA= Long-acting PDE-4= phosphodiesterase-4

Oxygen therapy

Pulmonary rehabSupplemental Therapy

Stepwise Drug Therapy

Health Care Maintenance

Symptoms

Combination of inhaled corticosteroid, long-acting β-agonist, and long-acting anticholinergic

Combination of anticholinergic and β-agonist bronchodilator

Short-acting inhaled bronchodilator for acute relief of symptoms

Pneumococcal and annual influenza vaccination, smoking cessation and regular assessment of lung function

FEV1

Sutherland, 2004

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= 40-56 hours

β₂-agonists

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

Anticholinergics

Do you choose between anticholinergic or β₂-agonist?

Comparison of Agents

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 0.77-

0.90◦ Increased time to 1st severe exacerbation

Hazard ratio 0.72; 95% CI 0.61-0.85◦ Reduced annual # severe exacerbations

0.09 vs 0.13, rate ratio 0.73; 95% CI 0.66-0.82

Tiotropium vs Salmeterol for Prevention of Exacerbations of COPD

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 0.79-0.93)

Symptom improvement & changes in lung function were similar between the two groups

NO significant difference◦ FEV◦ Quality of life◦ Overall all-cause hospitalizations ◦ Mortality

Tiotropium vs. long-acting β-agonists for stable chronic obstructive pulmonary disease

Mechanism of action: Anti-inflammatory, exact mechanism is unknown

Fluticasone (Flovent) Budesonide (Pulmicort Flexhaler) Beclomethasone (QVAR)

Inhaled Corticosteroids

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

Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD

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

Phosphodiesterase-4 Inhibitor & Methylxanthine

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%

Beta-agonists Adverse Effects

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)

Adverse Effects with Anticholinergic Medications

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

Steroid Adverse Effects

Daliresp◦ Endocrine metabolic: decreased weight 7-20%◦ GI: diarrhea 10%

Theophylline◦ Cardio: tachycardia, arrhythmia◦ GI: nausea/vomiting/diarrhea◦ Neuro: headache◦ Psychiatric: irritability/restlessness/insomnia

Adverse Effects with Alternative Treatment

Pricing $$$

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

SA β-agonists  Usual Dose Price

ProAir (albuterol) 2 inhalations q4-6h prn

$59.17

Xopenex (levalbuterol) 2 inhalations q4-6h prn

$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

Beta-agonists

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

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

Anticholinergics

Inhaled Corticosteroids  Usual Dose Price

Flovent HFA (fluticasone)

1-2 inhalations BID $216.22

Pulmicort Flexhaler (budesonide)

1-2 inhalations BID $156.63

QVAR (beclomethasone) 1-2 inhalations BID $150.00

Systemic Corticosteroids

   

methylprednisolone 40-80mg daily in 1-2 divided doses then taper

$27.75

Steroids & Alternative Treatments

Phosphodiesterase-4 Inhibitor

 Usual Dose Price

Daliresp (roflumilast 500mcg daily $287.83 (#30)Methylxanthine    Theophylline 300mg ER 300mg ER BID $57.80 (#100)

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 $ 340.00

Breo Ellipta(fluticasone/vilanterol)

1 inhalation QD $320.00

Combination Products

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.

Chronic Antibiotic Therapy

Summary

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

References

Questions?Thank you!