Introduction

Conclusion

Certification

References

SECTION 2
Measures of Assessment and Monitoring

Control of Factors Contributing to Asthma Severity

Pharmacologic Therapy

Delivery Methods

Counseling Issues

TABLES
Table 1

Table 2

Table 3

Table 4

Outpatient Management of Asthma in Children

Amy Rorstad, PharmD, and 
Varsha Bhatt-Mehta, PharmD, FCCP

Dr. Rorstad is a Clinical Instructor at the University of Michigan College of Pharmacy and Chief Pharmacist of CVS in Ann Arbor, Michigan. Dr. Bhatt-Mehta is a Clinical Associate Professor at the University of Michigan College of Pharmacy and Clinical Pharmacist at the University of Michigan Medical Center.

Introduction

Asthma is estimated to affect 14 million to 15 million people in the United States, with children comprising 4.8 million of this total.¹ Asthma is characterized as a chronic inflammatory disease of the airways that often presents as recurrent episodes of wheezing and breathlessness. It is the most common chronic disease found in children.¹ This disease most frequently develops in children who have genetic susceptibility to produce IgE when exposed to common environmental allergens.¹ Asthma is most commonly diagnosed during childhood. Pharmacists in the community are in a perfect setting to educate children and their caregivers on basic disease concepts, environmental control measures, and proper techniques in therapy administration, as well as development and implementation of asthma action plans.

Pathogenesis

Many cells and cellular elements contribute to the pathogenesis of asthma. Specifically these include mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells, which are key players in the inflammatory process of asthma.² Airway inflammation is recognized as contributing to acute bronchoconstriction, airway edema, chronic mucous plug formation, and airway remodeling, making it the primary target for asthma therapy. Chronic inflammation results in a persistent level of cell damage and subsequent repair process. This effect on the airways may be partially irreversible and leads to an inability to fully reverse airway obstruction over an extended period of time.³ The degree of airway remodeling is associated with the severity of inflammation as well as the clinical severity of asthma.¹ Evidence now indicates that subbasement membrane fibrosis may occur and these changes may ultimately cause persistent airway abnormalities.⁴ 

Anti-inflammatory therapy has become the cornerstone of treatment in asthma. High-dose inhaled corticosteroids (see Table 1 for definition) are used as first-line agents. Nevertheless, use of high- dose inhaled corticosteroids may have adverse effects when used continuously for periods in excess of a few months.^5,6 New anti-inflammatory agents, the leukotriene receptor antagonists, have emerged as promising nonsteroidal anti-inflammatory agents in the treatment of asthma. Treatment with anti-inflammatory agents, not as-needed bronchodilators alone, has demonstrated long-term improvement in prognosis. Thus, early treatment with anti-inflammatory agents is important.⁷

The Second Expert Panel Report Guidelines for the Diagnosis and Management of Asthma was published by the National Asthma Education and Prevention Program (NAEPP) in 1997 and is based on this current understanding of the pathogenesis of asthma.

Measures of Assessment and Monitoring

Diagnosis of asthma includes the presence of episodic symptoms of airflow obstruction, which is at least partially reversible. All other diagnoses that may involve similar symptoms must be excluded. Other disease states included in the differential diagnosis of asthma in children include vocal cord dysfunction, bronchiolitis, cystic fibrosis, bronchopulmonary dysplasia, and upper airway diseases, such as allergic rhinitis and sinusitis. A thorough physical examination, detailed medical history, pulmonary function tests, and identification of

 precipitating factors help establish the diagnosis of asthma.¹ In the community, pharmacists need to be aware of the signs and symptoms of asthma, and know when to refer patients for further evaluation from their physician. Classic symptoms of asthma include all or some of the following: coughing, wheezing, shortness of breath, and chest tightness. Referral for further evaluation should be made if patients have a history of these symptoms, especially if symptoms occur or worsen at night, awakening the patient. A physician should evaluate asthma symptoms that occur or worsen in the presence of exercise, viral infection, or other precipitating factors. The severity of asthma is classified according to the 1997 NAEPP guidelines as being mild intermittent, mild persistent, moderate persistent, or severe persistent. This classification excludes acute exacerbations, which may present with any level of severity.¹ A further description of these classifications of asthma severity is found in Table 2.

The 1997 NAEPP guidelines recommend routine monitoring in asthma patients to include signs and symptoms, pulmonary function tests, pharmacotherapy, functional status, episodes of asthma exacerbations, medications, patient-provider communication, and patient satisfaction. Peak flow monitoring is helpful in assessing pulmonary function by allowing for detection of early changes in disease status that require treatment. This device can be used in children as young as 5 years old. Peak flow monitoring can be used for short-term monitoring and, managing exacerbations, as well as daily long-term monitoring.¹

Pharmacists need to counsel patients on the importance of peak flow measurement and technique. Noncompliance is an issue as a result of the inconvenience of daily measurements and incorrect readings caused by poor technique, device failure, or misinterpretation of results. Children and caregivers should be taught how to modify the asthmatic child’s therapy or seek help based on their performance relative to their personal best peak flow value. The personal best value may be used as a standard to compare other values. The personal best value is obtained by measuring peak flows at least once daily over a 2- to 3-week period and taking the best result. Determination of a personal best is optimally accomplished with the patient on therapy, and after each use of a short-acting beta₂-agonist. A short course of oral corticosteroids may be needed to establish a personal best value.¹ Since the measurement is effort-dependent, parents and/or pharmacists initially will need to coach patients to get their best value. The technique of peak flow measurement is described in Table 3. Use of color zone indicators is helpful in monitoring therapy and is individualized based on the child’s personal best. The green zone represents 80% to 100% of personal best and signals “clear.” No symptoms are present and no change in therapy is warranted. Consistent green zone readings may even indicate opportunity for a reduction in therapy. Yellow zone readings represent 50% to 80% of personal best and signal “caution.” Readings in this zone may indicate an early exacerbation. Therapy may be suboptimal and might warrant a change in the child’s asthma medication. Peak flow readings in the red zone signal a “medical alert.” The child’s physician should be notified and emergency instructions followed. Pulmonary function testing should be done at least every 1 to 2 years to document maintenance of airway function.¹

Table 3. Peak Flow Motor Technique

Control of Factors Contributing to Asthma Severity

Asthma symptoms and/or exacerbation are often brought on by exposure to seasonal allergens and irritants, as well as perennial indoor allergens. It is important when counseling to try and assist the patient to identify and reduce exposure to any precipitants of asthma. Inhalant allergens include animal allergens, house dust mites, cockroach allergens, and indoor fungi (molds), as well as outdoor allergens (pollen). Irritants such as tobacco smoke, strong odors, and indoor/outdoor pollution can result in worsening of asthma symptoms.¹ Some suggestions for avoidance of these precipitants include closing windows and doors and using air conditioning and filters, which may reduce exposure to outdoor allergens. Removal of animals/pets from the child’s environment may be necessary. In the bedroom, washing bedding in hot water every 1 to 2 weeks and reducing humidity to less than 50% can reduce house dust mites. The child should avoid being around areas being cleaned or vacuumed, because this may precipitate asthma symptoms. Using a damp cloth for dusting helps in keeping the irritants from becoming airborne. Cessation of smoking is strongly advised for parents of children with asthma. Other factors that may influence asthma severity in children are rhinitis, gastroesophageal reflux, and viral respiratory infections, as well as sensitivity to sulfites, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen.¹ It is important to counsel patients with severe persistent asthma who are hypersensitive to aspirin or NSAIDs about the risk of severe, and possibly fatal, exacerbations that could result after the intake of these medications. If factors contributing to asthma in the child cannot be easily detected, a skin test may be useful in determining sensitivity to a perennial indoor allergen.¹

Pharmacologic Therapy

The goals of pharmacologic therapy are to prevent and control chronic and bothersome symptoms (ie, coughing and shortness of breath), maintain normal pulmonary function and activity levels, prevent recurrence of asthma exacerbations, decrease the number of emergency department visits or hospitalizations, minimize or prevent adverse effects from asthma medications, and satisfy patients’ and parents’ expectations pertaining to the patients’ asthma care. A stepwise approach is emphasized whereby the amount and frequency of medication to be administered is determined by a patient’s level of asthma severity. This approach calls for initiation of treatment at a higher level than the patient’s step of severity to emphasize prompt medications for control of the disease. Once adequate control has been achieved and maintained for several weeks, a reduction in pharmacologic therapy (a step down) can occur.¹ This allows for minimum amounts of medication to be used while maintaining control of asthma. This stepwise approach is described in Table 2.

The 1997 NAEPP guidelines categorize asthma medications into two groups: medications for long-term control used to achieve and maintain control of persistent asthma, and quick-relief medications used to treat acute symptoms. Long-term control medications include inhaled corticosteroids, cromolyn sodium, nedocromil, long-acting beta₂-agonists, methylxanthines, and leukotriene modifiers.¹ Therapy should emphasize treatment of inflammation in long-term management of asthma.⁸ Quick-relief medications include short-acting beta₂-agonists, anticholinergics, and systemic corticosteroids. Systemic corticosteroids are reserved for quick recovery and prevention of exacerbations in moderate-to-severe asthma.¹
Corticosteroids are the most potent and effective anti-inflammatory agents in the treatment of asthma. The inhaled form is used in long-term treatment and to manage severe persistent asthma, slow growth velocity in some children.^7,10 Prior to puberty, this occurs more frequently in males than females.¹ However, the potential for adverse effects of inhaled corticosteroids is well balanced by their benefits.

Cromolyn sodium and nedocromil are anti-inflammatory medications useful in mild-to-moderate asthma. These agents are often used for initial long-term control of asthma in children. Both agents are also useful as preventive agents in exercise-induced asthma. The mechanism of action of cromolyn sodium and nedocromil is through stabilization of mast cells and prevention of mediator release. These medications are for prevention only and will not relieve an attack that has already started. The NAEPP guidelines suggest that children with mild persistent asthma be given an adequate trial of cromolyn or nedocromil before starting inhaled corticosteroids.¹ It may take up to 4 weeks before the patient feels the full effects of the medicine. Therefore, patients should not be classified as therapeutic failures until a sufficient trial has been given. The most common side effects are minor throat irritation, cough, and unpleasant taste. 

Long-acting beta₂-agonists, used in addition to anti-inflammatory medications, are effective at preventing nocturnal symptoms and exercise-induced bronchospasm. However, they should not be used as rescue medications for acute symptoms since they do not act quickly enough. They have a gradual onset of 30 to 60 minutes and a prolonged duration of action lasting 12 hours. Salmeterol is currently the only inhaled long-acting beta₂-agonist available in the United States. Because the effects of salmeterol last approximately 12 hours, doses should never be taken more than twice a day or less than 12 hours apart.¹ A study demonstrated that patients with inadequate control of asthma on low-to-medium doses of inhaled corticosteroid benefited more from the addition of salmeterol than from increasing the dose of inhaled corticosteroid.¹¹

Methylxanthines, such as theophylline, have mild-to-moderate bronchodilator activity and mild anti-inflammatory effects that are useful in preventing nocturnal symptoms. They are also used as an adjuvant to corticosteroids. However, newer and more effective agents have largely replaced their use. Therapy with theophylline requires close monitoring of theophylline levels to avoid subtherapeutic or toxic concentrations. Also, drug interactions, age, and environmental factors all have an effect on theophylline metabolism. Adverse effects are common and increase in severity with higher serum levels. Recommended peak serum levels are between 5 and 15 mcg/mL. However, some patients require levels higher than the recommended therapeutic maximum to obtain a better response. Adverse effects that may present when patients are maintained within therapeutic range are tremors, nausea, vomiting, headaches, and palpitations. These, and more severe reactions, including seizures, arrhythmia, and death, may occur when serum levels are above the therapeutic range.¹

Newer agents such as leukotriene modifiers are considered alternatives to low-dose inhaled corticosteroids, cromolyn, or nedocromil in patients with mild persistent asthma. Zafirlukast and montelukast are leukotriene receptor antagonists and zileuton is a 5-lipoxygenase inhibitor. Zileuton is approved for use in children 12 years and older, whereas montelukast has been approved by the FDA in children 2 years and older, and zafirlukast, for those 7 years and older.^1,12,13 

The mechanism of action of the leukotriene modifiers is through their prevention of the harmful effects of leukotrienes. Leukotrienes are potent inflammatory mediators that contribute to the pathogenesis of asthma.¹⁴ They are lipid mediators derived from arachidonic acid via the 5-lipoxygenase pathway. The cysteinyl leukotrienes (cysLTs) formed by this pathway were formally known as a slow-reacting substance of anaphylaxis (SRS-A).¹⁴ The cysLTs cause contraction of airway smooth muscle, vasodilatation, increased vascular permeability, alteration of airway patency by stimulating mucous secretion and decreasing mucocillary clearance, and recruitment of eosinophils into the airways where they bind and activate specific receptors.^14,15 The most potent cysLT1 receptor antagonists are zafirlukast and montelukast.¹⁵ Their receptor affinity is approximately twofold greater than the natural ligand.¹⁶

Montelukast sodium. The FDA approved montelukast sodium in 1998 for oral prophylaxis and chronic treatment of asthma.¹⁷ Montelukast is available in 10-mg film-coated tablets or 5- and 4-mg chewable tablets. In children 6 to 14 years old the recommended dose is 5-mg. Earlier this year the FDA approved montelukast 4-mg chewable tablets for use in children 2 to 5 years old.¹² The results of a pharmacokinetic study indicated that montelukast 4-mg chewable tablets administered to 2- to 5-year-olds produced a similar area under the curve when compared to montelukast 10-mg film-coated tablets given to adults.¹⁸ Montelukast should be taken in the evening without regard to food intake.¹⁷ Near-maximum response is achieved after the first dose versus up to 6 weeks with inhaled corticosteroids.¹⁹

The efficacy of montelukast in children aged 6 to 14 years with intermittent or persistent asthma, was evaluated in an 8-week, multicenter, double-blind, randomized study. Two hundred one patients received montelukast 5-mg chewable tablets at bedtime, and 135 children were treated with placebo. Results indicated that the number of puffs/day of the beta₂-agonist decreased by 0.58 puffs/day in children taking montelukast versus 0.22 puffs/day in those receiving placebo. Also, mean morning forced expiratory volume at 1 second (FEV1) increased by approximately 8% in the treated group compared to an increase of about 4% in the placebo group.²⁰

Montelukast is generally well tolerated. Headache was the most common side effect, occurring in about 18.4% of patients in a study by the manufacturer in adolescents and adults 15 years of age and older. Other side effects that occurred in <5% of patients were fatigue, fever, abdominal pain, trauma, dyspepsia, gastroenteritis, dental pain, dizziness, nasal congestion, cough, influenza, rash, alanine transaminase and aspartate transaminase increases, and pyuria.¹⁷ Churg-Strauss syndrome, associated with the use of montelukast, has recently been reported.²¹ Montelukast has no clinically significant drug interactions that require dosage adjustment.¹⁷

Zafirlukast. The FDA approved zafirlukast in September 1996 for the prophylaxis and long-term treatment of asthma. Zafirlukast is available in 10- and 20-mg tablets, with a recommended dose of 20 mg orally twice daily in children over 12 years of age and 10 mg twice daily in children 7 to 11 years old. Since the bioavailability of zafirlukast decreases by 40% when administered with food, it should be taken on an empty stomach either 1 hour before meals or 2 hours after meals.¹³ Treatment with zafirlukast should be continued even during symptom-free periods, and can be continued throughout episodes of acute asthma.²² 

Since zafirlukast inhibits the cytochrome P-450 isoenzymes 2C9 and 3A4, drug interactions may develop, and appropriate clinical monitoring should be incorporated into therapy. Concurrent administration of erythromycin or theophylline decreases zafirlukast levels; and when given with aspirin, an increase in zafirlukast levels has been reported.¹³ Patients taking other medications metabolized through either CYP2C9 (such as phenytoin or carbamazepine) or through CYP3A4 (such as dihydropyridine calcium channel blockers, cyclosporine, or cisapride) should be monitored closely.¹³

Zafirlukast is generally well tolerated. The most common adverse effects of short-term use reported include pharyngitis (15%), headache (18%), rhinitis (9%), and gastritis (4%). Other adverse effects include fever, weakness, exacerbation of asthma, and abnormal serum chemistry.²³ Rare adverse effects associated with zafirlukast include elevations in serum liver enzymes. Patients should be warned to contact their physician immediately if they develop signs and symptoms of liver dysfunction.²⁴ Churg-Strauss syndrome has been reported in eight adult patients following marketing of zafirlukast.²⁵

Zileuton. Zileuton, a 5-lipoxygenase inhibitor, blocks the production of leukotrienes by enzyme inhibition. It is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is available in a 600-mg tablet that must be taken four times a day. It can be taken without regard to meals. Several clinically significant drug interactions exist since its metabolism occurs via the cytochrome P-450 system. Zileuton has shown to decrease clearance of theophylline. Other interactions exist, but the medications involved are generally used only in adults. Elevation in hepatic transaminases is the most serious side effect associated with zileuton. Monitoring of liver enzymes prior to initiation of therapy, every month for the first 3 months, then every 2 to 3 months for the first year is recommended by the manufacturer.²⁶

Short-acting beta₂-agonists are used for quick relief of acute symptoms as well as in exercise-induced asthma. They have a rapid onset of action of 5 to 30 minutes and duration of 4 to 6 hours. Mild asthma symptoms may be effectively controlled by beta₂-agonist use alone; however, chronic beta₂-agonist use should be combined with inhaled corticosteroid therapy. Short-acting beta₂-agonists exert their beneficial effects by specifically binding to beta₂-receptors on airway smooth muscle cells. This stimulates production of cyclic adenosine monophosphate from adenylate cyclase, resulting in a decrease in intracellular calcium concentration. This mechanism is responsible for producing the bronchodilating action that causes smooth muscles surrounding the airways to relax so that the airways open more fully, allowing oxygen inflow. These agents do not reduce or inhibit inflammation. Long-term control medications, such as inhaled corticosteroids, should in fact minimize the need for use of short-acting beta₂-agonists. Tremors, palpitations, tachycardia, and agitation may occur when short-acting beta₂-agonists are administered via inhalation, but are less frequent than if taken by systemic route. For short-acting inhaled beta₂-agonists, increasing use, or the use of more than one canister per month, is indicative of uncontrolled asthma and indicates the need to begin or increase the dose of preexisting anti-inflammatory therapy.

Anticholinergics are used as adjunctive agents to inhaled beta₂-agonists or as alternative bronchodilators for patients intolerant of beta₂-agonists in severe exacerbations.¹ The beneficial effects of anticholinergics are a result of blockage of acetylcholine effects, which result in bronchoconstriction and production of airway secretions. Inhaled anticholinergics have bronchodilator effects, but no beneficial anti-inflammatory effects. They have a slower onset of action than inhaled short-acting beta₂-agonists, with a peak onset of 30 to 60 minutes. Adverse effects are minor and include cough, dry mouth/secretions, and an increase in wheezing.

Delivery Methods

The dosing of the previously described medications in children is shown in Table 1. It should be noted that infants and small children using metered-dose inhalation therapy need doses equivalent to adult doses because they inhale aerosols during tidal breathing without holding a breath. Thus the retention time and effective drug delivery to the lungs is decreased.¹ 

Nebulizer therapy is an effective means for administering beta2-agonists, cromolyn sodium, or ipratropium bromide to pediatric patients. This method of delivery is especially useful in children who are uncooperative or unable to correctly use metered-dose inhalers. Nebulizer therapy can even be administered to a sleeping infant or child. However, the downside to using a home nebulizer is that delivery of medication is a time-consuming process, lasting from 10 to 20 minutes. Furthermore, home nebulizers have not been shown to be more effective than metered-dose inhalers in the management of asthma.¹ Some parents find using play therapy is an effective means to get the child comfortable with using a nebulizer. Parents will simulate the nebulizer treatment by placing the mask on the child’s favorite doll or stuffed animal.

When metered-dose inhalers are used in children, spacing devices are helpful in assisting with proper technique. Children should be instructed on how to use the spacer by a trained clinician and should be encouraged to practice the technique. Spacers are particularly recommended for young children for use with inhaled corticosteroids.²⁷ If a metered-dose inhaler is used without a spacing device, proper technique will be crucial to delivery of medication to the lungs. If a child fails to use proper technique, the medicine may end up on the back of the child’s throat. Pharmacists should reassess therapy periodically when prescriptions for inhalers are renewed or refilled. Refer to Table 4 for complete instructions on inhaler technique.

Table 4.  Recommended Metered-Dose Inhaler Technique

Counseling Issues

Counseling children on their asthma medications can definitely be challenging. However, with careful, successful, and thorough counseling, children and their caregivers will feel more confident about how to administer their medications and what to expect. An effective management plan should include written and verbal instructions describing when and how medication should be taken, how much medication to take, how to evaluate their response, when to seek medical care, and what to do if side effects occur. Children should understand the optimal order of administration of inhalers. When a beta₂-agonist is used in combination with another inhaler, the beta₂-agonist should be administered first. The beta₂-agonist will assist in opening the airways, allowing subsequently administered medications to travel deeper into the lungs. Inhaled corticosteroids should be administered last. Also, children and their caregivers should be counseled to record on a calendar or actual canister the date the inhaler is first used. The number of days the canister will last can be calculated by dividing the number of doses in the canister by the number of inhaled doses per day. Alternatively, with as-needed inhalers, a diary is useful for recording doses.

Pharmacists are in a key position to detect overuse by checking a patient’s medical profile and duration between refills. Overuse and reliance of short-acting beta₂-agonists may represent poorly controlled asthma. However, also keep in mind that poor technique can be one of the causes of overuse of a metered-dose inhaler.²⁷

Children are very active and need to be educated about their disease, especially while involved in school sports. Active participation in school sports and physical activities should be encouraged. Nothing can be more frustrating for children than not being able to participate fully with their peers in sports. However, symptoms of asthma resulting from increased activity are often not present when asthma is controlled with anti-inflammatory therapy. Using a beta₂-agonist (albuterol), cromolyn sodium, or both, 15 to 30 minutes before exercising may prevent exercise-induced asthma.²⁸ The long-acting beta₂-agonist, salmeterol, is a good choice for active children 12 years and older because it has been demonstrated to prevent exercise-induced bronchospasm for 12 hours or more.²⁹ 

Scheduling long-term control medications so that they are not taken at school is preferable. However, asthmatic children often require medications during school to treat acute symptoms or prevent exercise-induced asthma. Challenges with school policies often prevent the child from carrying their beta₂-agonist inhaler (rescue inhaler) with them at school. Pharmacists can play a role as patient advocates within the school system to help endorse policies that allow students to carry and self-administer medications when considered appropriate. Thorough instructions for use of the beta₂-agonist and all other medications that the asthmatic child may be taking should be provided to the child’s teacher.

Conclusion

Asthma is a disease of chronic inflammation and is the most common chronic disease found in children. The 1997 NAEPP guidelines emphasize the need for early use of anti-inflammatory agents. As members of the health care team, pharmacists can have a significant impact on the management of patients’ drug therapy and education. A pharmacist fostering the need for repetition of proper technique of metered-dose inhalers and peak flow meters is essential. Of equal importance is teaching older children to take responsibility for their disease and understand how to manage their own therapy. With these efforts, children with asthma will have improved control of their disease as well as quality of life, enabling them to live the active and productive lives they deserve.

References

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13.Zeneca Pharmaceuticals. Accolate‚ package insert.
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18.Knorr B, Larson P, Chervinsky P, et al. Selection of a montelukast dose in 2- to 5-year-olds by comparison of pediatric and adult single-dose pharmacokinetics (PK) profiles. Clin Pharmacol Ther 1998;63:191.
19.Lipworth BJ. The emerging role of leukotriene 
receptor antagonists in asthma therapy. Chest 1999;115:313-315.
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22.Suissa S, Rodolfo D, Ernst P, et al. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild- to-moderate asthma: A randomized, double-blind, placebo-controlled trial. Ann Int Med 1998;126:188-183.
23.Spector SL, Smith LJ, Glass M, et al. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med 1994;150:618-623.
24.FDC Reports-Pink Sheet. Zeneca Accolate liver enzyme elevation precaution added to labeling. 16 June 1997 T&G-7.
25.Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998;289:455- 457.
26.Abbott Laboratories. Zyflo product information. 1997
27.National Institutes of Health. The role of the pharmacist in improving asthma care. Bethesda,MD:National Institutes of Health 1995;NIH publication no.95-328.
28.Committee on Sports Medicine and Fitness. Metered- dose inhalers for young athletes with exercise-induced asthma. Pediatrics 1994;94:129-130.
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[Introduction] [References]

American Council on Pharmaceutical Education