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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.