Incorporating Omalizumab into Asthma Treatment ... - CiteSeerX

CONTINUING EDUCATION CREDIT

Incorporating Omalizumab into Asthma Treatment Guidelines: Consensus Panel Recommendations Submitted on Behalf of the Consensus Panel by Lanny J. Rosenwasser, MD, FAAAAI National Jewish Medical and Research Center Denver, Colorado

and

Abstract

Educational Objectives ■ Describe the current NAEPP Guidelines for the diagnosis and treatment of asthma. ■ Assess the NAEPP Guidelines in light of new and emerging therapies. ■ Review the issues of suboptimally controlled asthma: diagnosis, management, patient outcome, economic impacts. ■ Delineate treatment strategies for the management of mild intermittent, mild persistent, moderate persistent, and severe persistent asthma.

Disclosure The Consensus Panel submitting this article was convened and funded by Genentech, Inc., and Novartis Pharmaceuticals. Panel participants are listed on page 402, and attention is directed to their disclosure of commercial relationships information (see below). This article discusses therapies (i.e., omalizumab) that have not been approved by the Food and Drug Administration (FDA) at the time of printing.

Panel Disclosure Information Panel members D. Nash, D. Chiefari, M. Kaliner, and B. Seeger have no relationships to disclose relating to this topic. The following panel members have disclosed relationships with Genentech and Novartis as consultants (CN), scientific advisors (SA), researcher/grant support (RE), Speakers Bureau (SP): J. Freudman (SA), J. Glassroth (CN), T. Morrow (CN), L. Rosenwasser (CN), S. Wenzel (RE, CN, SP—all with Genentech only), R. Zeigler (CN). The following panel members have dis-

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David B. Nash, MD, MBA, FACP Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Effective asthma management is hindered by several factors, such as (1) variability in clinical diagnosis and treatment patterns, (2) low adherence to therapy caused by improper use of medications, (3) poor technique in using therapeutic devices, (4) medication side effects, (5) inadequate responses to therapy, and (6) patients’ acceptance of a poor quality of life. These barriers increase hospitalizations and emergencydepartment visits, reduce productivity, and cause persistent morbidity and mortality. New therapies target mechanisms that cause airway disease, reduce utilization of health care resources, and improve patient adherence. Omalizumab (Xolair TM), an immunoglobulin E (IgE) blocker, reduces the clinical burden of asthma and the associated use of health care resources. This report

closed relationships with multiple organizations as consultants (CN), scientific advisors (SA), researcher/grant support (RE), Speakers Bureau (SP): L. DuBuske (RE and CN—Genentech, GlaxoSmithKline, Merck, Novartis, Schering; SA and SP—Merck, Schering); H. Kaiser (RE—3M, Altana, AstraZeneca, Aventis, Forrest, Genentech, GlaxoSmithKline, Ivex, Merck, Schering; CN —Aventis, AstraZeneca, Genentech, Merck; SP—AstraZeneca, Aventis, GlaxoSmithKline, Schering); A. Luskin (CN—3M, AstraZeneca, Genentech, Merck; SA—Aventis); E. Meltzer (RE—Abbott, Alcon, AstraZeneca, Aventis, Baker Norton, Boehringer Ingelheim, Bristol-Myers Squibb, Dura, Ferraris, Flemington, Forrest, Genentech, GlaxoSmithKline, Hoffmann–LaRoche, Immunex, Inspire, Janssen, KOS, Mast, McNeil Consumer Products, Medeva, Merck, Millennium, Muro, Novartis, Pfizer, Sanofi Winthrop, Schering-Plough, Sepracor, Synergen, TAP, 3M, UCB, Wallace, Whitehall-Robins, Winston, Zambon; CN—Abbott, Aerogen, Agouron, Alcon, Almirall, Arris, AstraZeneca, Aventis, Axys, Bausch and Lomb, Boehringer-Ingleheim, Dey, Entelos, Genen-

tech, GlaxoSmithKline, Hoffmann–LaRoche, Immunologic, Inspire, Janssen, McNeil, Merck, Miles, Muro, Nastech, Novartis, Parke-Davis, Pfizer, Pharmacia-Upjohn, Rigel, Sanofi/Synthelabo, Schering-Plough, Sepracor, 3M, Wallace, Warner Lambert, Whitehall, Robins and Zambon; SP—Aventis, AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Merck, Pfizer, ScheringPlough, UCB, and Wallace); T. Platts-Mills (SA—Aerocrine); S. Spector (various relationships with Abbott, Allen & Hansbury, Aventis, Boehringer Ingleheim, GlaxoSmithKline, Forrest, ICN, Key, Eli Lily, 3M, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Sepracor, Schering, Wallace, Whitby, AstraZeneca, Sepracor, Genentech); W. Storms (RE—3M, AstraZeneca, Aventis, Bayer, Bristol-Myers Squibb, Byk Gulden, GlaxoSmithKline, Immunex, Inspire, Merck, Novartis/Genentech, Pfizer, Pilot Therapeutics, Schering, Sepracor; CN—Adams Labs, Aerogen, Atlana, Ascent Pediatrics, AstraZeneca, Aventis, GlaxoSmithKline, Inspire, Ivax, Medpoint, Merck, Pilot Therapeutics, Schering, Sepracor; SP—AstraZeneca, Aventis, Merck, Novartis, Schering).

CONTINUING EDUCATION CREDIT advises health care professionals on how to best incorporate IgE blocker therapy into current treatment guidelines.

Introduction Asthma remains a daunting challenge for health care professionals. Management of this chronic condition is complicated by the dynamic nature of the disease, the presence of comorbid conditions, widespread variation in the implementation of treatment guidelines, the improper use of medications, the incorrect use of asthma devices, adverse drug events (ADEs), poor patient compliance, and acceptance by patients of a substandard quality of life. In response to these challenges, treatment guidelines have been published and new therapies have been developed to improve clinical outcomes and to reduce the use of health care resources. Despite these advances, however, the prevalence, morbidity, and mortality associated with asthma remain high.1 Successful management of asthmatic patients requires therapies that treat the underlying causes of the disease, reduce hospitalization and patients’ use of the emergency department, maximize patient adherence to therapy, and improve quality of life. Without these, optimal asthma management will remain elusive. Recent advances in our understanding of the role of immunoglobulin E (IgE) in inflammatory processes have led to the development of new therapeutic agents that address many of the unmet needs in asthma care. Generally, however, a substantial “lag time” exists from approval of the agent by the Food and Drug Administration (FDA) until its inclusion in nationally recognized treatment guidelines. In this article, we review the epidemiology of asthma and the role of IgE in the pathogenesis of this disease, followed by an overview of the clinical response of patients with suboptimally managed asthma to IgE blocker therapy with omalizumab (XolairTM, Genentech/Novartis). (Tanox has partnered in the development, manufacturing, and marketing of XolairTM with Genetech and Novartis.) We then describe current treatment guidelines, issued by the National Asthma Education and Prevention Program (NAEPP), second Expert Panel Report, and discuss the possible clinical role of IgE blockers in the treatment of moderate-to-severe asthma.

Epidemiology and Economic Impact of Asthma More than 31 million persons in the U.S., including nearly 9.2 million children, have been told by a health care professional that they have asthma.1 In 1998, the total cost of the disThe Office of Health Policy and Clinical Outcomes, Thomas Jefferson University Hospital, is approved by the American Council on Pharmaceutical Education (ACPE) ® as a provider of continuing pharmaceutical education and complies with the Criteria for Quality for continuing pharmaceutical education programming. This program (079-999-03-018-H01) is acceptable for 1.0 hour of continuing education credit (0.1 CEUs) in states that recognize ACPE-approved providers. Statements of Credit indicating hours/CEUs will be mailed quarterly to participants who completed this activity and submitted a completed evaluation with payment.

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ease was estimated to be in excess of $12 billion, with direct medical expenses (medications, hospitalizations, emergencydepartment visits, and physician services) accounting for nearly $7.4 billion and a reduced quality of life, loss of productivity at work or school, and other indirect costs accounting for the balance.2 The cost of asthma treatment is closely related to the severity of the illness,3,4 with a small cohort of patients consuming 80% of all asthma-related health care resources.5 High-cost patients require substantially more emergency visits and hospitalizations, and their condition is usually suboptimally controlled.5 Patients at greatest risk for asthma-related morbidity seem to be those with a history of the most frequent use of health care resources, including multiple prescriptions and hospitalizations as well as a history of intubation.6–8

Pathophysiology of Asthma: Current Knowledge Airway inflammation is found in virtually all individuals with asthma symptoms.37 Susceptibility to asthma appears to be established during infancy; its course has been attributed to genetic features, such as atopy (the predisposition to form antibodies and to acquire allergies),9,10 and environmental factors, including viruses,11 allergens,12 and occupational exposures.13 Although a full description of the pathogenesis awaits elucidation, research on the factors that initiate, intensify, and modulate airway inflammation continues.14,15 Immune mechanisms appear to be causally related to the development of asthma in more than 90% of asthma patients younger than 16 years of age, in more than 70% of those between 17 and 30 years of age, and in more than 50% of patients over 31 years of age.16 In addition, patients with elevated serum IgE levels show a high incidence of self-reported asthma.16 Asthma prevalence has been shown to be associated with increased levels of total IgE, even in subjects who have tested negative for specific IgE to common allergens and in non-atopic (non-hypersensitive) individuals.16 Persistent wheezing, early sensitization, and bronchial hyperresponsiveness are associated with high serum IgE levels at all ages.17,18 It also has been reported that patients with non-atopic asthma produce IgE throughout the airways.19 IgE-dependent mechanisms are involved in many of the allergic responses at the level of the airway.15 After IgE antibodies are produced, mast cells and other airway cells are sensitized and become activated when specific antigens are encountered. Following sensitization, a two-phase reaction occurs upon exposure to an allergen: • The early-phase response peaks approximately 30 minutes after the allergen challenge and is mediated primarily by IgE-dependent processes. This response is initiated when IgE, bound to FcεRI receptors on the surface of effector cells, is subsequently cross-linked by an allergen. This interaction causes the release of stored inflammatory mediators from the effector cell. The early response is closely associated with the level of free IgE.20

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CONTINUING EDUCATION CREDIT • IgE is also postulated to be involved in the initiation of the late-phase response.18 Even though the role of IgE in the pathogenesis of the late response is not well defined, however, it appears as if this phase of the asthma response follows IgE-dependent activation of the allergic reaction.2 Non-IgE processes might also be involved.21

IgE also plays a central role in the pathogenesis of other atopic diseases, including seasonal allergic rhinitis, atopic dermatitis, latex allergies, various food allergies, anaphylaxis, and urticaria. 22 Many of these conditions frequently present together with asthma, and the combination can lead to an increased use of the emergency department and hospital services and can exert a negative effect on daily functioning and

Members of the Consensus Panel David B. Nash, MD, MBA, FACP, Program Chairman The Dr. Raymond C. and Doris N. Grandon Professor of Health Policy and Medicine Associate Dean for Health Policy Jefferson Medical College of Thomas Jefferson University Director of Health Policy and Clinical Outcomes Thomas Jefferson University Hospital Philadelphia, Pennsylvania Donna M. Chiefari, RPh, FASHP Director of Clinical Services National Medical Health Card Latham, New York Lawrence M. Du Buske, MD Clinical Instructor in Medicine Harvard Medical School Boston, Massachusetts Director, Immunology Research Institute of New England Fitchburg, Massachusetts Jonathan M. Freudman, MD Assistant Clinical Professor University of California, San Francisco Medical Director, Medical Policy Department Blue Shield of California San Francisco, California Jeffrey Glassroth, MD George R. and Elaine Love Professor Chairman, Department of Medicine University of Wisconsin Medical School Madison, Wisconsin Harold B. Kaiser, MD Clinical Professor of Medicine University of Minnesota Medical School Allergy and Asthma Specialists Minneapolis, Minnesota Michael A. Kaliner, MD Clinical Professor of Medicine George Washington University School of Medicine Medical Director, Institute for Asthma and Allergy Chevy Chase and Wheaton, Maryland

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Allan T. Luskin, MD Clinical Associate Professor of Medicine University of Wisconsin Medical School Director, Respiratory Institute Dean Medical Center Madison, Wisconsin Eli O. Meltzer, MD Clinical Professor of Pediatrics University of California, San Diego Co-Director, Allergy and Asthma Medical Group and Research Center San Diego, California Thomas J. Morrow, MD Vice President and Medical Director One Health Plan, Southeast Regional Headquarters President, National Association of Managed Care Physicians Atlanta, Georgia Thomas A. E. Platts-Mills, MD, PhD Professor, Department of Medicine and Microbiology Head, Division of Allergy, Asthma and Clinical Immunology Director, Asthma and Allergic Diseases Center University of Virginia School of Medicine Charlottesville, Virginia Lanny J. Rosenwasser, MD, FAAAAI Marjorie and Stephen Raphael Chair in Asthma Research Professor, Division of Allergy and Clinical Immunology National Jewish Medical and Research Center Professor of Medicine and Immunology University of Colorado Health Sciences Center Denver, Colorado

Barbara P. Seeger, PharmD Clinical Adjuct Faculty University of Florida School of Pharmacy Gainesville, Florida Sheldon L. Spector, MD Clinical Professor of Medicine University of California, Los Angeles California Allergy and Asthma Medical Group Los Angeles, California William W. Storms, MD Clinical Professor of Medicine University of Colorado Health Sciences Center Co-Director, The Research Center Asthma and Allergy Associates Colorado Springs, Colorado André van As, MD, PhD Executive Director Global Respiratory Section Head Respiratory/Dermatology Therapeutic Franchise Novartis Pharmaceuticals Corporation East Hanover, New Jersey Sally E. Wenzel, MD Professor of Medicine University of Colorado Health Sciences Center and National Jewish Medical and Research Center Co-Director of the Harry and Jeanette Weinberg Clinical Research Unit National Jewish Medical and Research Center Denver, Colorado Robert S. Zeiger, MD, PhD Clinical Professor of Pediatrics University of California, San Diego Director, Allergy Research Southern California Permanente Medical Group San Diego, California

CONTINUING EDUCATION CREDIT quality of life.23 Early diagnosis and aggressive management of these disorders seem to offer the possibility of successfully altering their natural history.

Unmet Needs: Barriers to Improved Outcomes Patients with the greatest unmet needs are those with moderate-to-severe asthma that is suboptimally controlled. These patients remain symptomatic despite the use of multiple medications. The hallmark feature of these patients is frequent, severe exacerbations that often require costly emergency treatment, hospitalization, or both.23 This observation supports the theory that current therapies are underused, are used inappropriately, or are not consistently effective.24 The Epidemiology and Natural History of Asthma Outcomes and Treatment Regimen (TENOR) Study was initiated to describe the natural history of asthma patients, to elucidate the relationship between IgE and disease, and to examine the relationship between severity of asthma, its treatment, and clinical outcomes.25 Early TENOR results identified a discrepancy between a physician assessment of asthma severity and the assessment of asthma severity based on the second NAEPP Expert Panel Report guidelines. Severity was deemed much greater when the physician assessment took into account the patient’s overall health status and the volume of asthma care resources utilized in addition to the frequency of symptoms and spirometry findings. The TENOR Study also confirmed that patients with moderate-to-severe, suboptimally controlled asthma had the highest rates of health care utilization and a high frequency of hospitalization and intubation, despite prescribed regimens of multiple “standard-of-care” asthma therapies.25 The study confirmed the need to effectively target the underlying pathological processes, to control symptoms, to reduce exacerbations and hospitalizations, to enhance patient quality of life, and to maximize patient adherence to therapy.

Therapies for Asthma Current Therapies Over the last 20 years, pharmacotherapeutic management of asthma has progressed, but it remains imperfect. Patients with suboptimally controlled asthma remain symptomatic and experience serious exacerbations despite regular treatment with multiple standard-of-care anti-inflammatory agents and quick-relief medications, suggesting persistent inflammation in the airways. Current pharmacotherapeutic interventions (e.g., anti-inflammatory agents and smooth-muscle relaxants) generally alleviate asthma symptoms but do not address the underlying mechanisms of the disease process.26 During the selection of a regimen for asthma, the effect of a therapy on hospitalization rates, emergency-department use, and quality of life should also be considered. The limitations of existing asthma treatment support the need for continued research into novel therapeutic options, particularly those that modify the disease process.

Heavy chain Light chain Mouse CDR

Omalizumab: A Schematic • Humanized mAb against IgE (95% human) • Binds circulating IgE regardless of specificity • Forms small, biologically inert omalizumab: IgE complexes • Does not cause anaphylaxis because it does not cross-link cell-bound IgE • Does not activate complement • Does not elicit anti-omalizumab antibodies (human anti-human antibodies; non-immunogenic) Figure 1 Characteristics of the humanized murine monoclonal antibody (mAb), omalizumab. (This schematic picture is a model and is not intended to be an accurate description of the actual molecular makeup.) CDR = complementarity-determining region; IgE = immunoglobulin E. (Adapted from Boushey HA. Experiences with monoclonal antibody therapy for allergic asthma. J Allergy Clin Immunol 2001:108: S77–S83. Copyright 2001 with permission of Mosby, Inc.)

Emerging Asthma Therapies Most patients with asthma are atopic (allergy-prone) and possess specific IgE antibodies to allergens responsible for driving airway inflammation.16 Although allergen avoidance is always recommended, this strategy is rarely completely effective. Because of the central role of IgE in atopic diseases, the inhibition of IgE-mediated events with IgE blockers represents a novel approach to reducing the severity of asthma.27 Omalizumab, a humanized murine monoclonal antibody, inhibits the binding of IgE to mast cells by forming complexes with circulating free IgE (Figure 1). This agent binds to the Cε3 domain of the IgE, the region where IgE binds to the mast cell FcεRI receptor (Figure 2). Omalizumab forms complexes only with free IgE and cannot displace or cross-link mast cell–bound IgE. Therefore, this agent is free from the undesirable side effects associated with receptor cross-linking, mast cell and basophil degranulation, and subsequent release of inflammatory mediators (Figure 3). Further, by removing free IgE from the circulation, omalizumab indirectly down-regulates FcεRI Vol. 28 No. 6 • June 2003 •

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Unbound IgE

IgE bound with omalizumab

Omalizumab binding site

Cε3

IgE

Omalizumab

Figure 2 Omalizumab binds to the Cε3 domain of immunogloblin E (IgE). This action prevents free IgE from binding to the mast cell FcεRI receptor. (Data courtesy of Genetech, Inc., South San Francisco, CA, and Novartis Pharmaceuticals Corporation, East Hanover, NJ.)

Free IgE

Omalizumab complexes with free IgE

Omalizumab–IgE complex cannot bind to mast cell receptors

inhaled corticosteroid (ICS) and beta-agonist therapy, as recommended by the NAEPP guidelines.33 The studies consisted of a run-in phase, a steroid-stable phase, a steroid-withdrawal phase, and a double-blind extension phase. During the run-in phase and before randomization, patients were switched to beclomethasone dipropionate (BDP) and were stabilized on this therapy. Omalizumab was administered once or twice monthly via subcutaneous injection, with doses adjusted to body weight and total serum IgE.31,32 The primary endpoint of the pivotal phase III omalizumab clinical trials was the number of asthma exacerbations experienced per patient during the steroid-stable and steroid-withdrawal phases.31, 32 An exacerbation was defined as an episode severe enough to require either a doubling of the baseline BDP dose or administration of a course of systemic corticosteroids. Exacerbation frequency was selected as the primary efficacy indicator because, unlike FEV1 (forced expiratory volume in one second) or other surrogates of clinical efficacy, exacerbations are a direct marker of disease control and are strongly related to morbidity and mortality,34 quality of life,35 and total cost of illness.3 The number of exacerbations also reflects the degree of control of airway inflammation. Secondary outcomes included corticosteroid requirements, the number and frequency of symptoms, the use of rescue medications, lung function, and quality of life.

Results Omalizumab therapy reduced asthma exacerbations even with the use of a significantly lower Allergen-driven B cell Omalizumab Mast cell dose of BDP. The reduction in the BDP dose secretes free IgE was achieved without precipitating asthma exacerbations, worsening symptoms, decreasFigure 3 The immunoglobulin E (IgE)–omalizumab complex prevents the ing lung function, or increasing the use of rescue initiation of the allergic cascade. (Data courtesy of Genentech, Inc., South medications. In addition, more subjects treated San Francisco, CA, and Novartis Pharmaceuticals Corporation, East with omalizumab were able to achieve complete Hanover, NJ.) discontinuation of corticosteroid therapy.31,32 In the omalizumab group, symptom control was enhanced during the steroid-stable phase as well as durexpression. This is an important feature because downing the steroid-withdrawal phase. Notably, symptom control regulation of IgE receptors further reduces the potential for was maintained with lower doses of steroids and with less frebasophil/mast cell activation by IgE molecules.28 quent use of rescue medications. Treatment of allergic individuals with omalizumab prevents Peak expiratory flow (PEF) rates improved significantly for IgE from triggering the release of inflammatory mediators in patients who received omalizumab, and smaller but significant response to an allergen. Blocking IgE has a clear advantage improvements in FEV1 were also observed. Improved pulover current anti-inflammatory therapies: instead of attempting to suppress inflammation once it has occurred, inflammamonary values were maintained throughout the steroidtion is inhibited at its source. Early trials demonstrated the abilwithdrawal phase, suggesting that omalizumab might improve ity of intravenously administered omalizumab to impede lung function on its own without concomitant use of steroids allergen-induced airway responses.29,30 and rescue medications.31,32 Randomized, double-blind, placebo-controlled, multicenter With omalizumab treatment, quality of life also improved sigphase III trials have included symptomatic adolescent and nificantly over baseline values, including a reduction in asthma adult patients (aged 12–75 years) with moderate-to-severe exacerbations, a lessening of the need for steroids and rescue allergic asthma.31,32 All enrolled patients were given standard medications, and better lung function and symptom scores.31

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CONTINUING EDUCATION CREDIT Table 1 Disease Severity Classification Scheme Recommended in Current Guidelines

Symptoms

Nighttime Symptoms Lung Function

Long-Term-Control Medications

Quick-Relief Medications

Frequent

• FEV1.0 or PEF ≤ 60% predicted • PEF variability > 30%

Preferred treatment: • High-dose inhaled corticosteroids and • Long-acting inhaled beta2 agonists and (if needed) • Corticosteroid tablets or syrup long-term

• Short-acting beta2 agonist (two to four puffs as needed) • Intensity of treatment depends on severity • Use of quick-relief more than two times per week might indicate need to step up long-termcontrol therapy

• FEV1.0 or PEF > 60% – 30%

Preferred treatment: • Low-to-medium dose inhaled corticosteroids and • Long-acting, inhaled beta2 agonists


Step 4 Severe persistent

• Continual • Limited physical activity • Frequent exacerbations

Step 3 Moderate persistent

• Daily > One time • Daily use of inhaled per week short-acting beta2 agonists • Exacerbations affect activity levels • Exacerbations occur one or more times a week; can last several days

• Occurring more than More than Step 2 two times a week two times Mild persistent but less than once a day • Exacerbations can affect activity levels

Step 1 Mild intermittent

per month

• Occurring two or Two or fewer times per fewer times week per month • Asymptomatic and normal PEF between exacerbations • Exacerbations brief (few hours for a few days); intensity varies

Alternative treatment: • Increase inhaled corticosteroids to a medium dose and add long-acting inhaled beta2 agonists or • Low- to medium-dose inhaled corticosteroids and either a leukotriene modifier or theophylline • FEV1.0 or PEF > 80% predicted • PEF variability 20%–30%

Preferred treatment: • Low-dose inhaled corticosteroids Alternative treatment: • Cromolyn sodium • Leukotriene modifiers • Nedocromil or • Sustained-release theophylline to serum concentration of 5–15 mcg/ml

• FEV1.0 or PEF > 80% predicted • PEF variability < 20%


Preferred treatment: • Short-acting beta2 • No daily medication agonist (two to four needed puffs as needed) • Systemic corticosteroids • Intensity of treatment may be required in event depends on severity of severe exacerbation • Use of quick-relief more than two times per week might indicate need to step up long-termcontrol therapy

FEV1 = forced expiratory volume in one second; PEF = peak expiratory flow. Adapted from the National Heart, Lung, and Blood Institute and the National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. Expert Panel Report 2. Pub. No. 97-4051. Bethesda, MD: U.S. Department of Health and Human Services, 1997.37

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CONTINUING EDUCATION CREDIT The need for unscheduled outpatient visits, emergencyroom treatments, and hospitalizations was also reduced.36 The number of hospitalizations in the omalizumab-treated group decreased by up to 92%, and the average duration of a hospital stay was up to 63% shorter than that in patients taking placebo. These decreases in hospital use have significant implications for both quality of life and the economic impact of the disease.36 Omalizumab therapy was well tolerated, and no complications associated with reduced circulating IgE or antibodies against omalizumab were observed. The incidence of ADEs was similar between treatment groups, and no drug-related serious adverse effects were reported.31,32 As with any protein, local or systemic reactions, including anaphylaxis and anaphylactoid reactions, have the potential to occur. Patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur. Parasitic infections may result in elevated serum IgE concentrations. The effects of omalizumab have not been examined in the presence of any known concurrent parasitic infections. In addition, current long-term clinical data do not indicate that treatment with omalizumab is associated with malignancies. These results confirm that omalizumab can be an effective therapy for patients with symptomatic, moderate-to-severe allergic asthma that is poorly controlled with inhaled corticosteroids. Omalizumab therapy reduced the frequency and severity of exacerbations and improved symptom control despite the reduction in the use of inhaled corticosteroids and rescue medications. Twice-monthly or monthly administration of omalizumab also reduced the use of unscheduled medical services, improved quality of life for patients, and was safe and well tolerated.

Treatment Guidelines The first Expert Panel Report on the Management of Asthma, published in 1991, provided clinicians with an evidence-based set of recommendations for the diagnosis and treatment of asthma. This report recognized the role of airway inflammation in the pathogenesis of asthma and recommended that anti-inflammatory agents form the foundation of asthma therapy. Subsequent editions of the Expert Panel Report were published in 199737 and 2002.33 Although the NAEPP has strived to keep clinical practice guidelines up to date, the continual emergence of new data makes this task challenging. The 1997 Expert Panel Report recommends that the primary goals of asthma therapy are to control symptoms, to reduce exacerbations, and to minimize the amount of time lost to asthma-related inactivity. A stepwise approach to asthma therapy is encouraged when the number and frequency of medications are increased as asthma severity increases and are decreased as asthma symptoms come under control.33 According to the guidelines, asthma is classified as (1) mild intermittent, (2) mild persistent, (3) moderate persistent, or (4) severe persistent, and patients are treated accordingly (Table 1). Patients are assigned to the grade of asthma that is consistent with their most severe symptoms. Because the natural course of asthma is highly variable, there are overlaps between clas-

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sifications, and classifications are likely to vary with time. Patients at any level of severity can have mild, moderate, or severe exacerbations. Treatment decisions are based on matching therapy to the intensity of symptoms. Hence, planning effective and safe strategies for managing asthma depends on the correct diagnosis of disease severity.

Current Guidelines: Consensus Panel Review Despite the existence of guidelines that provide evidencebased asthma-treatment strategies, asthma remains suboptimally controlled in a significant number of patients.25 Several factors might account for this difficulty in asthma control, such as: • the dynamic nature of the disease. • poor patient adherence to therapy. • ignorance of the effect of comorbid conditions on treatment outcomes. • a focus on increasing FEV1 and other surrogate markers as indicators of clinical effectiveness. • poor access to care and the cost of health care (critical factors). Genentech, Inc., and Novartis Pharmaceuticals recently convened a panel of experts to review the current asthma treatment guidelines and to evaluate IgE blocker therapy and its place in the guidelines. The goal of this meeting was to create a practical treatment guide that specifically addressed gaps in the current recommendations, particularly for patients with moderate-to-severe asthma who have a history of frequent, severe exacerbations and poor asthma control (Table 2). The primary proposals set forth by the Panel included (1) the implementation of comprehensive asthma evaluation and patient-education programs and (2) recommendations on the use of IgE blocker therapy to treat moderate-to-severe asthma. Many features of the Panel’s treatment recommendations are consistent with the current NAEPP guidelines. Both sets of proposals encourage the use of a modified stepwise approach to asthma therapy, with the initial treatment matched to asthma severity. After symptoms are controlled, the drug dose is titrated to a level that most effectively minimizes their reoccurrence and lessens the chance of exacerbations. Mild Intermittent Asthma

The Panel recommends that patients with mild intermittent asthma continue to adhere to the current NAEPP guidelines. Accordingly, no daily anti-inflammatory medication is necessary, because these patients exhibit daytime and nocturnal symptoms less than twice a week and they experience infrequent exacerbations.33 The use of a short-acting beta2 agonist is recommended, as needed, for acute symptom relief. It is important to note that frequent or sustained use of a relief medication can indicate worsening asthma. A course of systemic corticosteroids might be required to regain control in cases of severe exacerbation.33 An education program emphasizing the basic facts of the disease, proper environ-

CONTINUING EDUCATION CREDIT Table 2 Approach for the Management of Asthma Daily Medication

Considerations for IgE Blocker Therapy

Severe persistent

Preferred treatment: • High-dose inhaled corticosteroids and • Long-acting inhaled beta2 agonists and (if needed) • Corticosteroid tablets or syrup long-term (2 mg/kg/day, generally do not exceed 60 mg/day). (Make repeated attempts to reduce systemic corticosteroid therapy and maintain control with high-dose inhaled corticosteroids.)

• Patient at least 12 years of age • Evidence of reversible disease (such as 12% or greater improvement in FEV1 with at least a 200-ml increase or 20% or greater improvement in PEF) • IgE level ≥ 30 IU/ml • Evidence of specific allergic sensitivity (i.e., positive skin test or blood test for IgE) • Inadequately controlled* despite medium dose of inhaled corticosteroids for at least three months in combination with a trial of long-acting inhaled beta2 agonists or a leukotriene modifier • Systemic corticosteroids or high-dose inhaled corticosteroids required to maintain adequate control • As directly observable therapy in patients who are not adherent to prescribed therapy

Moderate persistent

Preferred treatment: • Low-to-medium dose inhaled corticosteroids and long-acting beta2 agonists Alternative treatment (listed alphabetically): • Increase inhaled corticosteroids within medium-dose range or • Low-to-medium dose of inhaled corticosteroids and either leukotriene modifiers or theophylline

Patient evaluation and education

All patients with persistent asthma require further evaluation and education,* including identification of allergic triggers and comorbidities, as well as detailed advice regarding management. Types of education: • Disease state • Environmental controls • Inhaler technique • Pharmacotherapy • Immunotherapy • Action plan

Mild persistent

Preferred treatment: • Low-dose inhaled corticosteroids Alternative treatment (listed alphabetically): • Cromolyn sodium, leukotriene modifiers, nedocromil or • Sustained-release theophylline to serum concentrations of 5–15 mcg/ml

Mild intermittent

Treatment: • No daily medication needed Possible occurrence of severe exacerbations, separated by long periods of normal lung function and no symptoms • A course of systemic corticosteroids is recommended.

None

*Examples of inadequate control: (1) utilization of emergency department, hospitalization, or urgent-care visits; (2) excessive use of a short-acting beta agonist or oral steroids; and (3) impairment in activities of daily living, such as work, school attendance, exercise, and sleep. IgE = immunoglobulin E; IU = International Units; FEV1 = forced expiratory volume in one second; PEF = peak expiratory flow. Adapted from the National Heart, Lung, and Blood Institute and the National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. Expert Panel Report 2. Pub. No. 97-4051. Bethesda, MD: U.S. Department of Health and Human Services, 1997.37

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CONTINUING EDUCATION CREDIT mental controls, and the correct use of rescue medications and delivery devices is a critical component of an asthmamanagement plan for these patients. Mild Persistent Asthma

The Panel recommendations are aligned with the NAEPP guidelines for the treatment of mild persistent asthma. Asthma control in these patients can be maintained with daily use of low-dose inhaled corticosteroids or with the use of cromolyn sodium (e.g., Cromolyn Sodium Inhalation Solution, Dey, or Intal®, Aventis/King), leukotriene modifiers,

Obtaining an accurate diagnosis is a challenge, because clinicians tend to underestimate the severity of asthma. According to one study, asthma specialists correctly classified the severity only 63% of the time. nedocromil (Tilade®, Aventis/King), or theophylline to serum concentrations of 5 to 15 mcg/ml. Acute asthma symptom relief is provided by the use of a short-acting beta2 agonist. Pharmacological management should be combined with an asthma-education program to increase the likelihood of success.33 Moderate-to-Severe Persistent Asthma

Many patients with moderate-to-severe persistent asthma remain symptomatic despite the use of multiple daily medications and the occasional to frequent use of systemic corticosteroids. Unscheduled visits to medical facilities are quite common. Features of suboptimal or inadequately controlled asthma include high rates of hospitalization and use of the emergency department, excessive use of rescue medications and/or oral steroids, and an impaired ability to work, attend school, exercise, or sleep. Some patients also exhibit a history of nonadherence with medication regimens. Consequently, the Panel recommends incorporating an aggressive, comprehensive, and ongoing evaluation and education program for all patients in these situations. The Panel also recommends the use of therapies proven to reduce the quantity of health care resources utilized by these patients. As presented in Table 2, the Panel recommends that patients with moderate-to-severe asthma be enrolled in an ongoing, intensive educational program along with their primary caregivers. Patients should receive instruction on the use of devices, environmental control and avoidance measures, rescue action plans, and self-management and adherence techniques through discussions with health care professionals, from brochures and videos, and from information acquired via the Internet or support groups. Educating patients is a cost-effective way to minimize exacer-

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bations and to reduce mortality for both children and adults, particularly among high-risk patients.38 Patients who are knowledgeable about their disease and the therapies being used to manage it are also more motivated to adhere to their treatment plans.39

Incorporating New Therapies into the Guidelines The 1997 NAEPP guidelines suggest that patients with moderate and severe persistent asthma be segregated into two groups and treated with increasingly aggressive therapy: • Moderate persistent asthma. The preferred treatment includes daily use of a combination of low-dose inhaled corticosteroids and long-acting beta agonists (LABAs). Alternative therapies include inhaled corticosteroids at a medium dose or a combination of low-dose to mediumdose inhaled corticosteroids and either a leukotriene receptor agonist or theophylline. • Severe persistent asthma. The currently recommended treatment is combination therapy with high-dose inhaled corticosteroids and long-acting beta agonists. If needed, corticosteroid tablets or syrup (2 mg/kg/day, not to exceed 60 mg/day) can be added to maintain control; however, all attempts should be made to reduce the use of systemic corticosteroids and to maintain control with high doses of inhaled corticosteroids.33 Dividing patients with suboptimally controlled asthma into two distinct groups increases the complexity of disease management, because it requires an accurate diagnosis of asthma severity and patient adherence to a medication regimen that fluctuates with symptoms. Obtaining an accurate diagnosis is a challenge, because clinicians tend to underestimate the severity of asthma. According to one study, asthma specialists correctly classified the severity only 63% of the time.40 Adherence to therapy can also be negatively affected because therapeutic regimens—to be successful—must be simple and convenient and should not cause side effects or additional deterioration in quality of life. Patient adherence to treatment plans is extremely low when therapies are timeconsuming, difficult to use, or expensive; that are perceived not to offer any benefit; or that necessitate fluctuations in dosages. Even patients with moderate-to-severe asthma and a history of frequent use of emergency-department services, hospitalizations, oral corticosteroid use, and nocturnal symptoms have poor adherence in these cases.41 The combination of improper diagnosis and poor adherence to therapy can contribute to suboptimal asthma control. To address this issue, the Panel has recommended that (1) the distinction between the moderate and severe categories of asthma be eliminated and (2) treatment strategies for both patient groups be standardized. The recommended goal of therapy is the true reduction of overall asthma burden, as indicated by actual markers of patients’ daily functioning and control of their asthma. The Panel encourages the use of a wider range of strategies for management, including control of infections, avoidance of allergens, and the use of IgE blockers to achieve this goal.31,32,37 Trial data indicate that IgE blockers present an attractive

CONTINUING EDUCATION CREDIT alternative in patients with moderate-to-severe, suboptimally controlled asthma after unsuccessful attempts with current standard measures to produce adequate control.31,32 This new intervention appears to reduce asthma exacerbations in patients who: • are at least 12 years of age. • have evidence of reversible airway disease (e.g., a greater than 12% improvement in FEV1 with at least a 200-ml increase or at least a 20% or greater improvement in PEF). • have an IgE level of 30 IU/ml or more. • show evidence of specific allergic sensitivity by positive skin or blood tests for a specific IgE. IgE blockers can be used as an alternative in patients with inadequately controlled asthma despite a combination of medium-dose inhaled corticosteroids and long-acting beta agonists or leukotriene receptor agonists, administered for three months. In addition, patients who are taking a course of systemic corticosteroids or who require high-dose inhaled corticosteroids for daily asthma control are also appropriate patients for IgE blockers. As a result of infrequent dosing requirements, IgE blockers are also effective for patients who do not adhere to prescribed therapy with multiple dosing requirements. Current NAEPP guidelines do not consider the impact of comorbidities on the treatment of asthma.33,37 The presence of coexisting conditions often warrants multiple medications and further hinders adherence and achievement of treatment goals. Asthma, particularly allergic asthma, rarely presents in isolation from other IgE-mediated diseases, such as seasonal allergic rhinitis and atopic dermatitis. IgE blockers have the potential to address both asthma and the comorbid conditions.

As additional clinical experience is gained, the ultimate role of IgE blockers will be further defined. Issues such as cost, long-term acceptability, and safety remain to be addressed.

References 1.

2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12.

Summary

13.

Asthma continues to impose a significant clinical and economic burden on society. Patients with suboptimally controlled, moderate-to-severe asthma pose a considerable challenge to physicians and are among the most frequent users of health care resources. Current treatment strategies recommend the use of multiple medications to control symptoms and to preserve surrogate markers of clinical efficacy, such as FEV1. The complexity of these regimens contributes to patient nonadherence. Successful asthma management is also hindered because of the cost of asthma care and limited access to health care resources. Novel treatments, such as IgE blockers, have demonstrated a direct impact on disease indicators by minimizing exacerbations, reducing hospitalization and emergencydepartment visits, and improving quality of life in patients with moderate-to-severe, suboptimally controlled asthma. Proposed treatment guidelines encourage the use of IgE blockers in these patients. The use of such therapies has proved beneficial in reducing the clinical and economic burden of asthma and therefore has important implications for patients, health care providers, and third-party payers.

14. 15. 16. 17.

18. 19. 20. 21.

U.S. Department of Health and Human Services, National Center for Health Statistics, Division of Data Services, Centers for Disease Control and Prevention. Asthma Prevalence, Health Care Use and Mortality, 2000–2001. Hyattsville, MD: Available at: www.cdc.gov/hchs/products/pubs/pubd/hestats/asthma/ asthma.htm. Accessed March 19, 2003. Weiss KB, Sullivan SD. The health economics of asthma and rhinitis: I. Assessing the economic impact. J Allergy Clin Immunol 2001;107:3–8. Godard P, Chanez P, Siraudin L, et al. Costs of asthma are correlated with severity: A 1-year prospective study. Eur Respir J 2002;19:61–67. Serr-Batlles J, Plaza V, Morejon E, et al. Costs of asthma according to degree of severity. Eur Respir J 1998;(12):1322–1326. Smith DH, Malone DC, Lawson KA, et al. A national estimate of the economic costs of asthma. Am J Respir Crit Care Med 1997;156: 787–793. Rea HH, Scragg R, Jackson R, et al. A case control study of deaths from asthma. Thorax 1986;41:833–839. Crane J, Pearce N, Burgess C, et al. Markers of risk of asthma death or readmission in the 12 months following a hospital admission for asthma. Int J Epidemiol 1992;21:737–744. Tough SC, Hessel PA, Ruff M, et al. Features that distinguish those who die from asthma from community controls with asthma. J Asthma 1998;35:657–665. Cookson W. The alliance of genes and environment in asthma and allergy. Nature 1999;402 (Suppl):B5–B11. Prescott SL, Macaubas C, Holt BJ, et al. Transplacental priming of the human immune system to environmental allergens: Universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998;60:4730–4737. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354:541–545. Halonen M, Stern DA, Lohman C, et al. Two subphenotypes of childhood asthma that differ in maternal and paternal influences on asthma risk. Am J Respir Crit Care Med 1999;160:564–570. Venables KM, Chan-Yeung M. Occupational asthma. Lancet 1997;349:1465–1469. Busse WW, Lemanske RF. Asthma. N Engl J Med 2001;344: 350–362. Sunyer J, Anto JM, Sabria J, et al. Relationship between serum IgE and airway responsiveness in adults with asthma. J Allergy Clin Immunol 1995;95:699–706. Burrows B, Martinez FD, Halonen M, et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989;320:271–277. European Community Respiratory Health Survey. Determinants of bronchial responsiveness in the European Community Respiratory Health Survey in Italy: Evidence of an independent role of atopy, total serum IgE levels, and asthma symptoms. Allergy 1998;53:673–681. Oddera S, Silvestri M, Penna R, et al. Airway eosinophilic inflammation and bronchial hyperresponsiveness after allergen inhalation challenge in asthma. Lung 1998;176:237–247. Menz G, Ying S, Durham SR, et al. Molecular concepts of IgEinitiated inflammation in atopic and nonatopic asthma. Allergy 1998;53(45 Suppl):15–21. Haugaard L, Iversen M, Dahl R. Predictors of early- and latephase reactions to bronchial allergen challenge. Allergy 1997; 52:999–1004. van der Veen MJ, Van Neerven RJ, De Jong EC, et al. The late asthmatic response is associated with baseline allergen-specific proliferative responsiveness of peripheral T lymphocytes in vitro and serum interleukin-5. Clin Exp Allergy 1999;29:217–227.

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CONTINUING EDUCATION CREDIT 22. Holgate ST. Therapeutic options for persistent asthma. JAMA 2001;285:2637–2639. 23. Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J 1998;12: 1209–1218. 24. Hoskins G, McCowan C, Neville RG, et al. Risk factors and costs associated with an asthma attack. Thorax 2000;55:19–24. 25. TENOR Investigators. Data on file: The epidemiology and natural history of asthma: Outcomes and treatment regimens. South San Francisco, CA: Genentech, Inc. 26. Szefler SJ. Challenges in assessing outcomes for pediatric asthma. J Allergy Clin Immunol 2001;107(Suppl 5):456S–464S. 27. Milgrom H, Fick RB Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody rhuMAb-E25 Study Group. N Engl J Med 1999;341:1966–1973. 28. MacGlashan DW Jr, Bochner BS, Adelman DC, et al. Downregulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158:1438–1445. 29. Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997;155:1828–1834. 30. Boulet LP, Chapman KR, Cote J, et al. Inhibitory effects of an antiIgE antibody E25 on allergen-induced early asthmatic response. Am J Respir Crit Care Med 1997;155:1835–1840. 31. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108:184–190. 32. Solèr M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18:254–261. 33. National Heart, Lung, and Blood Institute and the National Asthma Education and Prevention Program. Expert Panel Report:

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34. 35. 36.

37.

38. 39. 40. 41. 42.

Guidelines for the diagnosis and management of asthma. Update on selected topics 2002. J Allergy Clin Immunol 2002;110(Suppl): S141–S183. British Asthma Guidelines Coordinating Committee. British guidelines on asthma management: 1995 review and position statement. Thorax 1997;52:S1–S20. Buhl R, Kunkel G, Soler M, et al. Rhu-MAb-25 improves asthmaspecific quality of life in patients with allergic asthma. Eur Resp J 2000;16:465S. Corren J. Casale T, Deniz Y, Ashby M. Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J Allergy Clin Immunol 2003;111:87–90. National Heart, Lung, and Blood Institute and the National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. Expert Panel Report 2, Pub. No. 97-4051. Bethesda, MD: U.S. Department of Health and Human Services; 1997. Trautner C, Richter B, Berger M. Cost-effectiveness of a structured treatment and teaching programme on asthma. Eur Respir J 1993;6:1485–1491. Partridge MR. Delivering optimal care to the person with asthma: What are the key components and what do we mean by patient education? Eur Respir J 1995;8:298–305. Doerschug KC, Peterson MW, Dayton CS, Kline JN. Asthma guidelines: An assessment of physician understanding and practice. Am J Respir Crit Care Med 1999;159:1735–1741. Apter AJ, Reisine ST, Affleck G, et al. Adherence with twice-daily dosing of inhaled steroids: Socioeconomic and health-belief differences. Am J Respir Crit Care Med 1998;157:1810–1817. Boushey HA. Experiences with monoclonal antibody therapy for allergic asthma. J Allergy Clin Immunol 2001;108:S77-S83.


Continuing Education Examination for Pharmacists TOPIC: Incorporating

Omalizumab into Asthma Treatment Guidelines: Consensus Panel Recommendations

ACPE Program #079-999-03-018-H01 CE Evaluation: Select the one best answer to each of the following questions, and record your response on the examination answer sheet. Complete additional the requested information. Forward the answer sheet, with appropriate payment, to the Office of Health Policy and Clinical Outcomes, Thomas Jefferson University Hospital, at the address indicated. A certificate of completion will be mailed within three weeks of receipt of your exam/payment. (A minimum test score of 70% is required.)

Multiple Choice Select the one correct answer. 1.

Which of the following is the mechanism by which omalizumab inhibits IgE from triggering the release of inflammatory mediators? a. forming complexes with the mast cell receptors b. forming complexes with circulating free IgE c. forming complexes with mast cell–bound IgE d. none of the above

2.

In phase III clinical trials, omalizumab reduced asthma exacerbations: a. but required doubling the corticosteroid dose. b. but required doubling the beclomethasone dipropionate (BDP) dose. c. despite the use of a higher dose of omalizumab. d. despite the use of a lower dose of BDP.

3.

According to the article, treatment decisions should be based on matching therapy to the intensity of symptoms. a. True b. False

4.

Which of the following statements is incorrect? a. Airway inflammation is found in virtually all individuals with asthma symptoms. b. The occurrence of asthma symptoms is correlated with elevated serum IgE levels. c. Asthma prevalence has been shown to be associated with decreased levels of total IgE. d. The occurrence of asthma symptoms is correlated with airway hyperresponsiveness.

5.

According to this article, patients with the greatest unmet needs are those: a. with moderate asthma that is suboptimally controlled. b. with severe asthma that is suboptimally controlled. c. with mild asthma that is suboptimally controlled. d. both a and b.

6.

According to the early results of TENOR, patients with moderate-to-severe, suboptimally controlled asthma have the highest rate of health care utilization and a high frequency of hospitalization. a. True b. False

7.

According to the Consensus Panel Recommendations, which of the following considerations may support the use of IgE blockers in the treatment of patients with severe and moderate persistent asthma? a. patients who are at least 12 years old b. evidence of specific allergic sensitivity by a positive skin test or blood test for specific IgE c. an IgE level of 30 IU/ml or greater d. all of the above

8.

Which of the following was not listed as a feature of suboptimally or inadequately controlled asthma? a. frequent usage of the emergency department b. impaired ability to work, attend school, exercise, or sleep c. excessive use of rescue medications and/or oral steroids d. low rates of hospitalization

9.

Which of the following was not mentioned in the article as a characteristic of therapy that is associated with low adherence? a. regimens that are time-consuming b. regimens that are easy to use c. regimens that are expensive d. regimens that fluctuate in dosing

10. According to the guidelines in Table 2, all patients with persistent asthma require further evaluation and education as well as detailed advice regarding the management of: a. disease. b. inhaler technique. c. pharmacotherapy. d. all of the above.

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Continuing Education for Pharmacists Examination Answer Sheet TOPIC: Incorporating

Omalizumab into Asthma Treatment Guidelines: Consensus Panel Recommendations P&T ® 2003;28(6):400–410

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Continuing Medical Education for Physicians TOPIC: Incorporating

Omalizumab into Asthma Treatment Guidelines: Consensus Panel Recommendations

Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Jefferson Medical College and MediMedia USA, Inc. Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Medical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their article(s). Full disclosure of these relationships appears on the last page of the article.

Continuing Medical Education Credit This CME activity is designed to assist physicians and other health care professionals who are P&T committee members in making formulary decisions. Its goal is to increase participants’ ability to recognize and treat important medical problems. Jefferson Medical College designates this continuing medical education activity for a maximum of one hour of Category 1 credit toward the Physician’s Recognition Award (PRA) of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. This credit is available for the period of one year from the date of publication. Although forms will be processed when received, certificates for CME credits will be issued every six months, in February and August. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education at (215) 955-6992.

How to Apply for CME Credit 1. Each CME article is prefaced by learning objectives for participants to use to determine whether the article relates to their in dividual learning needs. 2. Read the article carefully, paying particular attention to the tables and other illustrative materials. 3. Complete the CME Registration and Evaluation Form. Type or print your full name and address in the space provided, and evaluate the activity as requested. In order for the form to be processed, all information must be complete and legible. 4. Send the completed form, with $20 payment to: Office of Continuing Medical Education/P&T Martin Building, Room 309 201 South 11th Street Philadelphia, PA 19107 5. Be sure to mail the Registration and Evaluation Form within one year of the date of publication. After that date, this article will no longer be designated for credit and forms cannot be processed.

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Pharmacy and Therapeutics

CME Registration and Evaluation Form Date of publication: June 2003 Title: Incorporating Omalizumab into Asthma Treatment Guidelines: Consensus Panel Recommendations Authors: Lanny J. Rosenwasser, MD, FAAAAI, and David B. Nash, MD, MBA, FACP Submission deadline: June 30, 2004

A Peer-Reviewed Journal for Managed Care and Hospital Formulary Management

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3. Which of the following best describes a change you might consider making in your practice as a result of something you learned from this activity? (Please circle only one response.) A. Slightly modify what I currently do. B. Make a major change in what I currently do. C. Follow a procedure, use a technique/technology that is completely new to me. D. Follow a procedure, use a technique/technology that I currently use but for a different purpose. E. None of the above, but some change. F. Not considering any changes. 4. Please describe any change(s) you plan to make in your practice as a result of this activity: ______________________________ ______________________________________________________________________________________________________________ ______________________________________________________________________________________________________________ 5. How committed are you to making these changes? 5 4 3 2 1 (very committed) (not at all committed) 6. Other comments: ____________________________________________________________________________________________ ______________________________________________________________________________________________________________

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