Component 4 Medications

Key Points - Medications 2 general classes: Long-term control medications Quick-Relief medications Controller medications: Corticosteroids Long Acting Beta Agonists (LABA’s) Leukotriene modifiers (LTRA) Cromolyn & Nedocromil Methylxanthines: (Sustained-release theophylline) Medications for asthma are categorized into two general classes: long-term control medications used to achieve and maintain control of persistent asthma and quick-relief medications used totreat acute symptoms and exacerbations. Long-term control medications (listed in alphabetical order) corticosteroids: Block late-phase reaction to allergen, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. They are the most potent and effective anti-inflammatory medication currently available (Evidence A). ICSs are used in the long-term control of asthma. Short courses of oral systemic corticosteroids are often used to gain prompt control of the disease when initiating long-term therapy; long-term oral systemic corticosteroid is used for severe persistent asthma. Cromolyn sodium and nedocromil: Stabilize mast cells and interfere with chloride channel function. They are used as alternative, but not preferred, medication for the treatment of mild persistent asthma (Evidence A). They can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens. Immunomodulators: Omalizumab (anti-IgE) is a monoclonal antibody that prevents binding of IgE to the high-affinity receptors on basophils and mast cells. Omalizumab is used as adjunctive therapy for patients 12 years of age who have allergies and severe persistent asthma (Evidence B). Clinicians who administer omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur. Leukotriene modifiers: Include LTRAs and a 5-lipoxygenase inhibitor. Two LTRAs are available—montelukast (for patients >1 year of age) and zafirlukast (for patients 7 years of age). The 5-lipoxygenase pathway inhibitor zileuton is available for patients 12 years of age; liver function monitoring is essential. LTRAs are alternative, but not preferred, therapy for the treatment of mild persistent asthma (Step 2 care) (Evidence A). LTRAs can also be used as adjunctive therapy with ICSs, but for youths 12 years of age and adults they are not the preferred adjunctive therapy compared to the addition of LABAs (Evidence A). Zileuton can be used as alternative but not preferred adjunctive therapy in adults (Evidence D). LABAs: Salmeterol and formoterol are bronchodilators that have a duration of bronchodilation of at least 12 hours after a single dose. LABAs are not to be used as monotherapy for long-term control of asthma (Evidence A). — LABAs are used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 care or higher in children 5 years of age and adults) (Evidence A for 12 years of age, Evidence B for 5–11 years of age). Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths 12 years of age and adults (Evidence A). — In the opinion of the Expert Panel, the beneficial effects of LABA in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of LABAs (see discussion in text). For patients 5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA. For patients 5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy. — In the opinion of the Expert Panel, the use of LABA for the treatment of acute symptoms or exacerbations is not currently recommended (Evidence D). Methylxanthines: Sustained-release theophylline is a mild to moderate bronchodilator used as alternative, not preferred, adjunctive therapy with ICS (Evidence A). Theophylline may have mild anti-inflammatory effects. Monitoring of serum theophylline concentration is essential. P 213 **See 2010 FDA recommendations regarding LABA’s

Key Points – Medications cont. Quick- relief medications Short acting bronchodilators (SABA’s) Systemic corticosteroids Anticholinergics

Key Points: Safety of ICS’s ICS’s are the most effective long-term therapy available, are well tolerated & safe at recommended doses The potential but small risk of adverse events from the use of ICS treatment is well balanced by their efficacy The dose-response curve for ICS treatment begins to flatten at low to medium doses Most benefit is achieved with relatively low doses, whereas the risk of adverse effects increases with dose

Key Points: Reducing Potential Adverse Effects Spacers or valved holding chambers (VHCs) used with non-breath-activated MDIs reduce local side effects There is little or no data on use of spacers with hydrofluoroalkane (HFA) MDIs Patients should rinse their mouths (rinse and spit) after (ICS) inhalation Use the lowest dose of ICS that maintains asthma control: Evaluate patient adherence and inhaler technique as well as environmental factors before increasing the dose of ICS To achieve or maintain control of asthma, add a LABA to a low or medium dose of ICS rather than using a higher dose of ICS Monitor linear growth in children

Key Points: Safety of Long-Acting Beta2-Agonists (LABA’s) Adding a LABA to the tx of patients whose asthma is not well controlled on low- or medium-dose ICS improves lung function, decreases symptoms, and reduces exacerbations and use of SABA for quick relief in most patients The FDA determined that a Black Box warning was warranted on all preparations containing a LABA For patients who have asthma not sufficiently controlled with ICS alone, the option to increase the ICS dose should be given equal weight to the option of the addition of a LABA to ICS It is not currently recommended that LABA be used for treatment of acute symptoms or exacerbations LABAs are not to be used as monotherapy for long-term control

FDA Recommendations for LABA’s February 2010 Are contraindicated without the use of an asthma controller medication such as an ICS Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone Should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications

FDA Recommendations for LABA’s Cont. Should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved Patients should then be maintained on an asthma controller medication Pediatric and adolescent patients who require the addition of a LABA to an ICS should use a combination product containing both an ICS and a LABA, to ensure compliance with both medications

Key Points: Safety of Short -Acting Beta2-Agonists (SABA’s) SABAs are the most effective medication for relieving acute bronchospasm Increasing use of SABA treatment or using SABA >2 days a week for symptom relief (not prevention of EIB) indicates inadequate control of asthma Regularly scheduled, daily, chronic use of SABA is not recommended

Managing Asthma Long Term “The Stepwise Approach” Section 4 Managing Asthma Long Term “The Stepwise Approach”

Key Points: Managing Asthma Long Term The goal of therapy is to control asthma by: Reducing impairment Reducing risk A stepwise approach to medication therapy is recommended to gain and maintain asthma control Monitoring and follow-up is essential Medications for asthma are categorized into two general classes: long-term control medications used to achieve and maintain control of persistent asthma and quick-relief medications used to treat acute symptoms and exacerbations. Long-term control medications Corticosteroids: Block late-phase reaction to allergen, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. They are the most potent and effective anti-inflammatory medication currently available (Evidence A). ICSs are used in the long-term control of asthma. Short courses of oral systemic corticosteroids are often used to gain prompt control of the disease when initiating long-term therapy; long-term oral systemic corticosteroid is used for severe persistent asthma. Cromolyn sodium and nedocromil: Stabilize mast cells and interfere with chloride channel function. They are used as alternative, but not preferred, medication for the treatment of mild persistent asthma (Evidence A). They can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens. Note that Cromolyn & Nedocromil will no longer be manufactured in the near future. Immunomodulators: Omalizumab (anti-IgE) is a monoclonal antibody that prevents binding of IgE to the high-affinity receptors on basophils and mast cells. Omalizumab is used as adjunctive therapy for patients 12 years of age who have allergies and severe persistent asthma (Evidence B). Clinicians who administer omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur (see discussion in text). Leukotriene modifiers: Include LTRAs and a 5-lipoxygenase inhibitor. Two LTRAs are available—montelukast (for patients >1 year of age) and zafirlukast (for patients 7 years of age). The 5-lipoxygenase pathway inhibitor zileuton is available for patients 12 years of age; liver function monitoring is essential. LTRAs are alternative, but not preferred, therapy for the treatment of mild persistent asthma (Step 2 care) (Evidence A). LTRAs can also be used as adjunctive therapy with ICSs, but for youths 12 years of age and adults they are not the preferred adjunctive therapy compared to the addition of LABAs (Evidence A). Zileuton can be used as alternative but not preferred adjunctive therapy in adults (Evidence D). LABAs: Salmeterol and formoterol are bronchodilators that have a duration of bronchodilation of at least 12 hours after a single dose. LABAs are not to be used as monotherapy for long-term control of asthma (Evidence A). — LABAs are used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 care or higher in children 5 years of age and adults) (Evidence A for 12 years of age, Evidence B for 5–11 years of age). Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths 12 years of age and adults (Evidence A). — In the opinion of the Expert Panel, the beneficial effects of LABA in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of LABAs (see discussion in text). For patients 5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA. For patients 5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy. — In the opinion of the Expert Panel, the use of LABA for the treatment of acute symptoms or exacerbations is not currently recommended (Evidence D). Methylxanthines: Sustained-release theophylline is a mild to moderate bronchodilator used as alternative, not preferred, adjunctive therapy with ICS (Evidence A). Theophylline may have mild anti-inflammatory effects. Monitoring of serum theophylline concentration is essential. Section 3, Component 4: Medications — Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths 12 years of age and adults (Evidence A). — In the opinion of the Expert Panel, the beneficial effects of LABA in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of LABAs (see discussion in text). For patients 5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA. For patients 5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy. February 2010 – FDA announcement regarding LABA’s – http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs)   Safety Announcement [02-18-2010] Due to safety concerns, the U.S. Food and Drug Administration (FDA) is requiring changes to how long-acting inhaled medications called Long-Acting Beta-Agonists (LABAs) are used in the treatment of asthma. These changes are based on FDA's analyses of studies showing an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma (see Data Summary below). LABAs are approved as single-ingredient products (Serevent and Foradil) and as an ingredient in combination products containing inhaled corticosteroids (Advair and Symbicort) for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They work by relaxing muscles in the airway and lungs. This helps patients breathe easier, and lessens symptoms such as wheezing and shortness of breath. The new recommendations only apply to the use of LABAs in the treatment of asthma. To ensure the safe use of these products: The use of LABAs is contraindicated without the use of an asthma controller medication such as an inhaled corticosteroid. Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone. LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications. LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication. Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications. FDA is also requiring a risk management program called a Risk Evaluation and Mitigation Strategy (REMS) for these products. The REMS for LABAs will include a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. In addition, FDA is requiring the manufacturers to conduct additional clinical trials to further evaluate the safety of LABAs when used in combination with inhaled corticosteroids. FDA will seek input on these studies at a public advisory committee meeting on March 10-11, 2010.  FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of LABAs. FDA believes the safety measures recommended above will improve the safe use of these drugs.

Treatment: Principles of “Stepwise” Therapy “The goal of asthma therapy is to maintain long-term control of asthma with the least amount of medication and hence minimal risk for adverse effects”. The distinction between assessing impairment and risk to make treatment decisions draws attention to the multifaceted nature of asthma and the need to consider all manifestations of the disease. Assessing both domains emphasizes the need to consider separately asthma’s effects on quality of life and functional capacity on an ongoing basis (i.e., at present) and the risks asthma presents for adverse events in the future, such as exacerbations or progressive reduction in lung growth. These domains may respond differentially to treatment. For example, a large study of children who had asthma revealed that 30 percent of the low-dose ICS treatment group, whose levels of impairment (symptoms, SABA use, lung function) improved, remained at risk of exacerbations requiring oral systemic corticosteroids (CAMP 2000) Deciding which step of care is appropriate for a patient depends on whether long-term control therapy is being initiated for the first time or whether therapy is being adjusted (i.e., stepped up to regain control or stepped down, for patients who have maintained control for a sufficient length of time, to determine the minimal amount of medication required to maintain control and/or reduce the risk of side effects). The classification of asthma severity, which considers the severity of both impairment and risk domains, provides a guide for initiating therapy for patients who are not currently taking long-term control medications

Principles of Step Therapy to Maintain Control Step up medication dose if symptoms are not controlled If very poorly controlled, consider an increase by 2 steps, add oral corticosteroids, or both Before increasing medication therapy, evaluate: Exposure to environmental triggers Adherence to therapy For proper device technique Co-morbidities

Follow-up Appointments Visits every 2-6 weeks until asthma control is achieved When control is achieved, follow-up every 3-6 months Step-down in therapy: When asthma is well-controlled for at least 3 months Patients may relapse with total discontinuation or reduction of inhaled corticosteroids

Assessing Control & Adjusting Therapy Children 0-4 Years of Age Notes: The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. The level of control is based on the most severe impairment or risk category. Assess impairment domain by caregiver’s recall of previous 2–4 weeks. Symptom assessment for longer periods should reflect a global assessment such as inquiring whether the patient’s asthma is better or worse since the last visit. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma. Before step up in therapy: Review adherence to medications, inhaler technique, and environmental control. If alternative treatment option was used in a step, discontinue it and use preferred treatment for that step.

Stepwise Approach for Managing Asthma in Children 0-4 Years of Age Intermittent Asthma Persistent Asthma: Daily Medication Consult asthma specialist if step 3 care or higher is required. Consider consultation at step 2 Step up if needed (first check adherence, environmental control) Step 6 Preferred High Dose ICS AND Either: Montelukast or LABA Oral corticosteroid Step 5 Preferred High Dose ICS AND Either: Montelukast or LABA Step 4 Preferred Medium Dose ICS AND Either: Montelukast or LABA Step 3 Preferred Medium Dose ICS Assess control Step 2 Preferred Low dose ICS Alternative Montelukast or Cromolyn Step 1 Preferred SABA PRN Step down if possible (and asthma is well controlled at least 3 months) Patient Education and Environmental Control at Each Step Quick-relief medication for ALL patients -SABA as needed for symptoms. With VURI: SABA every 4-6 hours up to 24 hours. Consider short course of corticosteroids with (or hx of) severe exacerbation

Assessing Control & Adjusting Therapy Children 5-11 Years of Age

Stepwise Approach for managing asthma in children 5-11 years of age Intermittent Asthma Persistent Asthma: Daily Medication Consult asthma specialist if step 4 care or higher is required. Consider consultation at step 3 Step up if needed (first check adherence, environmental control, and comorbid conditions) Preferred High Dose ICS + LABA + oral corticosteroid Alternative High dose ICS + either LTRA, or Theophylline Step 6 Preferred High Dose ICS + LABA Alternative High dose ICS + either LTRA, or Theophylline Step 5 Preferred Medium Dose ICS + LABA Alternative Medium dose ICS + either LTRA, or Theophylline Step 4 Preferred Either Low Dose ICS + LABA, LTRA, or Theophylline OR Medium Dose ICS Step 3 Preferred Low dose ICS Alternative LTRA, Cromolyn Nedocromil or Theophylline Step 2 Preferred SABA PRN Step 1 Assess control Step down if possible (and asthma is well controlled at least 3 months) Patient Education and Environmental Control at Each Step Quick-relief medication for ALL patients SABA as needed for symptoms. Short course of oral corticosteroids maybe needed.

Assessing Control & Adjusting Therapy in Youths > 12 Years of Age & Adults *ACQ values of 0.76–1.4 are indeterminate regarding well-controlled asthma. Key: EIB, exercise-induced bronchospasm; ICU, intensive care unit Notes: The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient’s recall of previous 2–4 weeks and by spirometry/or peak flow measures. Symptom assessment for longer periods should reflect a global assessment, such as inquiring whether the patient’s asthma is better or worse since the last visit. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had ≥2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma. Validated Questionnaires for the impairment domain (the questionnaires do not assess lung function or the risk domain) ATAQ = Asthma Therapy Assessment Questionnaire© (See sample in “Component 1: Measures of Asthma Assessment and Monitoring.”) ACQ = Asthma Control Questionnaire© (user package may be obtained at www.qoltech.co.uk or juniper@qoltech.co.uk) ACT = Asthma Control Test (See sample in “Component 1: Measures of Asthma Assessment and Monitoring.”) Minimal Important Difference: 1.0 for the ATAQ; 0.5 for the ACQ; not determined for the ACT. Before step up in therapy: Review adherence to medication, inhaler technique, environmental control, and comorbid conditions. If an alternative treatment option was used in a step, discontinue and use the preferred treatment for that step.

Persistent Asthma: Daily Medication Stepwise Approach for Managing Asthma in Youths >12 Years of Age & Adults Intermittent Asthma Persistent Asthma: Daily Medication Consult asthma specialist if step 4 care or higher is required. Consider consultation at step 3 Step up if needed (first check adherence, environmental control & comorbid conditions) Step 6 Preferred High dose ICS + LABA + oral corticosteroid AND Consider Omalizumab for patients who have allergies Step 5 Preferred High Dose ICS + LABA AND Consider Omalizumab for patients who have allergies Step 4 Preferred: Medium Dose ICS + LABA Alternative: Medium-dose ICS + either LTRA, Theophylline, or Zileuton Step 3 Preferred: Low-dose ICS + LABA OR – Medium dose ICS Alternative: Low-dose ICS + either LTRA, Theophylline, or Zileuton Assess control Step 2 Preferred: Low dose ICS Alternative: Cromolyn, LTRA, Nedocromil or Theophylline Step 1 Preferred: SABA PRN Step down if possible (and asthma is well controlled at least 3 months) Each Step: Patient Education and Environmental Control and management of comorbidities Steps 2 – 4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma Quick-relief medication for ALL patients -SABA as needed for symptoms: up to 3 tx @ 20 minute intervals prn. Short course of o systemic corticosteroids may be needed. Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control & the need to step up treatment.

Managing Exacerbations of Asthma Section 5 Managing Exacerbations of Asthma

Key Points – Managing Exacerbations Early treatment of asthma exacerbations is the best strategy for management: Patient education includes a written asthma action plan (AAP) to guide patient self‑management of exacerbations especially for patients who have moderate or severe persistent asthma and any patient who has a history of severe exacerbations A peak‑flow‑based plan for patients who have difficulty perceiving airflow obstruction and worsening asthma is recommended EPR -3 Pg. 373

Key Points – cont. Recognition of early signs of worsening asthma & taking prompt action Appropriate intensification of therapy, often including a short course of oral corticosteroids Removal or avoidance of the environmental factors contributing to the exacerbation Prompt communication between patient and clinician about any serious deterioration in symptoms or peak flow, decreased responsiveness to SABAs, or decreased duration of effect

Exacerbations Defined - RISK Are acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing, and chest tightness? — or some combination of these symptoms Are characterized by decreases in expiratory airflow that can be documented and quantified by spirometry or peak expiratory flow These objective measures more reliably indicate the severity of an exacerbation than does the severity of symptoms

Classifying Severity of Asthma Exacerbations in the UC or ER Setting Symptoms & Signs Initial PEF (or FEV1) Clinical Course Mild Dyspnea only with activity (assess tachypnea in young children) PEF 70 percent predicted or personal best Usually cared for at home Prompt relief with inhaled SABA Possible short course of oral systemic corticosteroids Moderate Dyspnea interferes with or limits usual activity PEF 4069 percent predicted or personal best Usually requires office or ED visit Relief from freq. inhaled SABA Oral systemic corticosteroids; some symptoms last 1–2 days after treatment is begun Severe Dyspnea at rest; interferes with conversation PEF <40 percent predicted or personal best Usually requires ED visit and likely hospitalization Partial relief from frequent inhaled SABA PO systemic corticosteroids; some symptoms last >3 days after treatment is begun Adjunctive therapies are helpful Subset: Life threatening Too dyspneic to speak; perspiring PEF <25 percent predicted or personal best Requires ED/hospitalization; possible ICU Minimal or no relief w/ frequent inhaled SABA Intravenous corticosteroids P.375

Managing Asthma Exacerbations at Home

What the EPR -3 Does NOT Recommend Drinking large volumes of liquids or breathing warm, moist air (e.g., the mist from a hot shower) Using over-the-counter products such as antihistamines or cold remedies Although pursed-lip and other forms of controlled breathing may help to maintain calm during respiratory distress, these methods do not bring about improvement in lung function