Download Asthma - The Rx Consultant

The
R Consultant
Improving
Spring 2003
patient care through drug education
Volume XII Number 12
Asthma
OVERVIEW
More than 14 million Americans have been diagnosed with
asthma and the prevalence of this disease continues to increase.
Every year, asthma is responsible for almost 500,000 hospitalizations and more than 5,000 deaths1 - even though effective therapies have been available for many years. In 1991 and again in
1997, the national guidelines for asthma management recommended inhaled antiinflammatory agents as first-line therapy for
persistent asthma.2 An update of these guidelines in July, 2002
specified inhaled corticosteroids as the preferred treatment for
patients of all ages, including infants.3 Although asthma guidelines are widely distributed, inhaled corticosteroids have remain
under-used. A survey evaluating asthma therapy 5 years after
publication of the national guidelines found that fewer than half
of patients with asthma in a California HMO had obtained a corticosteroid inhaler in the previous 6 months.4 This pattern of use
not only increases the risk for asthma attacks, but also results in
over use of health care resources.
While inhaled corticosteroids are the most effective medications
for asthma control, several alternatives are available. This issue
outlines the role of each medication, including the newest inhaled products, formoterol (Foradil®) and fluticasone / salmeterol
(Advair Diskus®). The "ozone safe" inhalers are detailed on page
3, so pharmacists can help patients understand how they differ
from older inhalers and use them correctly. Pharmacists are in an
ideal position to improve asthma care, and their participation is
strongly encouraged by health care experts. (See inset at right.)
ACPE#
Continuing Education Objectives 428-000-03-012-H01
• Describe the 4 classes of asthma severity and the medications
recommended for initial management of patients in each class.
• Explain the appropriate use of currently available inhaled
antiinflammatory agents, inhaled bronchodilators and
leukotriene modifiers in asthma therapy.
• Describe the differences between dry powder inhalers, inhalers
with CFC propellants and inhalers with HFA propellants.
• List 6 steps a pharmacist can take to improve asthma
care.
1
The Bottom Line
• All asthma patients need a short-acting inhaled bronchodilator to use as needed for
quick symptom relief. All patients except
those with mild, intermittent disease should
use long-term control medication(s) on a
scheduled basis to prevent symptoms.
• Low-dose inhaled corticosteroids are the
preferred treatment for children and adults
with mild, persistent asthma.
• Low-to-medium dose inhaled corticosteroids
plus a long-acting inhaled bronchodilator is
the preferred treatment for adults and children
older than 5 years with moderate asthma.
• High-dose inhaled corticosteroids plus a
long-acting inhaled bronchodilator is the
preferred treatment for adults and children
older than 5 years with severe asthma.
• Low-to-medium dose inhaled corticosteroids
may transiently slow growth, but the effect is
not sustained with long-term treatment and
may be reversible. Current evidence suggests
that normal final height is attained.
• The National Asthma Education Prevention
Program highlights the importance of pharmacists in the guide, The Role of the Pharmacist
in Improving Asthma Care.35 Six steps are
recommended:
1. Educate patients about each asthma drug.
2. Teach patients how to use asthma inhalers.
3. Monitor refill intervals for inhaled
bronchodilators. Using more than 1 canister a
month can be a sign of poor asthma control.
4. Encourage patients who purchase OTC
asthma inhalers or tablets to get medical care.
5. Help patients use peak flow meters correctly.
6. Help patients leaving the hospital after an
asthma attack understand their treatment
plan.
Information for Patients
FAO's
• What are the two types of medications used to treat
asthma?
Long-term control medications and quick relief medications are used to treat asthma. Controllers are used on a
regular, daily schedule to reduce and prevent asthma
symptoms. Quick relief drugs are used on an "as
needed" basis to rapidly relieve symptoms by opening
up the airways. (See Table 1.)
ticosteroids (if needed) and should not be used for quick
relief. Inhaled cromolyn and nedocromil reduce airway
inflammation less effectively than corticosteroids, but
have no serious side effects. The leukotriene modifiers,
montelukast, zafirlukast and zileuton, are oral drugs
that reduce airway inflammation. Currently, these
agents are considered second-line alternatives for patients with mild or moderate persistent asthma.
Montelukast and zileuton can be taken with or without
food. Zafirlukast should be taken at least one hour before or two hours after meals. Liver damage is a rare
side effect of zileuton and blood tests to measure liver
function should be done periodically during therapy.
Any symptoms of liver damage (e.g., fatigue, nausea, abdominal pain, flu-like symptoms, jaundice) should be
reported to your doctor immediately.
• Which medications are long-term controllers?
Inhaled corticosteroids reduce airway inflammation and
are the most effective inhaled drugs for preventing
asthma symptoms. Some benefit may be felt in less than
a week, but it usually takes 2-8 weeks before the full benefit is apparent. The serious side effects seen with oral
steroids are rare with usual inhaled doses. Rinsing the
mouth then spitting after each dose, and using a spacer
(with metered dose inhalers) helps reduce side effects.
Inhaled salmeterol and formoterol are long-acting
bronchodilators. They should be used with inhaled cor-
• Which medications are quick symptom relievers?
Inhaled, short-acting bronchodilators are used for quick
symptom relief or to prevent exercise-induced asthma.
Table 1. Commonly Prescribed Drugs for the Treatment of Asthma in Adults 2,3,25,36-38
Long-term Control Medications
Inhaled
Corticosteroids
Cromones
Strength
Low daily dose
beclomethasone dipropionate MDI
42 µg/puff
Beclovent®,Vanceril® (CFC)
Vanceril
(CFC) Drugs for the
84 µg/puff
Table
1.® DSSome
Preventive
40, 80 µg/puff
QVAR® (HFA)
budesonide DPI Pulmicort Turbuhaler® 200 µg/inh
250 µg/puff
flunisolide MDI (CFC) Aerobid®
fluticasone MDI (CFC) Flovent®
44, 110, 220 µg/puff
fluticasone DPI Flovent Rotadisk®
50, 100, 250 µg/inh
triamcinolone acetonide MDI (CFC)
100 µg/puff
Azmacort®
cromolyn sodium MDI (CFC) Intal®
800 µg/puff
nedocromil MDI (CFC) Tilade®
1.75 mg/puff
Medium daily dose
4-12 puffs
12-20 puffs
>20 puffs
2 puffs
2-6 puffs
6-10 puffs in Adults>10
Treatment
of Asthma
2-6 puffs (40 µg/puff)
1-3 inh
2-4 puffs
2-6 puffs (44 µg/puff)
2-6 inh (50 µg/inh)
4-10 puffs
3-6 puffs (80 µg/puff)
3-6 inh
4-8 puffs
2-6 puffs (110 µg/puff)
3-6 inh (100 µg/inh)
10-20 puffs
>6 puffs (80 µg/ puff)
>6 inh
>8 puffs
>3 puffs (220 µg/puff)
>6 inh (100 µg/inh)
>20 puffs
6-16 puffs (2-4 puffs tid-qid)
4-16 puffs (2-4 puffs bid-qid)
Long-acting
Inhaled
Bronchodilators
salmeterol MDI (CFC) Serevent®
salmeterol DPI Serevent Diskus®
formoterol DPI Foradil®
21 µg/puff
50 µg/inh
12 µg/inh
4 puffs (2 puffs q12hr)
2 inh (1 inh q12hr)
2 inh (1 inh q12hr)
Leukotriene
Modifiers
montelukast Singulair®
zafirlukast Accolate®
zileuton Zyflo®
10 mg tablet
20 mg tablet
600 mg tablet
10 mg q hs
40 mg (20 mg bid)
2400 mg (600 mg qid)
Methylxanthine
theophylline (extended release) ‡
Combination
fluticasone propionate/salmeterol DPI
Advair Diskus®
10 mg/kg/day; usual maximum 800 mg/day
100/50, 250/50, 500/50 µg/inh
Quick Symptom Relievers
Short-acting
Inhaled
Bronchodilators
High daily dose
Strength
albuterol MDI (CFC) Ventolin®, Proventil®
albuterol MDI (HFA) Ventolin HFA®, Proventil HFA®
bitolterol MDI (CFC) Tornalate®
pirbuterol MDI (CFC) Maxair Autohaler®
90 mcg/puff
90 mcg/puff
370 mcg/puff
200 mcg/inh
2 inh (1 inh bid)
Usual daily dose
2 puffs tid-qid prn or 2 puffs 5 min before exercise
2 puffs tid-qid prn or 2 puffs 5 min before exercise
2 puffs tid-qid prn or 2 puffs 5 min before exercise
2 inh tid-qid prn or 2 inh 5 min before exercise
MDI: metered dose inhaler; DPI: dry powder inhaler; inh: inhalation ‡Routine serum theophylline level monitoring is important.
CFC= chlorofluorocarbons (including trichloromonofluoromethane, dichlorodifluoromethane, & fluorochlorohydrocarbon) HFA = hydrofluoroalkane
2
Ozone-Safe Inhalers
Background
Metered dose inhalers (MDIs) containing ozone-depleting
chlorofluorocarbon (CFC) propellants will be phased out
over the next few years. Two alternatives currently available in the U.S. are MDIs with hydrofluoroalkane propellants and dry powder inhalers.
Asthma is a chronic inflammatory disease of the airways. Airway inflammation produces recurrent episodes of airflow reduction (e.g., bronchoconstriction)
and an increased sensitivity of the airways to a variety of
stimuli, such as cold air and inhaled allergens. Airflow
reduction is usually reversible, but it can be severe and
even fatal. Symptoms include shortness of breath,
wheezing, chest tightness, increased sputum production
and cough. Asthma symptoms are variable; not all patients wheeze, and persistent cough alone may be the
first symptom.
Hydrofluoroalkane (HFA) Inhalers
Hydrofluoroalkanes are propellants that do not deplete
the ozone layer. The HFA-MDIs currently available in
the U.S. are:
Proventil HFA® (albuterol)
Ventolin HFA® (albuterol)
QVAR® (beclomethasone)
Key Points
• HFA-MDIs are pressurized metered dose inhalers.
• The taste and "feel" of the spray may be different
compared to a CFC-MDI containing the same drug.
• The canister should not be immersed in water.
• Do not wash or put any part of the QVAR inhaler in
water (the port may clog). The mouthpiece should be
cleaned weekly with a clean, dry tissue or cloth.
• The mouthpiece for Proventil HFA and Ventolin HFA
should be removed from the canister, washed under
warm, running water and air dried at least once a
week.
Provoking Factors
Individuals with asthma are particularly sensitive to
various stimuli which can cause or worsen airway inflammation, bronchoconstriction, or both. Inhaled allergens such as house dust mites, pollen, animal dander,
and fungal spores can trigger asthma. Upper airway infections may also provoke symptoms. Other potential
triggers include exercise, cold air, laughter, emotional
upset, metabisulfite (a preservative), aspirin, NSAIDs,
beta blockers (including eye drops) and inhaled irritants
like cigarette smoke, fumes from household cleaning
products and air pollutants. An essential step in asthma
management is the elimination or reduction of exposure
to allergens and irritants, and the control of other factors
that increase symptoms or precipitate acute attacks.
Dry Powder Inhalers (DPIs)
DPIs do not use propellants and are activated by inspiration. The medication is either held in a capsule, which is
perforated manually just before inhalation, or in a reservoir from which a dose is released manually just before
inhalation. The DPIs currently available in the U.S. are:
Pulmicort Turbuhaler® (budesonide)
Flovent Rotadisk® (fluticasone)
Foradil Aerolizer® (formoterol)
Serevent Diskus® (salmeterol)
Advair Diskus® (salmeterol/fluticasone)
Peak Expiratory Flow Rate (PEFR) Monitoring
A peak flow meter measures the highest velocity of expired air that can be obtained during a forced expiration,
starting with fully inflated lungs. This provides a
simple, objective measurement of large airway function.
Regular, home measurement of the PEFR helps patients
detect early changes in asthma control, determine the
severity of asthma attacks, and decide when to adjust
asthma medications and/or consult a clinician about
making adjustments. It is also useful in evaluating the
response to a change in therapy. Home PEFR monitoring is recommended for patients who have moderate to
severe persistent asthma.2 Home monitoring is especially useful for those who have difficulty identifying
early symptoms, since worsening lung function can be
recognized and treated before severe symptoms develop.
Proper technique is essential for reliable peak flow measurements. The first step is to take a deep breath and
blow hard and fast into the peak flow meter. This is repeated twice, and the PEFR is the highest value obtained
from the three attempts. The patient’s PEFR is then compared to a nomogram of predicted flow rates based on
the patient’s age, gender and height, and reported as a
percent of 1) the predicted value, or 2) the patient’s “per-
Key Points:
• The inhaled powder may not have much taste or "feel".
• Since there is no need to coordinate inhalation with
depressing the actuator, a DPI may be easier for some
patients to use than a pressurized MDI.
• A deep, forceful inhalation is required for most DPI
devices; this may be difficult for some patients.
sonal best” value. The personal best PEFR is the highest
peak flow value achieved over a 2-3 week period when
the patient's asthma is under good control. The personal
best PEFR is the most appropriate reference value.2
Goals of Therapy
There is no cure for asthma and long term treatment is
generally required to prevent and relieve symptoms.
Treatment goals include preventing chronic symptoms
3
Table 2. Mechanism of Action and Adverse Effects of Asthma Medications
Product
Mechanism of Action
Long-Term Control Medications
Adverse Effects
Corticosteroids
Inhaled: beclomethasone,
budesonide, flunisolide,
fluticasone propionate,
triamcinolone
interfere with the functions of
cells that cause or maintain
airway inflammation (eg, eosinophils, macrophages, mast
cells); reduce the sensitivity of
airway smooth muscle
• hoarseness1, throat irritation1, oral thrush (candidiasis) 2,
• prolonged high dose therapy may cause systemic
effects (eg, thinning of the skin, cataracts, easy
bruising, growth retardation in children, bone loss
in adults); Churg-Strauss syndrome 3 *
Systemic:
methylprednisolone,
prednisolone, prednisone
as above
• Short-term: abnormalities in glucose metabolism,
increased appetite, weight gain, fluid retention,
hypertension, mood swings, peptic ulcer
• Long-term: growth suppression, osteoporosis, adrenal
suppression, skin thinning, easy bruising, diabetes,
hypertension, cataracts, weakness, Cushing's syndrome
Inhaled Long-Acting
Bronchodilators
formoterol, salmeterol
relax airway smooth muscle
Cromones
cromolyn sodium,
nedocromil
inhibit activation and prevent
release of inflammatory
mediators from mast cells,
eosinophils and epithelial cells
Leukotriene Modifiers
montelukast, zafirlukast
prevent receptor binding of
leukotrienes
• headache1, gastrointestinal upset2; abnormal liver function
tests infrequently with zafirlukast; Churg-Strauss syndrome 3*
inhibits leukotrienes synthesis
• headache1, upset stomach1, abnormal liver function tests2
relax airway smooth muscle
• therapeutic serum levels: insomnia 2, GI upset2
• dose related toxicities: tachycardia, nausea, vomiting,
arrhythmias, CNS stimulation, headache, seizures,
hyperglycemia, hypokalemia
relax airway smooth muscle
• headache1, tachycardia1, palpitations1, tremor1, paradoxical
bronchospasm3
• hypokalemia and adverse cardiovascular effects may occur;
use cautiously in patients with cardiovascular disorders
zileuton
Methylxanthines
theophylline
Quick Relief Medications
Inhaled Short-Acting
Bronchodilators
albuterol, bitolterol,
pirbuterol
1= more common
2=less common
• headache2, tachycardia2, palpitations2, tremor2,
paradoxical bronchospasm 3
• hypokalemia and adverse cardiovascular effects may occur;
use cautiously in patients with cardiovascular disorders
• unpleasant taste1 (primarily with nedocromil)
3=rare
* a potentially fatal syndrome involving eosinophilia and vasculitis; has been reported in association with discontinued or decreased corticosteroid therapy
and recurrent exacerbations, maintaining normal activity
levels (including exercise), maintaining lung function as
close to normal as possible, and optimizing drug
therapy.2 Meeting patients' and families' expectations of
therapy and satisfaction with care is also important.
because prescription drugs generally provide better control with fewer side effects.
Drug therapy should be implemented in a step-wise
manner based on the severity of the disease.2 The national guidelines describe four classes of asthma severity,
determined by the frequency of symptoms and measurements of lung function before treatment (the peak expiratory flow rate or the forced expiratory volume in one
second). These classes are 1) mild intermittent, 2) mild
persistent, 3) moderate persistent, and 4) severe persistent asthma.
Drug Therapy
Asthma medications are categorized according to their
use as quick symptom relievers or long-term control
medications. The symptom relievers, short-acting inhaled ß2-agonist bronchodilators, are used only as
needed. Long-term control medications are used on a
scheduled, daily basis to prevent symptoms. The use of
over-the-counter bronchodilators should be discouraged,
Patients in every class require a short-acting inhaled
bronchodilator for quick symptom relief or prevention of
exercise induced symptoms. Long-term control medica4
tion is recommended for all asthma patients except those
with mild intermittent disease. Patients with mild intermittent asthma have symptoms no more frequently than
twice a week and nocturnal symptoms up to twice a
month. If symptoms occur more than twice a week but
less than daily, or nocturnal symptoms occur more than
twice a month, asthma is classified as mild persistent.
Daily inhaled low-dose corticosteroid therapy is the preferred treatment.3 Moderate persistent asthma, characterized in part by daily symptoms or nocturnal symptoms more than once a week, requires the addition of a
long-acting inhaled bronchodilator. Some patients also
need an increase in the inhaled corticosteroid dose,
within the medium-dose range. Severe persistent
asthma, which may feature continual symptoms or frequent nocturnal symptoms, is less common and requires
aggressive treatment. High dose inhaled corticosteroids
and a long-acting inhaled bronchodilator are required.
Long-term oral corticosteroid therapy may be necessary.
Once symptoms are under control, asthma therapy
should be reviewed every 3 to 6 months. A gradual,
step-wise reduction in drug therapy may be possible.2
See Table 1 for the recommended doses of the medications discussed below. Adverse effects and mechanisms
of action are summarized in Table 2.
(ICS) are the cornerstone of asthma therapy and are the
drugs of first choice for patients with persistent mild,
moderate or severe asthma.2 Treatment with ICS for 2 to
8 weeks significantly reduces the signs of airway inflammation, the frequency and severity of symptoms, and the
need for symptom relief with an inhaled bronchodilator.5
The optimal daily ICS dose is the lowest dose that controls symptoms. In patients with mild to moderate
asthma, high doses are only modestly more effective
than much lower daily doses.6,7 High doses may be necessary in patients with severe asthma to control symptoms and minimize oral corticosteroid dosages. Twice
daily dosing of ICS is effective for many patients and one
daily dose may suffice for those with mild asthma.
Local side effects include hoarseness, thrush and throat
irritation. Systemic effects generally are not a concern
with conventional doses (e.g., less than 1000 µg inhaled
beclomethasone CFC per day). With prolonged high
dose therapy, systemic effects may occur (see Table 2),
but are much less likely with ICS than with chronic oral
corticosteroid therapy.
Two recent clinical trials investigated the effect of ICS on
growth in children. While previous studies were 12
months or less in duration, one of the recent trials followed participants for 4-6 years8 and the other continued
until participants reached adulthood.9 Both studies
evaluated budesonide in doses of about 400 µg per day.
The results indicate that low to moderate dose inhaled
budesonide is unlikely to affect adult height, although
growth slows transiently early in therapy.
Quick Relief Medications
Short-acting Bronchodilators
Short-acting, inhaled ß2-agonists are the most effective
bronchodilators available and are recommended for
rapid relief of acute asthma symptoms in all patients.2
These drugs usually relieve symptoms within 3 to 15
minutes and prevent exercise induced asthma if used 5
minutes before an activity. The usual duration of action
is 4-6 hours. Scheduled dosing is generally not recommended. The use of a short-acting ß2-agonist inhaler
more often than twice per week is an indication that a
control medication, such as an inhaled corticosteroid,
should be initiated or increased.2 High, frequent doses
(e.g., 4 puffs every 20 minutes for 1 hour) are occasionally required, however, to control acute asthma attacks.
The effect of long term ICS use on bone density in adults
has not been established. While some evidence suggests
long-term, high dose therapy predisposes patients to osteoporosis,10 a recent clinical trial provides reassurance.
This four year study of asthmatics using an average of
765 µg inhaled beclomethasone daily found no overall
effect on spinal bone mineral density.11 Participants who
had more than 2.5 courses of oral corticosteroids per
year, however, did experience significant bone loss.
Systemic absorption of an inhaled corticosteroid can occur from the lungs or the GI tract. The portion of a dose
delivered to the lungs varies with the delivery device.
The rest of the dose is deposited in the throat, swallowed, and may be absorbed through the GI tract. The
fraction swallowed after using an MDI can be markedly
reduced by adding a spacer. Rinsing the mouth after
each dose (and spitting) also helps minimize local and
systemic side effects. These steps are particularly important for patients on high dose therapy.
Long-term Control Medications
Antiinflammatory Agents
Control of airway inflammation is the most important
target for asthma drug therapy. Antiinflammatory
agents effective in asthma therapy include inhaled and
oral corticosteroids, inhaled cromones, and the oral
leukotriene modifiers.
Corticosteroids
Corticosteroids are the most potent and effective medications for the control of asthma. Inhaled corticosteroids
A new formulation of beclomethasone dipropionate
(BDP) with a non-ozone depleting hydrofluoroalkane
5
Resources
• National Asthma Education and Prevention Program
Expert Panel Report: Guidelines for the Diagnosis and
Management of Asthma-Update on Selected Topics 2002, and
Expert Panel Report 2: Guidelines for the Diagnosis and
Management of Asthma
For information, contact:
NHLBI Health Information Network
(301) 592-8573
http://www.nhlbi.nih.gov/guidelines/index.htm
• NIH National Heart, Lung, and Blood Institute
www.nhlbi.nih.gov/nhlbi/nhlbi.htm
(301) 496-4236
• American Academy of Allergy, Asthma and Immunology
http://www.aaaai.org
(800) 822-ASMA
• American Lung Association
http://www.lungusa.org
(800) LUNG-USA
• Asthma and Allergy Foundation of America
http://www.aafa.org
(800) 7-ASTHMA
• Global Initiative for Asthma
http://www.ginasthma.com
(HFA) propellant has improved delivery of the inhaled
drug to the lungs. This new formulation provides an
extra fine aerosol particle size. Studies have shown lung
deposition to be 51%-60% with HFA-BDP compared to
about 10% for CFC-BDP.12 As a result, HFA-BDP has
equivalent efficacy at about half of the total daily dose of
CFC-BDP.13
The ideal inhaled corticosteroid has high topical potency,
low systemic bioavailability (of the portion swallowed),
and is rapidly metabolized. While the newer inhaled
corticosteroids, fluticasone (Flovent®) and budesonide
(Pulmicort Turbuhaler®) have more ideal characteristics
than older agents, differences in safety or efficacy have
not been established. Comparative studies of ICS are
complicated by differences in potency and delivery devices. In trials comparing equipotent doses of these
drugs in various combinations, asthma symptoms improved to a similar extent.14,15,16 The primary advantage
of the more potent agents may be ease of use and improved compliance, especially for patients on high
doses, since fewer puffs or inhalations are required.
The use of oral corticosteroids is recommended in "short
bursts" to control acute symptoms when a long-term
controller is started or if symptoms are worsening despite optimal controller therapy. Bursts, such as prednisone 40-60mg per day, are continued until the patient
achieves a PEFR of 80% of personal best or symptoms
resolve (usually 3-7 days). Tapering the dose following
improvement is not necessary with short term use (up to
10 days).2 ICS should be continued during oral therapy.
Long-term oral corticosteroid therapy may be necessary
to control severe asthma, but inhaled products are safer
and should be used whenever possible.
Cromones
The inhaled cromones, cromolyn sodium and nedocromil
sodium, are less effective antiinflammatory agents than
inhaled corticosteroids. These agents are second-line alternatives for the treatment of mild persistent asthma.3
Nedocromil and cromolyn are primarily prescribed for
children, because they have no serious side effects. A
four to six week trial may be required to determine
whether a cromone is effective. These agents may also be
used to prevent exercise induced asthma,17 although an
inhaled bronchodilator is generally more effective. A disadvantage of cromones is the requirement for three or
four daily doses in most patients.
Leukotriene Modifiers
The leukotriene modifiers, montelukast (Singulair®),
zafirlukast (Accolate®) and zileuton (Zyflo®), are the most
recent additions to the list of drugs used as controllers in
asthma therapy. Leukotrienes are potent inflammatory
mediators in the airways, causing bronchoconstriction
and increased inflammation. Montelukast and
zafirlukast block the actions of leukotrienes by preventing
binding to leukotriene receptors. Zileuton prevents
leukotriene synthesis.
Currently, these agents are recommended as second line
alternatives to low-dose ICS for the treatment of mild, persistent asthma.2,3 In patients with moderate persistent
asthma, the combination of an ICS and a leukotriene modifier is a second-line alternative, while an ICS plus a longacting, inhaled bronchodilator (salmeterol, formoterol) is
the preferred treatment. As oral medications (tablets), the
leukotriene modifiers have the potential to improve adherence compared to inhaled therapy. The use of
leukotriene modifiers in asthma therapy is an area of active
research and their role may change as more evidence accumulates.
It has been suggested that leukotriene modifiers are especially appropriate options for the 10% of asthmatics who
are aspirin/NSAID-sensitive. This arises from the fact
that aspirin-induced asthma is associated with excessive
leukotriene release. The response to leukotriene modifiers has been similar, however, in asthmatics with or without aspirin/NSAID sensitivity.18
Montelukast and Zafirlukast
Both montelukast and zafirlukast have been more effective than placebo, but less effective than low-dose inhaled beclomethasone or fluticasone in the treatment of
persistent asthma.19-23 Among patients with persistent
asthma who were using inhaled corticosteroids, the addition of montelukast24,25 or zafirlukast26 has been less effective than salmeterol in improving overall asthma control.
The Rx Consultant (ISSN 10667741) is published monthly except August for $89 per year by CEN, Inc.
5325 Stonehurst Drive, Martinez, CA 94553-6619. Periodicals Postage Paid at Martinez, CA and additional mailing offices.
POSTMASTER: Send address changes to THE RX CONSULTANT, P.O. Box 1516, Martinez, CA 94553-0516.
Few side effects have occurred much more frequently
with zafirlukast or montelukast than with placebo. A
dose-related increase in liver enzyme levels has been reported in small numbers of patients taking zafirlukast,
and rarely, symptomatic hepatitis and hyperbilirubinemia
have occurred. Zafirlukast inhibits the drug metabolizing
enzyme cytochrome P450 2C9, increasing warfarin blood
levels and the risk of bleeding. The INR (normalized
prothrombin time) should be closely monitored if these
drugs are co-administered. Although drug interaction
studies did not identify an interaction with theophylline,
rare cases of theophylline toxicity have been reported.20
Theophylline and erythromycin decrease zafirlukast
plasma levels by 30-40%, and aspirin (650mg QID) has
increased zafirlukast levels by a similar percent. The
clinical importance of these interactions is unknown.
Montelukast appears to have few drug interactions and
does not interact with warfarin or theophylline within
the recommended dose range.
exercise induced asthma. Tolerance may develop if the
drugs are used daily, resulting in less protection many
hours after the dose.2 Salmeterol or formoterol may be
preferable to a short-acting ß2-agonist in patients who
occasionally require prolonged prevention of exercise
induced asthma.
Combination Therapy with Inhaled Corticosteroids
In patients who remain symptomatic despite inhaled
corticosteroid therapy, adding a long-acting bronchodilator improves asthma control and can be more effective
than increasing the corticosteroid dose.28-30 This combination is the preferred treatment for patients with moderate or severe persistent asthma. The addition of a
long-acting bronchodilator has also been shown to allow
reduction of the steroid dose without a decrease in shortterm asthma control.31 Whether a dose reduction can be
maintained long term without any deleterious effects
remains unknown. Salmeterol or formoterol cannot replace an inhaled steroid. Among patients well-controlled on a low-dose ICS, switching to a long-acting
bronchodilator resulted in loss of asthma control.31,32
Salmeterol and formoterol should only be used as controllers in patients also taking an inhaled corticosteroid.
In comparison to zafirlukast, montelukast has a favorable
drug interaction profile and a more convenient dosing
regimen. It is taken once a day without regard to meals,
while zafirlukast is taken twice a day on an empty stomach. Montelukast is approved for use in children 2 years
of age and older, while zafirlukast is approved for use in
children ≥5 years of age.
Advair Diskus® is a new, combination DPI for preventive
therapy in patients who require both fluticasone and
salmeterol. It is as effective and more convenient than
using two separate inhalers concurrently, and may be
less expensive. The inability to titrate the corticosteroid
dose independently can be a disadvantage, however.
For example, the corticosteroid dose cannot be increased
in response to an acute asthma exacerbation.
Zileuton
Although zileuton has been effective for the treatment of
mild to moderate asthma, adverse effects on liver function, drug interactions, and the need for frequent dosing
(four times a day) have limited its use. Zileuton is contraindicated in patients with active liver disease and
should be avoided in patients with a history of heavy alcohol use or liver disease. Liver function tests are recommended before therapy is started, every month for the
first 3 months, every 2-3 months for the rest of the first
year and periodically thereafter.27
Ipratropium
Inhaled ipratropium, available as a metered dose inhaler
and nebulizer solution, can improve the response to
therapy when added to a ß2-agonist for the treatment of
a severe, acute asthma attack. The role of ipratropium in
the management of stable asthma is unclear.
Bronchodilating Agents
Long-acting ß2-agonists
Salmeterol (Serevent®) and formoterol (Foradil®) are inhaled ß2-agonists with a duration of action of at least 12
hours. In contrast to the short-acting agents, long-acting
inhaled bronchodilators are used on a scheduled basis as
controllers and should not be used for quick symptom
relief. Patients on salmeterol or formoterol therapy
should have a short-acting ß2-agonist inhaler for as
needed use. Formoterol has a faster onset of action than
salmeterol (1-3 minutes vs 10-20 minutes). This difference is not expected to be clinically important when
these agents are used as controllers.
Theophylline
Theophylline has a modest bronchodilating effect and
may have mild antiinflammatory, immune modifying,
and bronchoprotective actions.33 With the introduction
of effective drugs with less potential for toxicity and
drug interactions, the use of theophylline has declined.
Several clinical trials comparing theophylline and inhaled salmeterol suggest that salmeterol is more effective, especially in reducing nocturnal symptoms.34 Patients taking salmeterol experienced fewer adverse effects, such as central nervous system and gastrointestinal
symptoms. Theophylline remains an alternative, however, for patients who have difficulty using an inhaler.
Salmeterol and formoterol are also effective in preventing
7
Updates
Pharmacy Headlines
FDA Safety Alert: A Public
Health Advisory has been issued
regarding the topical use of Lindane® lotion and shampoo for
treatment of scabies and lice. A
boxed warning in the prescribing
information emphasizes
Lindane's status as second-line
treatment, its neurologic toxicity,
and contraindications.
Women At Risk: Many women
with heart disease may not receive standard treatment to prevent heart attacks and other serious coronary events. Of 2,763
women with coronary heart disease in the recent HERS II study
of hormone replacement, an
alarming number were
undertreated with standard preventive medications such as aspirin, beta blockers and cholesterol
lowering medications.
Ephedra Safety Questions: The
safety of ephedra (ma huang)
continues to be questioned. A
recent study found that ephedra
accounted for 64% of all reported
adverse reactions to herbs in the
U.S. This raises a red flag because these products represent
less than 1% of total herbal product sales. Adverse effects reported with ephedra include nervousness, insomnia, heart attack
and stroke. An FDA advisory
committee is currently assessing
the safety of ephedra products.
Vitamin Combination Slows
Progression of Atherosclerosis
Salonen RM, et al. Six-year effect of combined
vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study.
Circulation 2003;107:947-953.
Summary: A six year study of 520
adults has shown that vitamins E
and C slow the progression of
carotid atherosclerosis, as measured
by ultrasound. The participants
were smoking and nonsmoking men
and postmenopausal women with
high cholesterol, aged 45 to 69 years.
Supplementation with d-alphatocopherol 136 IU plus 250 mg slowrelease ascorbic acid twice daily
significantly reduced the progression
of carotid atherosclerosis in men, but
not in women.
Comment: This study demonstrated that supplementation with
vitamins E and C slows the progression of atherosclerosis in men.
Reasons for the different results in
men and women are unknown. In
contrast to this study, large clinical
trials looking at the outcomes of
atherosclerosis (e.g., the incidence of
heart attack and stroke) have not
shown a benefit from vitamin
supplementation. The effects of
vitamins E and C on cardiovascular
disease remain controversial.
By Mary Chavez, PharmD
The Status of Serevent®
FDA Talk Paper: Study of Asthma Drug Halted.
1/23/03. and GlaxoSmithKline Dear Health Professional letter. www.fda.gov/bbs/topics/ANSWERS/2003/ANS01192.html
Summary: In early 2003, the FDA
and GlaxoSmithKline (GSK) issued
advisories about the asthma drug
Serevent® (salmeterol xinafoate). An
interim analysis of GSK's Salmeterol
Multi-center Asthma Research Trial
(SMART) suggested the drug may
increase the risk of life-threatening
asthma episodes and asthma-related
deaths. The interim analysis further
suggested that African Americans
and patients not taking inhaled corticosteroids may be at greater risk than
others. However, the FDA emphasized that the benefits of Serevent®
continue to outweigh the risks and
serious problems were rare.
Comment: Pharmacists should
counsel patients to consult a physician before stopping Serevent®, and
to avoid stopping it abruptly. Patients should know that salmeterol
should not be used to treat acute
symptoms, nor to replace inhaled
corticosteroids. Those using
salmeterol should also be using an
inhaled corticosteroid and have a
short-acting inhaled bronchodilator
to treat acute symptoms. The FDA
plans to evaluate the data from the
interim analysis, and further guidance is anticipated.
By Terry M. Baker, PharmD
The Rx Consultant is a monthly publication dedicated to providing pharmacists with the information they need to effectively
educate patients about drugs. Any opinions expressed are those of The Rx Consultant staff. The reader is responsible for confirming
the information presented here and interpreting it in relation to each patient's specific situation before utilizing the information.
Author: Judy Im, Pharm.D., Ambulatory Care Pharmacist Specialist, Kaiser Permanente, Santa Clara, California. Dr. Im
developed the Adult Asthma Clinic at Kaiser Medical Center, Bellflower, implemented a similar program at Kaiser
Permanente, Santa Clara, and currently manages the Adult Asthma/COPD Clinic in Santa Clara.
Editor: Terry M. Baker, PharmD; Associate Editors: James Chan, PharmD, PhD, Ron Finley, RPh, Candy Tsourounis, PharmD
Assistant Editor and CE Coordinator: Tracy Farnen, PharmD; Senior Editorial Advisor: Gerard Hatheway, PharmD, PhD;
Editorial Advisors: Belinda M. Danielson, RPh, Christopher M. DeSoto, PharmD, Elisabeth Walts, PharmD;
Production Manager: Patrick Marrinan; Technical Assistant: Linda Jones
To begin a subscription, contact The Rx Consultant office. The yearly subscription rate of $89 includes 11 issues, 11 Patient Drug
Advisor Cards, and 16.5 hours of CE credit. Direct inquiries to: The Rx Consultant, P.O. Box 1516, Martinez, CA 94553
Toll Free Number 1-800-798-3353 • 1-925-287-9207 • FAX 1-925-287-9210 • www.rxconsultant.com
Copyright 2003, Continuing Education Network, Inc.
8
References
1. Pappas GM, Hadden WC, Kozak LJ, et al. Potentially avoidable hospitalizations: inequalities in rates between US socioeconomic groups.
Am J Public Health 1997; 87-811-16.
2. National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma.
National Heart Lung and Blood Institute, National Institutes of Health. NIH Publication No. 97-4051. July 1997.
3. National Asthma Education and Prevention Program. Expert Panel Report : Guidelines for the Diagnosis and Management of AsthmaUpdates on selected Topics 2002. National Heart Lung and Blood Institute, National Institutes of Health. NIH Publication No. 02-5075.
July 2002.
4. Jatilus DE, Meng YY, Elashoff RM, et al. Preventive pharmacologic therapy among asthmatics: five years after publication of guidelines.
Ann Allergy Asthma Immunol 1998; 81(1):82-88.
5. Shelhamer JH, Levine S, Wu T, et al. Airway inflammation. Ann Intern Med 1995; 123(4)288-303.
6. Adams N, Bestall J, Jones P. Inhaled beclomethasone at different doses for long-term asthma.(Cochrane Review).
In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software.
7. Adams N, Bestall J, Jones P. Inhaled fluticasone propionate for chronic asthma.(Cochrane Review).
In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software.
8. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.
N Engl J Med 2000; 343:1054-63.
9. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma..
N Engl J Med 2000; 343:1064-69.
10.Wong CA, Walsh LJ, et al. Inhaled corticosteroid use and bone mineral-density in patients with asthma. Lancet 2000;355:1399-1403.
11.Matsumoto H, Ishihara K, Hasegawa T, et al. Effects of inhaled corticosteroid and short courses of oral corticosteroids on bone mineral
density in asthmatic patients. Chest 2001; 120:1468-73.
12.Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler
compared with CFC-beclomethasone. Eur Respir J 1998; 12(6):1346-53.
13.Gross G, Thompson PJ, Chervinsky P, et al. Hydrofluoroalkane-134a beclomethasone dipropionate, 400mcg, is as effective as chlorofluo
rocarbon beclomethasone dipropionate, 800 mcg, for treatment of moderate asthma. Chest 1999; 115(2):343-351.
14.Leblanc P, Mink S, Keistenen T, et al. A comparison of fluticasone propionate 200mcg/day with beclomethasone dipropionate 400mcg/day
in adult asthma. Allergy 1994; 49:380-85.
15.Kelly HW. Comparison of inhaled corticosteroids. Ann Pharmacother 1998; 32:220-32.
16.Ferguson AC, Spier S, Manjra A, et al. Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of
fluticasone propionate with budesonide. J Pediatr 1999; 134(4):422-716.
17.Spooner CH, Saunders LD, Rowe BH. Nedocromil sodium versus sodium cromoglycate for preventing exercise-induced
bronchoconstriction in asthmatics (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software.
18.Blake KV. Montelukast: Data from clinical trials in the management of Asthma. Ann Pharmacother 1999; 33(12):1299-1311.
19.Jarvis B, Markham A. Montelukast: a review of its therapeutic potential in persistent asthma. Drugs 2000; 59(4):891-928.
20.Dunn C, Goa K. Zafirlukast. An update of its pharmacology and therapeutic efficacy in asthma. Drugs 2001; 61(2);285-315.
21.Adkins JC, Brogden RN. Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma.
Drugs 1998; 55(1):121-44.
22.Brabson JH, Clifford D, Kerwin E, et al. Efficacy and safety of low-dose fluticasone propionate compared with zafirlukast in patients with
persistent asthma. Am J Med 2002; 113(1):15-21.
23.Meltzer EO, Lockey RF, Friedman BF, et al. Efficacy and safety of low-dose fluticasone propionate compared with montelukast for
maintenance treatment of persistent asthma. Mayo Clin Proc 2002; 77(5):437-45.
24.Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving
concomitant inhaled corticosteroid therapy. Chest 2001; 120(2):423-30.
25.Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/salmeterol combination provides more effective asthma control than lowdose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 2000; 106(6):1088-95.
26.Busse W, Nelson H, Wolfe J, et al. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma.
J Allergy Clin Immunol 1999;1 0(6):1075-1080.
27.Prescribing Information (Zyflo™ Filmtab®) Abbott Laboratories, Chicago, IL 1998.
28.Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma
(MIASMA). BMJ 2000; 320:1368-73.
29.Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and
corticosteroids establishing therapy (FACET) International Study Group. N Engl J Med 1997; 337(20):1401-11.
30.Holimon TD, Chafin CC, Self TH. Nocturnal asthma uncontrolled by inhaled corticosteroids: theophylline or long-acting beta 2 agonists?
Drugs 2001; 61(3):391-418.
31.Lemanske RF Jr, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma
receiving salmeterol. JAMA 2001; 285:2594-2603.
32.Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting B-2 agonist monotherapy vs continued therapy with inhaled corticosteroids in
patients with persistent asthma. JAMA 2001; 285(20):2583-2593.
33.Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996; 334(21):1380-88.
34.Wilson AJ, Gibson PG, Coughlan J. Long-acting beta-agonists vs theophylline for maintenance treatment of asthma
(Cochrane Review). In The Cochrane Library. Issue 4, 2001. Oxford: Update Software.
35.The Role of the Pharmacist in Improving Asthma Care. National Heart Lung and Blood Institute, National Institutes of Health.
NIH Publication No. 95-3280. July 1995.
36.Prescribing Information. Foradil® Aerolizer™ (formoterol fumarate inhalation powder).
Novartis Pharmaceutical Corporation, East Hanover, NJ, 2001.
37.Prescribing Information. Advair™ Diskus® (fluticasone propionate/salmeterol) GlaxoWellcome Inc., Research Triangle Park, NC, 2000.
38.Prescribing Information. Singulair® (montelukast sodium). Merck & Co., Inc. Whitehouse Station, NJ, August 2001.
TEST QUESTIONS
Write your answers on the Credit Request/answer form provided or take the test online at:
www.rxconsultant.com
This program is valid through May, 2005
1.Which of the following are appropriate steps
pharmacists can take to improve asthma care?
a. Instruct patients about the proper
techniques for inhaling medications.
b. Monitor medication use and refill intervals
to help identify patients with poorly
controlled asthma.
c. Encourage patients purchasing OTC asthma
inhalers or tablets to seek medical care.
d. All of the above.
2. In which situation should initiation of, or an
increase in control medication be considered?
a. use of 1 canister of a short-acting inhaled
bronchodilator in 3 months
b. mild, intermittent asthma
c. use of more than 1 canister of inhaled
albuterol in 1 month
d. mild nocturnal symptoms occur once or
twice a month
3. Inhaled corticosteroids are the preferred
antiinflammatory medications for the
control of asthma. A trial of 2 to 8 weeks
may be required before the full benefit is
apparent.
a. True
b. False
4. Which of the following inhalers is a dry
powder formulation?
a. Proventil HFA®
c. Advair Diskus®
b. QVAR®
d. Vanceril®
5. Which of the following is considered a
quick-relief medication?
a. fluticasone
c. formoterol
b. budesonide
d. pirbuterol
6. A peak flow meter measures the highest
velocity of expired air that can be obtained
during a forced expiration, starting with
fully inflated lungs.
a. True
b. False
®
7. Which of the following is required for the
effective use of a dry powder inhaler?
a. spacer use
b. a deep inspiration
c. a propellent
d. hand/breath coordination
8. Common side effects of moderate dose,
inhaled corticosteroid therapy include:
a.
b.
c.
d.
irreversible growth suppression
easy bruising
mood swings
none of the above
9. What is the medication of choice for
the initial treatment of mild intermittent
asthma?
a.
b.
c.
d.
an inhaled corticosteroid
an inhaled short-acting bronchodilator
montelukast
an inhaled long-acting bronchodilator
10.What is the recommended initial medication for the control of persistent asthma?
a.
b.
c.
d.
a leukotriene modifier
a long-acting bronchodilator
an inhaled corticosteroid
a xanthine derivative
11.How should zafirlukast be administered?
a
b.
c.
d.
on an empty stomach
at the onset of shortness of breath
5 minutes before strenuous exercise
with food or immediately after a meal
12. What is the preferred therapy for an
adult with moderate persistent asthma?
a. an inhaled corticosteroid plus a long-acting
inhaled bronchodilator
b. high-dose inhaled corticosteroids
c. an inhaled corticosteroid plus sustained
release theophylline
d. a or c
The Rx Consultant is a publication of Continuing Education Network, Inc.
Continuing Education Network, Inc. is approved by the American Council on
Pharmaceutical Education as a provider of continuing education.
Universal program #428-000-03-012-H01. This program is valid through May, 2005.
Upon successful completion (70%) of the test, 1.5 hours of continuing pharmaceutical education
credit (0.15 CEU'S) will be awarded in states that recognize ACPE approved providers. CE
certificates are mailed every week for all successfully completed tests. Please allow 2-3 weeks after
mailing your CE Credit Request for delivery of your certificate. The CE is free for subscribers.
If you are not a subscriber to The Rx Consultant and would like to receive 1.5 hours of CE credit for
this issue, include a check for $7.50 with your Credit Request or take the test for free online:
www.rxconsultant.com.