Pharmacologic Options for Treating Asthma

1
Section 3

• Pharmacologic Options for Treating Asthma

2
Long-Term Control Medications
Use
Mechanism
Class

• Most potent anti-inflammatory
• Long term use for severe persistent asthma (oral)
• Long term use for persistent asthma (inhaled)

• Block allergen reaction
• Reduce airway hyperresponsiveness
• Inhibit inflammatory cells

Corticosteroids

• Combo w/ ICS for moderate or severe persistent
  asthma

• Beta2 adrenergic receptor agonist
• Bronchodilation gt 12 h after dose

Long Acting Beta2 Agonists (LABA)

• Alternative for mild persistent asthma
• Preventative prior to exercise or allergen
  exposure

• Stabilize mast cells
• Interfere w/ Cl-channels

Cromolyn Sodium Nedocromil

• Adjunctive Tx for allergic pts with severe
  persistent asthma

• Anti-IgE mAb that prevents receptor binding

Immunomodulators

• LTRA alternative Tx for mild persistent asthma
• 5-LPO inhibitor alternative adjunctive Tx in
  adults

• Interfere with leukotriene cascade

Leukotriene Modifiers (LTRA 5-LPO inhibitor)

• Alternative adjunctive Tx w/ ICS

• Bronchodilation

Methylxanthines
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
3
Long-Term Control Corticosteroids
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
4
Daily ICS Dosages
Patients 12 years of age
Indicated for patients 18 years of age DPI
dry powder inhalation, HFA hydrofluoroalkane Ad
apted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
5
Long-Term Control Long Acting Beta2 Agonists
(LABA)
DPIdry powder inhalation Adapted from 2007 NHLBI
Expert Panel Guidelines (EPR-3)
6
LABA Safety

• Several trials raise safety issues
• Daily salmeterol added to usual therapy was
  associated with an increased risk of
  asthma-related mortality1
• Formoterol associated with increased numbers of
  severe asthma exacerbations2
• Black Box warning required by FDA for
  preparations containing LABAs
• Expert panel does not recommend LABA for treating
  acute symptoms or exacerbations3
• LABAs are not to be used as monotherapy for
  long-term control ICS therapy should not be
  stopped while taking LABAs3
• LABAs can produce cardiovascular effects
  (tachycardia, QTc interval prolongation and
  hypokalemia) at 4?5x recommended dose, as well as
  tremor and hyperglycemia

• Nelson HS, et al. Chest. 200612915-26.
• Mann M, et al. Chest. 200312470-74.
• NHLBI Expert Panel Report-3. 2007.

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Combinations of Corticosteroids and LABAs
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
8
Combined Salmeterol and Fluticasone Trial Design
n 356
PBO
Screen
Active Asthma Age 12y
FLUT 100 ug
SAL 50 ug
FLUTSAL Combination
Week
0
12
-2

• Predose FEV1
• Serial FEV1 AUC
• Probability of remaining in study

• bid dosing
• Dosing with Diskus device
• Albuterol as needed for relief

Kavuru M, et al. J Allergy Clin Immunol.
20001051108-1116.
9
Combined Salmeterol and Fluticasone Primary
Efficacy Results
P lt 0.001 compared to placebo P 0.008
compared to other treatment groups Combination
group different than others, P 0.020 FLUT
SAL groups different from PBO, P 0.007
Kavuru M, et al. J Allergy Clin Immunol.
20001051108-1116.
10
Combined Salmeterol and Fluticasone Safety

• No differences noted between groups in PE or lab
  tests
• No serious drug-related AEs
• 4 patients withdrew due to AEs not considered by
  investigators to be drug-related

Conclusion A combination of salmeterol 50 ug and
fluticasone 100 ug offers significant clinical
advantages over the individual medications at the
same doses. All treatments were equally well
tolerated.
Kavuru M, et al. J Allergy Clin Immunol.
20001051108-1116.
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Combined Budesonide and Formoterol Trial Design
n 596
PBO
BUD 320 ug
Active Asthma Age 12y
Budesonide Run-in 160 ug bid
FOR 9 ug
BUD FOR, 2 inhalers
BUD/FOR Combination, single inhaler
Week
0
12
-2

• Dosing
• bid
• DPI inhaler formoterol, PBO
• pMDI inhaler budesonide, BUD/FOR, PBO

• Predose FEV1
• 12h postdose FEV1

Noonan M, et al. Drugs. 2006662235-2254.
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Combined Budesonide and Formoterol 1o Endpoint
1
Baseline-adjusted Average 12-hour FEV1 Treatment
Comparisons at Week 2 LOCF
Change
0 1 2 3 4
5 6 7 8
9 10 11 12
COMBO BUD FOR
BUD PBO



Combo BUD/FOR combination in single inhaler
Noonan M, et al. Drugs. 2006662235-2254.
13
Combined Budesonide and Formoterol 1o Endpoint
2
Predose FEV1 Treatment Comparisons
15 ? 13 ? 11 ? 9 ? 7 ? 5 ? 3 ? 1 ? -1 ? -3 ? -5
? -7 ? -9 ? -11 ? -13 ?


Change








0 1 2 3 4 5
6 7 8 9 10 11
12 EOT
Hours
Treatment



COMBO BUD FOR
BUD PBO
FOR



Combo BUD/FOR combination in single inhaler
Noonan M, et al. Drugs. 2006662235-2254.
14
Combined Budesonide and Formoterol Study
Withdrawal Rates
Noonan M, et al. Drugs. 2006662235-2254.
15
Combined Budesonide and Formoterol Adverse
Event Rates
Conclusion A combination of budesonide/formoterol
pMDI provides asthma control significantly
greater than the individual components or placebo
and comparable with budesonide pMDI formoterol
DPI. Safety profiles were similar for all
treatments.
Noonan M, et al. Drugs. 2006 66(17)2235-2254.
16
Long-Term Control Cromolyn/Nedocromil
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
17
Long-Term Control Immunomodulator
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
18
Long-Term Control Leukotriene Modifiers
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
19
Long-Term Control Methylxanthines
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
20
Quick-Relief Medications
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
21
Short-Term Control Anticholinergic

• Combination inhaled formulation of
  anticholinergic and SABA
• Ipratropium/albuterol MDI (2-3 puffs q6h),
  solution (3 ml q4-6h)

Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
22
Short-Term Control Short-Acting Beta2 Agonists
(SABA)
CFC chlorofluorocarbon, HFA
hydrofluoroalkane Adapted from 2007 NHLBI Expert
Panel Guidelines (EPR-3).
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Steps of Asthma Management
Intermittent Asthma
Persistent Asthma Daily Medication Consult with
asthma specialist if step 4 care or higher is
required. Consider consultation at step 3.
Step 6 Preferred High-dose ICS LABA oral
corticosteroid AND Consider Omalizumab for pati
ents who have allergies
Step 5 Preferred High-dose ICS
LABA AND Consider Omalizumab for patients
who have allergies
Step Up If Needed
Step 4 Preferred Medium-dose ICS
LABA Alternative Medium-dose ICS either
LTRA, Theophylline, or Zileuton
Step 3 Preferred Low-dose ICS
LABA OR Medium-dose ICS Alternative Low-dose
ICS either LTRA, Theophylline,or Zileuton
Step 2 Preferred Low-dose ICS Alternative Cro
molyn, Nedocromil, LTRA, or Theophylline
Step 1 Preferred SABA PRN
Step Down If Possible
Moderate
Mild
Intermittent
Severe
Adapted from 2007 NHLBI Expert Panel Guidelines
(EPR-3).
Patients 12 years of age
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Physician Nonadherence to Asthma Guidelines

• Lack of familiarity
• Lack of agreement
• Lack of self-efficacy
• Lack of outcome expectancy
• Presence of external barriers
• Lack of equipment or space
• Lack of time
• Lack of educational materials
• Lack of reimbursement
• Lack of appropriate infrastructure

Cabana MD, et al. Arch Pediatr Adolesc Med.
20011551057-1062.
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Conclusions

• New NHLBI guidelines for asthma have been
  published
• Goals
• Reduce impairment
• Reduce risk
• Critical to assess severity at diagnosis and
  control to monitor disease management
• Assessment guided by symptoms, questionnaires,
  and lung function measures
• Biomarkers may provide control assessment, but
  have not been validated
• Physicians should employ guidelines in managing
  patients