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Clinical Implications: The Need for LABAs

4. Clinical Implications: The Need for LABAs. James F. Donohue, MD Professor of Medicine Chief of Pulmonary Division University of North Carolina, Chapel Hill, NC. Life Before LABAs. Alternatives SABAs, theophylline, epinephrine, oral β-agonists Treatment effects/disadvantages

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Clinical Implications: The Need for LABAs

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  1. 4 Clinical Implications: The Need for LABAs James F. Donohue, MD Professor of MedicineChief of Pulmonary Division University of North Carolina, Chapel Hill, NC

  2. Life Before LABAs • Alternatives • SABAs, theophylline, epinephrine,oral β-agonists • Treatment effects/disadvantages • Rollercoaster effect • Lack of nocturnal coverage • SABA compliance • Concern in school-aged children who need to be dosed frequently

  3. Life Before LABAsSABAs • SABA overusage • Tremor • Hypokalemia • Tachycardia • Hyperglycemia • Saskatchewan data

  4. 23 Asthma Death Rates by Inhaledβ-Agonist Use 250 200 150 Death rate per 10,000 per year 100 50 0 0 1 2 3 4 5 6 7 8 Canister units (20,000 µg ofβ-agonist per month) Suissa S, et al. Am J Respir Crit Care Med 1994;149:604-610.

  5. Life Before LABAs—Side-effect Profile of Theophylline and Oral Corticosteroids • Increased use of theophylline • Narrow therapeutic window • Drug-drug interactions • GI and cardiovascular side effects • Insomnia/convulsions • Oral corticosteroids • HPA and growth suppression • Osteoporosis/fractures • Diabetes • Hypertension • Glaucoma • Capillary fragility/skin thinning • Psychological effects • Immune suppression

  6. 3 New Zealand Australia Republic of Ireland Peru Costa Rica Brazil Paraguay Uruguay Panama Kuwait South Africa Malta Finland Lebanon Kenya Thailand Sweden Hong Kong Philippines Belgium Austria Iran Argentina Estonia Nigeria Spain Chile Singapore Malaysia Portugal Uzbekistan Oman Pakistan Latvia Poland Algeria South Korea Morocco Mexico Ethiopia India Taiwan China Greece Georgia Romania Albania Indonesia Germany UK France Russia Japan Italy Canada USA Worldwide Variation in Prevalenceof Asthma SymptomsInternational Study of Asthma and Allergies in Childhood (ISAAC) MBM 6-6-05 GINASlideset2004.ppt s18 40 35 30 25 20 Prevalence rate ofasthma symptoms, % 15 10 5 0 Lancet 1998;351:1225-1232.

  7. 17 Age-Adjusted Asthma-Related Death Ratesin the United States by Race NHLBI Chart book on cardio lung-blood Chart 4-28 NHLBI guidelines LABAsintroduced SABAs introduced Fluticasone ICS introduced LABAFDC † Nonwhite from 1960 to 1967. FDC = Fixed dose combination.Centers for Disease Control and Prevention. Compressed Mortality File: Underlying Causes of Death, 1979 - 2001. Available at http://wonder.cdc.gov/mortSQL.html.National Center for Health Statistics, Division of Vital Statistics. Unpublished mortality tabulations for 113 selected causes by 10-year age groups, race, and sex for 2001 and 2002. Personal communication. 2004

  8. LABAs Confer Benefits in the Treatment of Asthma • More consistent bronchodilation • Reduction in “roller-coaster” effect • Greater control of nocturnal symptoms • Improved morning lung function (PEF) • Reduced diurnal lung function variability • Prolonged protection against exercise-induced bronchospasm

  9. 4 Foradil® Efficacy in Patients With Asthma • Efficacy established in • 3 pivotal trials in asthma (n = 1613) • Significant improvement in • Superior FEV1 vs placebo over 12 hr • Duration of action sustained over 12 wk • Reduced need for nighttime rescue medication† • Onset of action similar to albuterol † Bensch G, et al. Ann Allergy Asthma Immunol. 2001;86:19-27.

  10. Ciba Protocol 040 CGP 25827A Exhibit 8.1-5; Protocol 041 25827A Exhibit 8.1-5 Sustained Improvement in FEV1 at 12 Wk Studies 040 and 041 Study 040 Study 041 Formoterol 12 µg Albuterol 180 µg Placebo 40 40 35 35 30 30 25 25 Mean change from baseline, % 20 20 15 15 10 10 5 5 0 0 12 12 0 15 1 3 5 7 9 11 0 15 1 3 5 7 9 11 Min Hr Min Hr Data on file. Novartis Pharmaceuticals.

  11. Ciba Protocol 040 CGP 25827A Exhibit 8.1-19; Ciba Protocol 041 CGP25827A Exhibit 8.1-20 Foradil® Reduces Rescue Medication Use Studies 040 and 041 Study 040 Study 041 Formoterol 12 µg 2.5 2.5 Albuterol 180 µg Placebo 2.0 2.0 1.5 1.5 Median puffs, n 1.0 1.0 * * * * * 0.5 0.5 * 0.0 0.0 Run-in 4 8 12 Run-in 4 8 12 Week Week * P < .001 vs placebo Data on file. Novartis Pharmaceuticals.

  12. Ciba Protocol 040 CGP 25827A Exhibit 8.1-11; Ciba Protocol 041 CGP25827A Exhibit 8.1-11 Foradil® Reduces Nocturnal Asthma Symptom Score Studies 040 and 041 Study 040 Study 041 Formoterol 12 µg 1.0 1.0 Albuterol 180 µg Placebo 0.8 0.8 0.6 0.6 Median symptom score 0.4 0.4 ** 0.2 0.2 * * * * *** 0.0 0.0 Run-in 4 8 12 Run-in 4 8 12 Week Week * P < .001 vs placebo; ** P = .004 vs placebo; *** P = .002 vs placebo. Data on file. Novartis Pharmaceuticals.

  13. 16 DV Improvement in FEV1 Run-in Pauwels et al NEJM 337_1405-1411,1997.pdf F 1 90 85 FEV1, % predicted 80 Higher-dose BUD plus formoterol 75 Lower-dose BUD plus formoterol Higher-dose BUD Lower-dose BUD –1 0 1 2 3 6 9 12 Month FEV1 = Forced expiratory volume in 1 second. Pauwels RA, et al. New Engl J Med. 1997;337:1405-1411.

  14. 16 DV Interaction Between LABAs and ICS on Asthma Control Lower-dose BUD plus placebo Pauwels et al NEJM 337_1405-1411,1997.pdf T 2 100 Lower-dose BUD plus formoterol Higher-dose BUD plus placebo Higher-dose BUD plus formoterol 80.8 80 71.8 70.3 61.4 60 Patients without severe exacerbation, % 40 20 0 BUD = Budesonide. Pauwels RA, et al. New Engl J Med. 1997;337:1405-1411.

  15. NHLBI Guidelines—Stepwise Approach to Asthma Therapy† • Controller: • High-dose inhaled corticosteroid and • Long-acting inhaledβ2-agonist • Theophylline-SR or • Long-acting β2-agonist tablets plus long-term oral corticosteroid • Controller: • Medium dose inhaled corticosteroid or • Low- to medium-dose inhaled corticosteroid plus long-acting inhaledβ2-agonist • (if needed) medium-to-high dose inhaled corticosteroid and long-acting bronchodilator • Controller: • Low-doseinhaled corticosteroid or • Cromolyn or nedocromil or • Theophylline-SR • Leukotrienemodifier Controller: None Reliever: Rapid-acting inhaled β2-agonist PRN STEP 1: Mild intermittent STEP 2: Mild persistent STEP 3: Moderate persistent STEP 4: Severe persistent SR = Sustained release. NIH Publication. 1997. No 97-4031.† Patients > 5 yr of age.

  16. LABAs Are Established as Part of the Current Standard of Asthma Treatment • Internationally accepted guidelines • Well established that LABAs have a place in the treatment regimen for asthma in conjunction with ICS • No alternative inhaled controller bronchodilator available for asthma

  17. Conclusions • LABAs have provided documented improvements in symptoms, airway function, and QoL • Since introduction of LABAs and controllers, asthma hospitalizations and mortality have decreased • LABAs in conjunction with ICS represent a medication category critical for optimal care of patients with moderate to severe asthma

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