Drugs for asthma and COPD

ICSs do not increase the risk of pneumonia in patients with asthma.9 Oral – Systemic glucocorticoids are the most effective drugs available for exacerbations of asthma incom-pletely resp

Treatment Guidelines

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IN THIS ISSUE (starts on next page)

Drugs for Asthma and COPD p 75

Drugs for Asthma and COPD

Tables

2 Some FDA-Approved Drugs for Asthma Pages 78-79

4 Some FDA-Approved Drugs for COPD Page 84

Treatment Guidelines

Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 11 (Issue 132) August 2013

(supercedes vol 8 [Issue 99] November 2010 and

vol 10 [Issue 114] February 2012)

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with a face mask or mouthpiece is less dependent on the patient’s coordination and cooperation, but more time-consuming, less efficient, and more costly than delivery through an MDI or DPI

short-acting beta2-agonists (SABAs) are used for rapid relief of asthma symptoms Their onset of action occurs within 5 minutes; their peak effect occurs within 30-60 minutes and they have a duration of action of 4-6 hours.1SABAs do not decrease the inflammation of the airways that occurs in asthma They should only be used as needed for relief of symptoms or for prevention

of exercise-induced bronchoconstriction (EIB) In patients whose asthma is well controlled, SABAs should be needed infrequently (<2 days/week).2

Adverse Effects – Inhaled SABAs can cause

paradox-ical bronchospasm, tremor, tachycardia, QT interval prolongation, hyperglycemia, hypokalemia and hypo-magnesemia, especially if used in high doses Tolerance can occur with regular use.3

CORTICOSTEROIDS — Inhaled – In all age groups

with persistent asthma, whether it is mild, moderate or severe, an inhaled corticosteroid (ICS) is the most effec-tive long-term treatment for control of the disease In randomized controlled trials, ICSs have been signifi-cantly more effective than long-acting beta2-agonists, leukotriene modifiers, cromolyn or theophylline in improving pulmonary function, preventing symptoms and exacerbations, reducing the need for emergency department treatment, and decreasing deaths due to

asth-ma.4 Patients with well-controlled asthma who stop using ICSs have an increased risk of exacerbations com-pared to those who continue using them.5 One 9-month study in patients with well-controlled mild-to-moderate asthma found that intermittent use of an ICS in combi-nation with a SABA did not increase the risk of an exac-erbation compared to daily use of an ICS.6

Patients whose symptoms are mild and infrequent can

use a short-acting bronchodilator as needed for relief

of symptoms Patients with more frequent cough,

wheeze, chest tightness or shortness of breath should

begin treatment with a long-term controller

medica-tion Low daily doses of an inhaled corticosteroid

sup-press airway inflammation and reduce the risk of

exacerbations For patients who remain symptomatic

despite compliance with inhaled corticosteroid

treat-ment and good inhalational technique, addition of a

long-acting beta2-agonist is recommended Patients

with more severe disease may need higher doses of

inhaled corticosteroids

Failure of pharmacologic treatment can often be

attributed to lack of adherence to prescribed

medica-tions, uncontrolled co-morbid conditions such as

aller-gic rhinitis, or continued exposure to tobacco smoke

or other airborne pollutants, allergens or irritants

INHALATION DEVICES — Metered-dose inhalers

(MDIs) require coordination of inhalation with

hand-actuation of the device Valved holding chambers

(VHCs) or spacers help some patients, especially

young children and the elderly, use MDIs effectively

VHCs have one-way valves that prevent the patient

from exhaling into the device, minimizing the need for

coordinated actuation and inhalation Spacers are

tubes or chambers placed between the canister and a

face mask or mouthpiece, which also avoids the need

to coordinate actuation and inhalation Both VHCs

and spacers retain the larger particles emitted from the

MDI, decreasing their deposition in the oropharynx

and leading to a higher proportion of small respirable

particles being inhaled

Dry powder inhalers (DPIs), which are

breath-actuated and do not require a propellant, can be used

in patients who are capable of performing a rapid deep

inhalation

For further information call: 800-211-2769

Related article(s) since publication

Most of the beneficial effects of ICSs are achieved at

relatively low doses The ideal dose for a given patient

is the lowest dose that maintains asthma control; this

dose may change seasonally and over time Current

evi-dence suggests that, at usual doses, all ICSs are similar

in efficacy; they are not interchangeable, however, on a

per-microgram or per-puff basis because the dose varies

with the drug, the formulation and the delivery device.7

Adverse Effects – Local adverse effects of ICSs may

include oral candidiasis (thrush), dysphonia, and reflex

cough and bronchospasm Their incidence can be

reduced by use of a valved holding chamber (VHC) or

a spacer, and by mouth-rinsing after inhalation

Clinically relevant adverse effects on

hypothalamic-pitu-itary-adrenal (HPA) axis function generally do not occur

with low- or medium-dose ICSs Regular administration

of low- or medium-dose ICSs may reduce growth

slight-ly during the first year of treatment, especialslight-ly in

prepu-bertal patients In the Childhood Asthma Management

Study (CAMP), which used a medium dose of an ICS,

mean adult height was 1.2 cm less with budesonide

com-pared to placebo.8Patients who require high-dose ICS

treatment should be monitored for HPA axis suppression,

changes in bone density, and development of cataracts or

glaucoma ICSs do not increase the risk of pneumonia in

patients with asthma.9

Oral – Systemic glucocorticoids are the most effective

drugs available for exacerbations of asthma

incom-pletely responsive to bronchodilators Even when an acute exacerbation responds to bronchodilators, addi-tion of a short course of an oral glucocorticoid can decrease symptoms and may prevent a relapse For asthma exacerbations, daily systemic glucocorticoids are generally required for only 3-10 days, after which

no tapering is needed

Oral glucocorticoids should only rarely be used as long-term control medications and then only in that small minority of patients with very poorly controlled severe persistent asthma despite compliance with an optimal treatment regimen of medications and environmental control In this situation, an oral glucocorticoid should

be given at the lowest effective dose, preferably on alter-nate mornings, in order to minimize toxicity

Mono-therapy with an inhaled long-acting beta2-agonist (LABA), such as salmeterol or formoterol, is not rec-ommended If a LABA is required, it should be used in combination with an ICS, preferably in the same inhaler The combination inhalers

salmeterol/flutica-sone (Advair), formoterol/budesonide (Symbicort) and formoterol/mometasone (Dulera) are FDA-approved

for use in patients with persistent asthma that is not well-controlled on an ICS alone The addition of a LABA improves lung function, decreases symptoms and exacerbations, and reduces rescue use of short-acting beta2-agonists.10,11 LABAs are not indicated for relief of acute bronchospasm

Adverse Effects – LABAs, especially if used in

high-er-than-recommended doses, can cause tremor, hypokalemia, tachycardia and other cardiac effects Tolerance (some loss of efficacy) can occur with daily use of a LABA.3

An FDA meta-analysis found that use of a LABA was associated with an increased risk of asthma-related hos-pitalization, intubation and death These results prompted the FDA to recommend that LABAs be dis-continued once asthma is controlled A secondary analy-sis of the original meta-analyanaly-sis did not find a significant increase in risk in a subset of patients who were assigned

to use an ICS with a LABA.12A meta-analysis of clini-cal trials in asthma patients controlled with a combina-tion of an ICS and a LABA found that discontinuacombina-tion of LABA therapy was associated with worsening asthma control.13 The manufacturers of LABAs are conducting post-marketing trials to assess the safety of a LABA-ICS combination compared to that of an ICS alone.14

LEUKOTRIENE MODIFIERS — Montelukast and

zafirlukast are less effective alternatives to low-dose ICS treatment for patients who are unable or unwilling

Table 1 Treatment of Asthma

Recommended Asthma Severity Regimen 1

Mild Persistent

Preferred Low-dose ICS 2

Alternatives Montelukast

or Theophylline

Moderate Persistent

Preferred Low-dose ICS 2

+ a LABA 3

or Medium-dose ICS2

Alternatives Low-dose ICS 2

+ a leukotriene modifier

or theophylline

Severe Persistent

Preferred Medium- or high-dose ICS 2

+ a LABA 3,4

Alternatives Medium-dose ICS 2

+ a leukotriene modifier

or theophylline SABA = inhaled shor t-acting beta 2 -agonist; ICS = inhaled cor ticosteroid;

LABA = inhaled long-acting beta2-agonist

1 For patients >12 years old.Treatment should be adjusted based on response.

All regimens include use of a SABA as needed.

2 The ideal dose of an ICS is the lo west dose that maintains asthma control.

3 The FDA recommends stopping a LABA once symptoms are controlled, but

the recommendation is controversial (SJ Szefler and WW Busse J Allergy

Clin Immunol 2012; 130:1256).

4 In patients who remain uncontrolled despite agg ressive treatment with a

high-dose ICS plus a LABA, or al glucocorticoids are sometimes added.

Addition of omalizumab can be considered in patients with allergic asthma.

to use an ICS.15Leukotriene modifiers are also

gener-ally less effective than an inhaled LABA as add-on

therapy for patients not well controlled on an ICS

alone Like LABAs, leukotriene modifiers are not

rec-ommended for treatment of acute asthma symptoms

Adverse Effects – Montelukast is considered safe for

long-term use Both zafirlukast and (especially)

zileuton have been reported to cause life-threatening

hepatic injury; liver function tests should be monitored

and patients should be advised to discontinue the

med-ication immediately if abdominal pain, nausea,

jaun-dice, itching or lethargy occur Rarely, Churg-Strauss

vasculitis has been reported with montelukast and

zafirlukast; in most cases, this was probably a

conse-quence of corticosteroid withdrawal rather than a

direct effect of the drug.15

ANTICHOLINERGICS — Ipratropium bromide is

an inhaled short-acting anticholinergic bronchodilator

FDA-approved only to treat chronic obstructive

pul-monary disease (COPD) It has been used off-label in

asthma as an alternative reliever medication in patients

who cannot take a SABA or in combination with a

SABA for treatment of acute bronchoconstriction

Tiotropium bromide, an inhaled long-acting

anti-cholinergic bronchodilator, is also approved only for

use in COPD (see Table 4) In patients with asthma

uncontrolled on an ICS, addition of tiotropium has

been as effective as adding a LABA in improving lung

function and symptoms.16 Addition of tiotropium to

combination treatment with an ICS and a LABA

improved lung function in patients with poorly

con-trolled severe asthma and increased the time to the first

severe exacerbation.17,18

Adverse Effects – Anticholinergics can cause dry

mouth, pharyngeal irritation, increased intraocular

pressure and urinary retention, but inhaled ipratropium

and tiotropium have limited systemic bioavailability

They should be used with caution in patients with

glau-coma, symptomatic prostatic hypertrophy, or bladder

neck obstruction

THEOPHYLLINE — Theophylline, taken alone or

concurrently with an ICS, is now used infrequently for

persistent asthma Monitoring serum theophylline

con-centrations is recommended to maintain peak levels

between 8 and 15 mcg/mL

Adverse Effects – Theophylline can cause nausea,

vomiting, nervousness, headache and insomnia At

high serum concentrations, hypokalemia,

hyper-glycemia, tachycardia, cardiac arrhythmias, tremor,

neuromuscular irritability, seizures and death can

occur Theophylline is metabolized in the liver, mainly

by CYP1A2 and CYP3A4 Many other drugs used concomitantly can interact with theophylline, either by increasing its metabolism and decreasing its serum concentrations and efficacy, or by decreasing its metabolism, leading to higher concentrations and tox-icity Clearance of theophylline is reduced in elderly patients and those with liver disease or heart failure

ANTI-IgE ANTIBODY — Omalizumab (Xolair) is a

recombinant humanized monoclonal antibody that pre-vents IgE from binding to mast cells and basophils, thereby preventing release of inflammatory mediators after allergen exposure It is FDA-approved for use in patients >12 years old with moderate to severe persist-ent asthma not well controlled on an ICS who have well-documented specific sensitization to a perennial air-borne allergen, such as mold, pollen or animal dander Subcutaneous injection of omalizumab every 2 or 4 weeks reduces asthma exacerbations and has a modest ICS-sparing effect In adults and adolescents, omal-izumab added to standard treatment improved symp-toms and reduced exacerbations.19,20When added to standard treatment in children with allergic asthma, omalizumab improved asthma control, decreased exac-erbations and reduced maintenance ICS doses.21 Use

of omalizumab does not preclude simultaneous use of allergen immunotherapy

Adverse Effects – Injection-site pain and bruising occur

in up to 20% of patients The labeling of omalizumab includes a boxed warning regarding the risk of anaphy-laxis Consensus analyses of post-marketing data have reported a 0.09% rate of anaphylaxis in asthma patients receiving omalizumab injections They should be administered in a healthcare setting by providers pre-pared to manage potentially life-threatening

anaphylax-is Patients should be kept under observation for 2 hours after the first three omalizumab injections, and for 30 minutes after subsequent injections Some cases of ana-phylaxis due to omalizumab have had an onset of symp-toms more than 2 hours post-injection Patients receiv-ing omalizumab should be instructed on how to recog-nize anaphylaxis and advised to self-inject epinephrine promptly if it occurs.22

IMMUNOTHERAPY — In selected patients with

allergic asthma, specific immunotherapy (subcuta-neous injections and [off label] sublingual tablets) may provide long-lasting benefits in reducing asthma symptoms and the need for medications.23

BRONCHIAL THERMOPLASTY — Approved by

the FDA in 2010 for use in adults with severe persistent asthma not well controlled on an ICS and a LABA, bronchial thermoplasty may lead to modest

improve-ments in exacerbation rates.24 Patients undergo

fiberop-tic bronchoscopy on 3 separate occasions 3 weeks apart

During the procedure, the walls of the central airways

are treated with radiofrequency energy that is converted

to heat (target tissue temperature 65°C), resulting in

ablation of airway smooth muscle Adverse effects,

mainly worsening of asthma, are common in the weeks

immediately following bronchial thermoplasty

TREATMENT FAILURE — Failure of

pharmaco-logic treatment can usually be attributed to lack of

adherence to prescribed medications, uncontrolled

co-morbid conditions, or continued exposure to tobacco

smoke and other airborne pollutants, allergens or irri-tants Smoking and exposure to second-hand smoke can cause airway hyperresponsiveness and decrease the effectiveness of ICSs Some patients with asthma may concurrently be taking aspirin or other NSAIDs that can cause asthma symptoms Oral or ophthalmic nonselective beta-adrenergic blockers, such as

propra-nolol (Inderal, and others) or timolol, can decrease the

bronchodilating effect of both endogenous and exoge-nous beta2-agonists in patients with asthma

Patients with moderate or severe asthma may benefit from meeting with trained asthma educators to have

Some Available Adult Pediatric

Inhaled Beta 2 -Agonists, Short-Acting

Albuterol –

ProAir HFA (Teva) HFA MDI (60 2 or 200 inh/unit) 90-180 mcg q4-6h >4 yrs: 90-180 mcg $45.00 Proventil HFA (Merck) 90 mcg/inhalation PRN q4-6h PRN 52.00

generic Solution for nebulization 3 1.25-5 mg q4-8h 2-4 yrs: 0.63-2.5 mg

single-dose vials 0.63, 1.25, 2.5mg/3mL PRN q4-6h PRN 24.00 4

multi-dose vials 100 mg/20 mL 5-11 yrs: 1.25-5 mg q4-8h 6.00 4

PRN AccuNeb (Dey) Solution for nebulization 3 —— 2-12 yrs: 0.63 or 1.25 mg 180.00 4

single-dose vials 0.63, 1.25 mg/3 mL tid-qid PRN

Levalbuterol –

Xopenex HFA (Sunovion) HFA MDI (80, 200 inh/unit) 90 mcg q4-6h >4 yrs: 90 mcg q4-6h PRN 48.00

45 mcg/inhalation PRN Xopenex (Sunovion) Solution for nebulization 3 0.63-1.25 mg 6-11 yrs: 0.31-0.63 mg tid 621.00 generic 0.31, 0.63, 1.25 mg/3 mL tid q6-8h PRN q6-8h PRN 536.00

>12 yrs: 0.63- 1.25 mg tid q6-8h PRN

Pirbuterol 5 – Maxair Autohaler Breath-actuated 200-400 mcg q4-6h >12 yrs: 200-400 mcg 409.00 (Valeant) CFC MDI (80, 400 inh/unit) PRN q4-6h PRN

200 mcg/inh

Inhaled Corticosteroids

Beclomethasone dipropionate –

QVAR (Teva) HFA MDI (100 or 120 inh/unit) 40-320 mcg bid 6 5-11 yrs: 40-80 mcg bid 6 120.00

40, 80 mcg/inhalation Budesonide – Pulmicort Flexhaler DPI (60, 120 inh/unit) 180-720 mcg bid 6-17 yrs: 180-360 mcg bid 161.00 (AstraZeneca) 90, 180 mcg/inhalation

Pulmicort Respules (AstraZeneca) Suspension for nebulization 7 —— 1-8 yrs: 0.25 mg bid or 308.00 8

single-dose ampules 0.25, 0.5 mg, 1 mg/2mL 0.5 mg once/day or bid

generic – single-dose vials 0.25, 0.5 mg/2mL or 1 mg once/day 6 220.00 8

Ciclesonide – Alvesco HFA MDI (60 inh/unit) 80-320 mcg bid 6 >12 yrs: 80-320 mcg bid 6 174.00 (Sunovion) 80, 160 mcg/inhalation

Flunisolide – Aerospan HFA HFA MDI (60, 120 inh/unit) 160-320 mcg bid 6 6-11 yrs: 80-160 mcg bid 6 N.A (Acton) 80 mcg/inhalation

Fluticasone propionate –

Flovent Diskus (GSK) DPI (60 inh/unit) 100-1000 mcg bid 6 4-11 yrs: 50-100 mcg bid 6 121.00

50, 100, 250 mcg/blister Flovent HFA (GSK) HFA MDI (120 inh/unit) 88-880 mcg bid 6 4-11 yrs: 88 mcg bid 121.00

44, 110, 220 mcg/inhalation Mometasone furoate –

Asmanex Twisthaler DPI (30, 60, 120 inh/unit) 220-880 mcg once/day in 4-11 yrs: 110 mcg 1x/d 142.00 (Merck) 110, 220 mcg/inhalation evening or 220 mcg bid in evening

CFC = Chlorofluorocarbon; DPI = Dry powder inhaler; HFA = Hydrofluoroalkane; MDI = Metered-dose inhaler; inh = inhalation; N.A = Not yet available

1 Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the lowest recommended adult dosage For SABAs, cost is for 100 doses $ource® Monthly (Selected from FDB MedKnowledge™) July 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013.

www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.

2 Only Ventolin HFA is available as 60 inhalations/unit.

3 Nebulized solutions may be used for very young, very old and other patients unable to use pressurized aerosols More time is required to administer the drug and the device may not be portable.

4 Cost of 100 2.5-mg doses (gener ics) or 1.25-mg doses (AccuNeb).

5 CFC-containing MDIs will not be mar keted after December 2013.

6 Dose is based on prior asthma therapy See package insert for specific dosing instructions.

7 Only approved for use in children 1-8 years old.

8 Cost based on the lowest recommended pediatric dosage.

Table 2 Some FDA-Approved Drugs for Asthma

their inhaler technique checked and to develop a

per-sonalized asthma management plan.25

MANAGING EXACERBATIONS — Intensifying

treatment at home when symptoms begin can prevent

exacerbations from becoming severe Management of

asthma exacerbations generally calls for increased

doses of a SABA and, sometimes, initiation of a short

course of an oral glucocorticoid Doubling the dose of

an ICS is not effective and quadrupling the dose is only marginally effective.26

Treatment of acute asthma in the urgent care setting

or emergency department generally involves supple-mental oxygen to relieve hypoxemia and a SABA (sometimes in combination with ipratropium), usually

Oral Glucocorticoids

15 mg/5 mL syrup, solution

Orapred ODT 10, 15, 30 mg disintegrating tabs 103.00

Prednisone – generic 1, 2.5, 5, 10, 20, 50 mg tabs; 2.00

5 mg/5 mL solution

Inhaled Beta 2 -Agonists, Long-Acting 8

Salmeterol – Serevent Diskus DPI (60 inh/unit) 50 mcg bid >4 yrs: 50 mcg bid 190.00 (GSK) 50 mcg/blister

Formoterol – Foradil Aerolizer DPI (60 inh/unit) 12 mcg bid >5 yrs: 12 mcg bid 183.00 (Merck) 12 mcg/capsule

Inhaled Corticosteroid/Long-Acting Beta 2 -Agonist Combinations

Fluticasone propionate/salmeterol –

Advair Diskus (GSK) DPI (60 inh/unit) 1 inhalation bid 4-11 yrs: 1 inhalation 215.00

100, 250, 500 mcg/ (100/50 mcg) bid

50 mcg per blister 9 >12 yrs: 1 inhalation bid Advair HFA (GSK) HFA MDI (60, 120 inh/unit) 2 inhalations bid >12 yrs: 2 inhalations bid 215.00

45, 115, 230 mcg/

21 mcg per inhalation Budesonide/formoterol –

Symbicort (AstraZeneca) HFA MDI (60, 120 inh/unit) 2 inhalations bid >12 yrs: 2 inhalations bid 206.00

80, 160 mcg/4.5 mcg per inhalation

Mometasone/formoterol –

Dulera (Merck) HFA MDI (60, 120 inh/unit) 2 inhalations bid >12 yrs: 2 inhalations bid 224.00

100, 200 mcg/5 mcg per inhalation

Leukotriene Modifiers 10

Montelukast – generic 10 mg tabs, 4, 5 mg chew tabs, 10 mg PO once/day >1 yr: 4 or 5 mg PO 25.00 Singulair (Merck) 4 mg oral granules once/day 11 166.00 Zafirlukast – generic 10, 20 mg tabs 20 mg PO bid 5-11 yrs: 10 mg PO bid 80.00 Accolate (AstraZeneca) >12 yrs: 20 mg PO bid 114.00 Zileuton – Zyflo (Cornerstone) 600 mg tabs 600 mg PO qid >12 yrs: 600 mg PO qid 1500.00 extended-release

Zyflo CR 600 mg ER tabs 1200 mg PO bid >12 yrs: 1200 mg PO bid 1500.00

Anti-IgE Antibody

Omalizumab – Xolair Powder for injection 150-300 mg SC q4wks >12 yrs: 150-300 mg q4wks 747.00 (Genentech) 150 mg/5 mL vial or 225-375 mg SC q2wks 12 or 225-375 mg q2wks 12

Theophylline 13

generic 100, 200, 300, 400, 450, 300-600 mg/once day 10 mg/kg/d 14 8.00

600 mg ER tabs; 80 mg/15mL or divided bid (max 300 mg/day) oral elixir

Theo-24 (Actient) 100, 200, 300, 400 mg ER caps 300-600 mg once/day 15 68.00 Theochron (Caraco) 100, 200, 300 mg ER tabs 300-600 mg once/day 15.00

8 Use of a long-acting beta 2 -agonist (LABA) alone without concomitant use of a long-ter m asthma controller medication is contraindicated in the treatment of asthma.

9 Only the 100 mcg/50 mcg formulation is approved for use in children.

10 Montelukast is taken once daily in the evening, with or without food Montelukast granules must be taken within 15 minutes of opening the packet Zafirlukast is taken 1 hour before or 2 hours after a meal Zileuton is taken within one hour after mor ning and evening meals.

11 Montelukast is approved for prevention of exercise-induced bronchoconstriction in patients >6 years old Dosage for 12-23 months: one packet of 4-mg oral gran-ules; for 2-5 yrs: 4-mg chewable tab once/d or one packet of 4-mg oral grangran-ules; for 6-14 yrs: 5-mg chewable tab once/d.

12 Dose depends on the patient’s body weight and total serum IgE level See package insert for specific dosing instructions.

13 Extended-release formulations may not be interchangeable.

14 Starting dose Usual maximum is 16 mg/kg/day (max 600 mg/day) in children >1 year old; in infants 0.2 x (age in weeks) + 5 = dose in mg/kg/day.

15 If Theo-24 is taken <1 hr before a meal, the entire 24-hour dose can be released in a 4-hour per iod.

Table 2 Some FDA-Approved Drugs for Asthma (continued)

7.5-60 mg once/day

or every other day

or

40-60 mg once/day

or divided bid x 3-10 days for an acute exacerbation

0-11 yrs: 0.25-2 mg/kg once/day

or every other day max 60 mg/day)

or

1-2 mg/kg/d divided bid

x 3-10 days (max 60 mg/d) for an acute exacerbation

administered by face mask and nebulizer In moderate

or severe exacerbations, an oral or intravenous

gluco-corticoid is added to reduce airway inflammation

Severe asthma exacerbations unresponsive to these

measures may respond to intravenous magnesium

sulfate, usually given as a single infusion of 2 g over

20 minutes, or to inhalation of heliox (typically a

mix-ture of helium 79% and oxygen 21%) to decrease

air-flow resistance and improve delivery of aerosolized

medications.27

EXERCISE-INDUCED

BRONCHOCONSTRIC-TION — Exercise-induced bronchoconstriction (EIB)

may be the only manifestation of asthma in patients with

mild disease EIB may also be a transient phenomenon

in non-asthmatic athletes.28 SABAs used just before

exercise will prevent EIB for 2-4 hours after inhalation

in most patients LABAs prevent EIB for up to 12 hours

Daily use of these drugs may lead to a reduction in the

duration of protection Montelukast decreases EIB in up

to 50% of patients within 2 hours after administration;

the protection may last for up to 24 hours and does not

wane with repeated use In patients who continue to

have symptoms despite use of a SABA before exercise

or who require daily use of a SABA, possibly because

of poorly-controlled persistent asthma, daily

anti-inflammatory medications should be started or

increased in dosage ICSs are the most effective

anti-inflammatory agents for EIB.3

ASTHMA IN PREGNANCY — Poorly controlled

asth-ma increases the risk of pregnancy-related complications

including pre-eclampsia, perinatal mortality, preterm

birth and low birth weight.29Albuterol is the preferred

SABA for use in pregnancy ICSs (budesonide is the best

studied) are the preferred long-term controller

medica-tions during pregnancy; they do not appear to have any

effects on fetal adrenal function.30In a cohort study of

13,280 pregnancies, the incidence of major congenital

malformations was increased with use of higher ICS

doses (>1000 mcg/day beclomethasone equivalent)

dur-ing the first trimester in women with more severe or

uncontrolled asthma, but not with low-to-moderate doses

of ICSs.31 Another cohort study of the offspring of

women who used an ICS during pregnancy found an

increased risk of endocrine and metabolic disturbances

after a follow-up of 6.1 years.32 LABAs and montelukast

appear to be safe during pregnancy.33,34Teratogenicity in

animals has been reported with zileuton Allergen

immunotherapy (without dose escalation) and

omalizum-ab can be continued in pregnancy

ASTHMA IN CHILDREN — For children with

inter-mittent asthma, a SABA should be used as needed For

mild, moderate or severe persistent asthma, ICSs are the

preferred long-term treatment for control of symptoms

ICSs do not, however, alter the underlying severity or progression of the disease In young children, a SABA

or an ICS may best be delivered through a metered-dose inhaler with a valved holding chamber and face mask or mouthpiece, or through a nebulizer Dry powder inhalers are not suitable for use in young children, who cannot reliably inhale rapidly or deeply enough to use them effectively Nebulized budesonide is FDA-approved for use in children as young as one year of age ICSs given in low doses for years are generally safe for use in children, but linear growth should be monitored Low- or medium-dose ICSs administered regularly may reduce growth slightly during the first year of treatment; in one study, mean adult height was 1.2 cm less with budesonide than with placebo.8 In another study, high-dose intermittent budesonide therapy was

as efficacious as low-dose daily budesonide in reducing the need for a course of oral corticosteroids in pre-school children with recurrent wheezing.35

Montelukast can be used as the controller in children whose parents prefer not to use an ICS It may also be used instead of a LABA as an add-on to an ICS, but it

is generally less effective

ASTHMA IN THE ELDERLY — Asthma in the

eld-erly is often associated with co-morbidities, such as car-diovascular disease, diabetes, dementia, depression and frailty, and with polypharmacy.36-38 Elderly asthmatic patients are more likely to have fixed airway obstruction with features that overlap COPD

The elderly have more adverse effects from ICSs, including skin bruising, cataracts, increased intraocular pressure, hyperglycemia and accelerated loss of bone mass They may have both a reduced response to beta2 -adrenergic bronchodilators, especially if concomitantly taking a beta blocker, and an increased incidence of tachycardia, arrhythmias and tremors In these patients, tiotropium (off-label) may be a useful bronchodilator Some older patients have difficulty inhaling any med-ication from a metered-dose or dry-powder inhaler and may require a nebulizer

ASTHMA AND CO-MORBID DISEASES —

Asthma is often associated with other co-morbid con-ditions including allergic rhinitis, gastroesophageal reflux disease (GERD), obesity, sinusitis, depression and anxiety Such co-morbidities can make asthma more difficult to treat.39

Allergic Rhinitis – Up to 95% of patients with asthma

also suffer from persistent rhinitis Concurrent pharma-cologic treatment of both asthma and rhinitis improves

asthma outcomes.40Patients with concomitant allergic

rhinitis and allergic asthma may benefit from specific

immunotherapy with standardized allergens.23

GERD – Patients with poorly controlled asthma have

a higher prevalence of GERD, but a cause-and-effect

relationship has not been demonstrated In adult

asth-ma patients who have concomitant GERD symptoms,

treatment with a proton pump inhibitor has been

reported to improve pulmonary function and

asthma-related quality of life.41In adult asthma patients with

asymptomatic GERD, treatment with a proton pump

inhibitor did not improve asthma control.42 A

random-ized controlled trial in children with poorly controlled

asthma without symptoms of GERD found that

lanso-prazole did not improve lung function or reduce

symp-toms, but did increase the risk of adverse effects.43

Obesity – Obesity has been associated with asthma

persistence and severity.4Overweight and obese

asth-matic patients may have a diminished response to

ICSs.44 Weight loss may improve lung function and

responsiveness to treatment Bariatric surgery has been

reported to improve asthma control and airway

hyper-responsiveness in overweight adults.45

1 CH Fanta Asthma N Engl J Med 2009; 360:1002.

2 PM O’Byrne Therapeutic strategies to reduce asthma exacerbations J

Allergy Clin Immunol 2011; 128:257.

3 JP Parsons et al An official American Thoracic Society clinical practice

guideline: exercise-induced bronchoconstriction Am J Respir Crit Care

Med 2013; 187:1016.

4 National Heart, Lung and Blood Institute National Asthma Education and

Prevention Program (NAEPP) Expert Panel Report (EPR) 3 Guidelines for

the diagnosis and management of asthma Full Report 2007 Available at

www.nhlbi.nih.gov/guidelines/asthma/index.htm Accessed June 13, 2013.

5 MA Rank et al The risk of asthma exacerbation after stopping low-dose

inhaled corticosteroids: a systematic review and meta-analysis of

ran-domized controlled trials J Allergy Clin Immunol 2013; 131:724.

6 WJ Calhoun et al Comparison of physician-, biomarker-, and

symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with

asthma: the BASALT randomized controlled trial JAMA 2012; 308:987.

7 HW Kelly Comparison of inhaled corticosteroids: an update Ann

Pharmacother 2009; 43:519.

8 HW Kelly et al Effect of inhaled glucocorticoids in childhood on adult

height N Engl J Med 2012; 367:904.

9 PM O’Byrne et al Risks of pneumonia in patients with asthma taking

inhaled corticosteroids Am J Respir Crit Care Med 2011; 183:589.

10 E Bateman et al Meta-analysis: effects of adding salmeterol to inhaled

cor-ticosteroids on serious asthma-related events Ann Intern Med 2008; 149:33.

11 RF Lemanske, Jr et al Step-up therapy for children with uncontrolled

asthma receiving inhaled corticosteroids N Engl J Med 2010; 362:975.

12 AW McMahon et al Age and risks of FDA-approved long-acting

ß-adrenergic receptor agonists Pediatrics 2011; 128:e1147.

13 JL Brozek et al Long-acting beta2 agonist step-off in patients with

con-trolled asthma Arch Intern Med 2012; 172:1365.

14 BA Chowdhury et al Assessing the safety of adding LABAs to inhaled

corticosteroids for treating asthma N Engl J Med 2011; 364:2473.

15 D Price et al Leukotriene antagonists as first-line or add-on

asthma-controller therapy N Engl J Med 2011; 364:1695.

16 SP Peters et al Tiotropium bromide step-up therapy for adults with

uncontrolled asthma N Engl J Med 2010; 363:1715.

17 HA Kerstjens et al Tiotropium improves lung function in patients with

severe uncontrolled asthma: a randomized controlled trial J Allergy

Clin Immunol 2011; 128:308.

18 HA Kerstjens et al Tiotropium in asthma poorly controlled with stan-dard combination therapy N Engl J Med 2012; 367:1198.

19 GJ Rodrigo et al Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review Chest 2011; 139:28.

20 NA Hanania et al Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial Ann Intern Med 2011; 154:573.

21 WW Busse et al Randomized trial of omalizumab (anti-IgE) for

asth-ma in inner-city children N Engl J Med 2011; 364:1005.

22 L Cox et al American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report.

J Allergy Clin Immunol 2011; 128:210.

23 MA Calderón et al Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond J Allergy Clin Immunol 2011; 127:30.

24 Bronchial thermoplasty for asthma Med Lett Dugs Ther 2010; 52:65.

25 FM Ducharme et al Written action plan in pediatric emergency room improves asthma prescribing, adherence, and control Am J Respir Crit Care Med 2011; 183:195.

26 J Oborne et al Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial Am J Respir Crit Care Med 2009; 180:598.

27 SC Lazarus Emergency treatment of asthma N Engl J Med 2010; 363:755.

28 V Bougault et al Airway hyperresponsiveness in elite swimmers: is it

a transient phenomenon? J Allergy Clin Immunol 2011; 127:892.

29 M Schatz and MP Dombrowski Asthma in pregnancy N Engl J Med 2009; 360:1862.

30 NA Hodyl et al Fetal glucocorticoid-regulated pathways are not

affect-ed by inhalaffect-ed corticosteroid use for asthma during pregnancy Am J Respir Crit Care Med 2011; 183:716.

31 L Blais et al High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations J Allergy Clin Immunol 2009; 124:1229.

32 M Tegethoff et al Inhaled glucocorticoids during pregnancy and off-spring pediatric diseases: a national cohort study Am J Respir Crit Care Med 2012; 185:557.

33 LN Bakhireva et al Safety of leukotriene receptor antagonists in preg-nancy J Allergy Clin Immunol 2007; 119:618.

34 B Cossette et al Impact of maternal use of asthma-controller therapy on perinatal outcomes Thorax 2013; 68:724.

35 RS Zeiger et al Daily or intermittent budesonide in preschool children with recurrent wheezing N Engl J Med 2011; 365:1990.

36 PG Gibson et al Asthma in older adults Lancet 2010; 376:803.

37 CE Reed Asthma in the elderly: diagnosis and management J Allergy Clin Immunol 2010; 126:681.

38 NA Hanania et al Asthma in the elderly: Current understanding and future research needs—a report of a National Institute on Aging (NIA) workshop J Allergy Clin Immunol 2011; 128:S4.

39 M Cazzola et al Asthma and comorbid medical illness Eur Respir J 2011; 38:42.

40 J Bousquet et al Allergic rhinitis and its impact on asthma (ARIA)

2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen) Allergy 2008; 63 Suppl 86:8.

41 TO Kiljander et al Effect of esomeprazole 40 mg once or twice daily

on asthma: a randomized, placebo-controlled study Am J Respir Crit Care Med 2010; 181:1042.

42 American Lung Association Asthma Clinical Research Centers et al Efficacy of esomeprazole for treatment of poorly controlled asthma N Engl J Med 2009; 360:1487.

43 JT Holbrook et al Lansoprazole for children with poorly controlled asthma JAMA 2012; 307:373.

44 E Forno et al Decreased response to inhaled steroids in overweight and obese asthmatic children J Allergy Clin Immunol 2011; 127:741.

45 AE Dixon et al Effects of obesity and bariatric surgery on airway hyper-responsiveness, asthma control, and inflammation J Allergy Clin Immunol 2011; 128:508.

Guidelines for treatment of COPD have been

pub-lished or updated in recent years.46,47

SMOKING CESSATION — Cigarette smoking is

the primary cause of COPD Smoking cessation offers

health benefits at all stages of the disease and can slow

the decline of lung function Counseling and

pharma-cotherapy can help patients quit Effective

medica-tions include varenicline (Chantix), nicotine

replace-ment therapies, and bupropion (Zyban, and others).48

Varenicline offers a unique mechanism of action as a

partial nicotinic receptor agonist, but the current

label-ing includes precautions regardlabel-ing possible

neuropsy-chiatric and cardiac side effects.49 Combining

smok-ing cessation therapies may offer additional benefit.50

SHORT-ACTING BRONCHODILATORS — For

patients with intermittent symptoms, therapy with an

inhaled short-acting bronchodilator is recommended

for acute relief Typically, these patients have mild

airflow obstruction and symptoms are usually

associated with exertion Short-acting agents, which

include inhaled beta 2 -agonists such as albuterol

(see Table 2) and the anticholinergic ipratropium (see

Table 4), improve forced expiratory volume in one

sec-ond (FEV1) and can relieve symptoms Short-acting

beta2-agonists have a more rapid onset than

ipratro-pium With chronic use, short-acting beta2-agonists

have a duration of action of less than 4 hours, while

ipratropium may continue to act for 6 hours (MDI) or

for as long as 8 hours (nebulized)

Combination Therapy – Combining a beta2-agonist

with ipratropium has an additive effect for acute relief

The combination of ipratropium and albuterol has been

more effective than either drug alone and is available

in a single inhaler In general, combining 2 bron-chodilators from different drug classes produces addi-tional therapeutic effects at lower doses, which may help to minimize dose-related adverse effects

Adverse Effects – Beta 2 -agonists can cause

tachycar-dia, skeletal muscle tremors and cramping, headache, palpitations, prolongation of the QT interval, insom-nia, hypokalemia, and increases in serum glucose They should be used with caution in patients with car-diovascular disease; unstable angina and myocardial infarction have been reported Tolerance can occur with continued use

Ipratropium is a quaternary ammonium

anticholiner-gic agent with limited systemic absorption Its most common adverse effect is dry mouth Pharyngeal irri-tation, urinary retention and increases in intraocular pressure may occur Anticholinergics should be used with caution in patients with glaucoma and in those with symptomatic prostatic hypertrophy or bladder neck obstruction

LONG-ACTING BRONCHODILATORS — For

patients with evidence of moderate to severe airflow obstruction and chronic symptoms, regular treatment with a long-acting bronchodilator is recommended Choices include an inhaled long-acting beta2-agonist

or an anticholinergic agent (see Table 4)

Long-acting beta 2 -agonists are intended to provide

sustained bronchodilation for at least 12 hours They have been shown to improve lung function and quality

of life and to lower exacerbation rates in patients with COPD.51 Indacaterol (Arcapta Neohaler) is a new

long-acting beta2-agonist that is administered once daily.52

All long-acting beta2-agonist products in the US include

a boxed warning about an increased risk of asthma-related deaths; there is no evidence to date that patients with COPD are at risk The adverse effects of long-act-ing beta2-agonists are similar to those of the short-acting agents Tolerance to the therapeutic effects of long-act-ing beta2-agonists can occur with continued use

Two long-acting anticholinergics are available in the

US Tiotropium has a long duration of action that

per-mits once-daily dosing, and there is no evidence of tol-erance to its therapeutic effects The UPLIFT trial enrolled 5993 patients with COPD and randomized them to either tiotropium or placebo, in addition to their usual medications, for 4 years Tiotropium improved lung function, and reduced the rates of exac-erbation and hospitalization, compared to placebo, but did not significantly reduce the rate of decline in FEV1

CHRONIC OBSTRUCTIVE

PULMONARY DISEASE (COPD)

Patients with COPD should stop smoking;

pharma-cotherapy may be helpful, especially with

vareni-cline (Chantix) Patients with mild, intermittent

symptoms can be treated with inhaled short-acting

bronchodilators for symptom relief When

symp-toms become more severe or persistent, inhaled

long-acting bronchodilators may be helpful Regular

use of long-acting bronchodilators may reduce the

frequency of acute exacerbations Combinations of a

beta2-agonist with an anticholinergic can be used for

patients inadequately controlled with a single agent

For patients with severe COPD who experience

fre-quent exacerbations, addition of an inhaled

cortico-steroid (triple therapy) is recommended For patients

with severe hypoxemia, oxygen therapy can

improve survival

during the study period.53,54 Tiotropium is generally

well tolerated and appears to be safe.55Adverse effects

are similar to those of ipratropium.56

Aclidinium (Tudorza Pressair) is a newer long-acting

anticholinergic for treatment of COPD.57 Twice-daily

inhaled therapy reduces symptoms and improves lung

function in patients with moderate to severe

COPD58,59; direct comparisons with tiotropium, which

is dosed once daily, are lacking, but the new device

may be easier to use.60

Choice of a Long-Acting Bronchodilator – The

choice of a long-acting bronchodilator lies between a

long-acting beta2-agonist and a long-acting

anticholin-ergic There is no strong evidence supporting the use of

either one over the other One population-based

retro-spective cohort study in >40,000 elderly patients found

that initial use of a long-acting beta2-agonist was

asso-ciated with lower mortality than initial use of

long-act-ing anticholinergics.61A 1-year trial in more than 7000

subjects with moderate to very severe COPD found

that use of tiotropium, compared to salmeterol,

result-ed in a longer time to an exacerbation, a rresult-eduction in

the risk of an exacerbation, and a decrease in overall

exacerbation frequency.62An accompanying editorial

cautioned that these results did not apply to patients

with milder disease and also indicated that therapy

with indacaterol, a newer long-acting beta2-agonist, in

doses of 150 and 300 mcg provided benefits similar to

those of tiotropium in other trials.63 How the

FDA-approved dosage of 75 mcg once daily compares to

approved doses of other inhaled bronchodilators

remains to be established

A nested case-control analysis of a retrospective cohort

study in 191,000 patients concluded that both inhaled

long-acting beta2-agonists and long-acting

anticholin-ergics were associated with an increased risk of

adverse cardiovascular events, including a

hospitaliza-tion or emergency department visit.64

When patients are not adequately controlled with a

sin-gle long-acting bronchodilator, combining a

long-act-ing anticholinergic with a long-actlong-act-ing beta2-agonist

may be helpful.65

THEOPHYLLINE — Slow-release theophylline can

be used as an oral alternative or in addition to inhaled

bronchodilators (see Table 2) Its primary mechanism

of action is bronchodilation Because of significant

inter- and intra-patient variability in theophylline

clearance, dosing requirements vary The drug has a

narrow therapeutic index; monitoring is warranted

periodically to maintain peak serum concentrations

between 8 and 15 mcg/mL for treatment of COPD

Adverse Effects – At theophylline serum

concentra-tions >12-15 mcg/mL, nausea, nervousness, headache and insomnia occur with increasing frequency in patients with COPD Vomiting, hypokalemia, hyper-glycemia, tachycardia, cardiac arrhythmias, tremors, neuromuscular irritability and seizures can also occur at higher serum concentrations Theophylline is metabo-lized in the liver, primarily by CYP1A2 and CYP3A4 Any drug that inhibits or induces these enzymes can affect theophylline metabolism.66 Clearance of theo-phylline is reduced in the elderly and in patients with liver disease or heart failure

CORTICOSTEROIDS — Inhaled corticosteroid

monotherapy is not approved for use in COPD Various combinations of inhaled corticosteroids and long-acting beta2-agonists are available as listed in Table 4 The most recent addition to these options is a combination

of fluticasone furoate and vilanterol (Breo Ellipta), the

Table 3 Treatment of COPD 1

Recommended Patient Group Regimen 2

Group A 3

Preferred Short-acting anticholinergic

as needed

or SABA as needed

Alternatives Long-acting anticholinergic

or LABA

or SABA + short-acting

anti-cholinergic

Group B 4

Preferred Long-acting anticholinergic

or LABA

Alternatives Long-acting anticholinergic

+ LABA

Group C 5

Preferred ICS + LABA

or Long-acting anticholinergic

Alternatives Long-acting anticholinergic

+ LABA or ICS

or PDE4 inhibitor + Long-acting

anticholinergic or LABA

Group D 6

Preferred ICS + LABA

and/or long-acting anticholinergic Alternatives ICS + LABA

+ long-acting anticholinergic

or ICS + LABA

+ PDE4 inhibitor

or Long-acting anticholinergic

+ LABA

or Long-acting anticholinergic

+ PDE4 inhibitor SABA = inhaled short-acting beta 2 -agonist; LABA = inhaled long-acting beta 2 -agonist; ICS = inhaled corticosteroid; PDE4 inhibitor = phosphodi-esterase-4 inhibitor

1 Adapted from global strategy for the diagnosis, management, and preven-tion of chronic obstr uctive pulmonary disease: GOLD executive summary Updated 2013 Available at www.goldcopd.com Accessed July 15, 2013.

2 Short-acting anticholinergics and shor t-acting beta 2 -agonists can be added to any regimen for acute relief Theophylline may be used as an oral alternative or in addition to inhaled bronchodilators

3 Group A = few symptoms and low risk of exacerbations.

4 Group B = more significant symptoms, but low risk of exacerbations.

5 Group C = few symptoms, but high risk of exacerbations.

6 Group D = many symptoms and high risk of exacerbations.