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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

4

Clinical Implications: The Need for LABAs

James F. Donohue, MD

Professor of MedicineChief of Pulmonary Division

University of North Carolina, Chapel Hill, NC

life before labas
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
life before labas sabas
Life Before LABAsSABAs
  • SABA overusage
    • Tremor
    • Hypokalemia
    • Tachycardia
    • Hyperglycemia
  • Saskatchewan data
asthma death rates by inhaled agonist use

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.

life before labas side effect profile of theophylline and oral corticosteroids
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
slide6

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.

age adjusted asthma related death rates in the united states by race

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

labas confer benefits in the treatment of asthma
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
foradil efficacy in patients with asthma

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.

sustained improvement in fev 1 at 12 wk studies 040 and 041

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.

foradil reduces rescue medication use studies 040 and 041

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.

foradil reduces nocturnal asthma symptom score studies 040 and 041

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.

improvement in fev 1

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.

interaction between labas and ics on asthma control

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.

nhlbi guidelines stepwise approach to asthma therapy
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.

labas are established as part of the current standard of asthma treatment
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
conclusions
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