UNIVERSAL ACTIVITY NUMBER (UAN): H04-P. 1.5 Contact Hours 0.15 CEUs expiration date: 12/12/2015

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1 Asthma Maintenance Whitney Hanks, Pharm.D. Candidate 2012 Stephen Jamison, Pharm.D. Candidate 2012 Brett Parrish, Pharm.D. Candidate 2012 Bernie R. Olin, Pharm.D., Associate Clinical Professor and Director Drug Information Center Harrison School of Pharmacy Auburn University UNIVERSAL ACTIVITY NUMBER (UAN): H04-P 1.5 Contact Hours 0.15 CEUs expiration date: 12/12/2015 Alabama Pharmacy Association

2 Asthma Maintenance Pharmacist learning objectives: Describe how and why asthma affects patients of different gender, ethnicity, and age. Explain the different environmental risk factors that affect the development of asthma. Discuss spirometry and its role in diagnosing asthma. Identify the two main goals of asthma therapy. Identify the most effective long term asthma control medications. Introduction Asthma is an intricate disorder characterized by variable and recurring symptoms, airflow obstruction, bronchial hyper-responsiveness, and underlying inflammation. The interaction of these characteristics can determine the clinical symptoms, the severity of asthma, and the patient s response to treatment. 1 An estimated 20.5 million persons in the United States have asthma, about 7% of the population. In addition, asthma is the most common chronic disease among children in the United States, with approximately 6.5 million children affected. The incidence rate is highest in children 5 17 years of age. 2,3 Over time the occurrence of asthma worldwide steadily continues to increase. Asthma accounts for 1.6% of all ambulatory care visits, results in more than 497,000 hospitalizations and 1.8 million emergency department visits per year. Asthma is the third leading reason of preventable hospitalization in the United States, and children younger than 15 years of age have the highest rate of hospitalization at 31 per 10,000 population. In young children, aged 0 to 10 years of age, the risk of asthma is greater in boys than in girls, the risk becomes about equal during puberty, and then is greater in women than in men. 2,3 Ethnic minorities continue to share the burden of asthma disproportionately. African Americans have a higher prevalence than whites, but this appears to be a result of urbanization and not race or socioeconomic status. African Americans are three times as likely to be hospitalized and approximately 2.5 times more likely to die from asthma. In addition, African Americans and Puerto Ricans living in inner cities are four times more likely to experience emergency department visits than whites. These patterns are likely a result of poor access to health care. 2 Etiology Asthma is a partially inherited, complex disease that requires a gene-by-environment interaction for its development. Epidemiologic studies strongly support the concept of a genetic predisposition to the development of asthma, yet the understanding remains multi-part and incomplete. Genetic factors are thought to account for 35% to 70% of the vulnerability. As a result, genetic predisposition to atopy (genetically determined state of hypersensitivity to environmental allergens) is a significant risk factor for developing asthma although not all atopic individuals develop asthma nor do all asthmatics exhibit atopy. 1,2 Environmental risk factors for the development of asthma include socioeconomic status, family size, exposure to secondhand tobacco smoke at infancy, allergen exposure, urbanization, and decreased exposure to common childhood infectious agents. The hygiene hypothesis proposes that genetically susceptible individuals develop allergies and asthma by allowing the allergic immunologic system (T-helper cell type 2 lymphocytes) to develop instead of the immunologic system used to fight infections (T-helper cell type 1 lymphocytes), and is being used to explain the increase of asthma in Western countries. 2 The first 2 years of life appear to be most important for the exposures to produce an alteration in the immune response system. Support for the hygiene hypothesis for asthma comes from studies demonstrating a lower risk for asthma in children who live on farms and are exposed to high levels of bacteria, in those with a large number of siblings, in those with early enrollment into child care, in those with exposure to cats and dogs early in life, or in those with exposure to fewer antibiotics. Risk factors for early (<3 years of age) recurrent wheezing associated with viral infections include low birth weight, male gender, and parental smoking. However, this early pattern is a result of smaller airways, and these risk factors are not necessarily risk factors for asthma in later life. Atopy is the predominant risk factor for children to have continued asthma. 2 Occupational asthma in previously healthy individuals depicts the effect of environment on the development of asthma. Although, a variety of triggers can have different degrees of importance from patient to patient. Environmental exposures are the most important precipitants of severe asthma exacerbations. Epidemics of severe asthma in cities have followed exposures to high concentrations of aeroallergens. Viral respiratory tract infections remain the single most significant precipitant of severe asthma in children, and are an important trigger in adults as well. Other possible factors include air pollution, sinusitis, food preservatives, and drugs. 1 Pathophysiology Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements 1 Asthma Maintenance Alabama Pharmacy Association

3 play a role. The elements normally involved consist of mast cells, eosinophils, neutrophils, T lymphocytes, macrophages, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of coughing, wheezing, breathlessness, and chest tightness. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. 1 Airflow limitation is caused by a variety of changes in the airway, but all changes are influenced by airway inflammation. Bronchoconstriction entails bronchial smooth muscle contraction that quickly narrows the airways in response to exposure to a variety of stimuli, including allergens or irritants. Airway hyper-responsiveness is an exaggerated bronchoconstrictor response to stimuli. Last, airway edema can develop as the disease becomes more persistent and inflammation becomes more progressive. Edema, mucus hypersecretion, and formation of mucus can further decrease and limit airflow. This can lead to remodeling of the airways. Reversibility of airflow limitation may be incomplete in some patients. Persistent changes in airway structure can occur including sub-basement fibrosis, mucus hypersecretion, injury to epithelial cells, smooth muscle hypertrophy, and formation of new blood vessels. 2 Diagnosis To establish a diagnosis of asthma, the clinician needs to determine that the patient s symptoms are of recurrent episodes of airflow obstruction or airway hyper-responsiveness. As well, other diagnoses need to be excluded. Airflow obstruction is thought to be at least partially reversible, measured by spirometry. Reversibility is determined by an increase in forced expiratory volume (FEV 1) of >200 ml and 12% from baseline measure after inhalation of a short-acting beta2- agonist (SABA). Some studies indicate that an increase of 10 percent of the predicted FEV 1 after inhalation of a SABA may have higher likelihood of separating patients who have asthma from those who have chronic obstructive pulmonary disease (COPD). 1 The recommended methods to establish the diagnosis are detailed medical history and physical examination. Physical exam may reveal findings that increase the probability of asthma, but the absence of these findings does not rule out asthma, because the disease is variable and signs may be absent between episodes. The examination focuses on the upper respiratory tract, the chest, and the skin. They look at the upper respiratory tract for increased nasal secretion, mucosal swelling, or nasal polyps. The exam of the chest cavity includes sounds of wheezing during normal breathing or prolonged phase of forced exhalation, hyper- expansion of the thorax, use of accessory muscles, appearance of hunched shoulders, or chest deformity. Finally, the skin is evaluated for atopic dermatitis and eczema. 1 Spirometry can demonstrate obstruction and assess reversibility in patients 5 years of age. Spirometry is an essential objective measure to establish the diagnosis of asthma because the medical history and physical examination are not reliable means of excluding other diagnoses or of assessing lung status. Spirometry is the most widely available and useful pulmonary function test. It provides information about the obstructive aspect of asthma, and allows for measurement of all lung volumes and capacities except residual volume, functional residual capacity, and total lung capacity. Spirometry is generally recommended, rather than measurements by a peak flow meter, due to wide variability in peak flow meters and reference values. Peak flow meters are an inexpensive way to measure a patient s peak expiratory flow, also known as the maximum forced expiratory flow. This is the maximum flow obtained during the forced vital capacity. Peak flow meters are more used for monitoring and not as diagnostic tools. 2 Goals of therapy The main two goals of asthma therapy are to reduce a patient s impairment and reduce the patient s risk of worsening asthma. The objectives that make up reducing impairment are to prevent chronic problems, reducing the need for SABAs for quick relief of symptoms, maintain normal pulmonary function, maintain normal daily activity for patients, and to meet the patients desires with satisfaction of care. The main points of reducing risk for asthma progression are to avoid recurrent exacerbations of asthma and minimize the need for emergency room visits or hospitalization, to prevent loss of lung function, and to provide optimal drug therapy with minimal or no adverse events. 1 Guidelines: Therapy Selection At the diagnosis of asthma, severity is assessed and therapy initiated. During follow up visits, asthma control is assessed and therapy adjusted. These assessments and therapy recommendations may be found in charts from the National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma from the National Heart, Lung and Blood Institute. These charts are based on patient age. It is also important to note that the charts for initially assessing severity differ from the charts used to assess control at follow up. 1 2 Asthma Maintenance Alabama Pharmacy Association

4 Initial Visit: Severity Classification At the initial visit, severity is assessed by measuring components of severity and of risk for exacerbations on the Classifying Asthma Severity and Initiating treatment charts. Symptoms, nighttime awakenings, SABA use, interference with normal activity, and risk for exacerbation based on past history make up this assessment. The patient is assigned a category of severity (intermittent, mild persistent, moderate persistent, or severe persistent) based on the worst component of severity and therapy is initiated based on this category. Initiation of therapy: After a patient s severity is classified on the initial visit, therapy is initiated. A recommendation is made for therapy initiation depending on the patient s severity. The Stepwise Approach for Managing Asthma is used to determine therapy. Each step contains therapy recommendations that are made with both preferred and alternative treatments. General stepwise recommendations follow (Table 1). It is important to note that the stepwise charts are dependent on patient age and that any therapy initiation should feature a SABA to be used as needed. For example, a patient with mild persistent asthma should be initiated at Step 2, which includes a low dose inhaled corticosteroid (ICS) with an as-needed SABA. Alternative regimens include cromolyn or montelukast with an as-needed SABA. Table 1: General Recommendations for Stepwise Therapy 1 Step 1 PRN SABA Step 2 Low dose ICS Step 3 Medium dose ICS Step 4 Medium dose ICS plus LABA/LTRA Step 5 High dose ICS plus LABA/LTRA Step 6 High dose ICS plus LABA/LTRA plus oral corticosteroid SABA Short-acting beta agonists ICS Inhaled corticosteroids LTRA Leukotriene receptor antagonists Follow up visits: Assessing Control Asthma control is assessed using the Assessing Asthma Control and Adjusting Therapy charts. This chart also measures symptoms, nighttime awakenings, interference with normal activity, SABA use, and risk of exacerbation. The patient is then assigned a level of control based on the worst component of control and therapy is adjusted using the Stepwise Approach chart. A patient who is not well controlled or poorly controlled will require an increased dose of ICS or additional drug therapy. Patients who are well controlled may remain on current therapy or be stepped down. Monitoring Patient monitoring requirements vary depending on the situation. Patients need to be seen by their physician more frequently at the start of therapy and during periods of poor control. Table 2: Monitoring Asthma Patients 1,2 Situation Timing of next follow up Initiation of therapy 2-6 weeks Well Controlled at follow 1-6 months up Well Controlled at 2-6 weeks follow up Very Poorly Controlled at 2 weeks follow up Drug Therapy The most effective long term control medications are drugs that treat chronic inflammation associated with asthma. SABAs and the ICSs are mainstays of asthma therapy. All patients with intermittent and persistent asthma should be prescribed a SABA for as-needed use. For persistent asthma, first line therapy is the ICSs and should be used at the lowest dose that imparts good asthma control. Patients who do not achieve asthma control on low dose ICSs should undergo ICS dose escalation or possibly additional therapy such as the addition of long-acting beta agonists (LABAs), leukotriene antagonists, or theophylline. Patients with documented allergies might be prescribed cromolyn. Omalizumab, an anti-ige antibody, is reserved for patients with documented allergies who do not achieve control despite multiple drug therapies. 1,4 3 Asthma Maintenance Alabama Pharmacy Association

5 Beta-adrenergic agonists The β 2 agonists are the most effective bronchodilators and short-acting β 2 agonists are considered first line treatment for asthma. 1,2 β 2 agonists stimulate β 2 adrenergic receptors in the usually affects duration of bronchodilation, but peak response may be affected as well. Most tolerance develops within a week of regular administration and can be overcome by increasing β-agonist doses or using ICSs instead of LABAs for chronic asthma control. 2 lungs, increasing cyclic adenosine monophosphate (camp) production in smooth muscle cells which decreases unbound intracellular calcium leading to a relaxation of smooth muscle and bronchodilation. Drug therapy for asthma maintenance requires β 2- selective medications, as β 1 agonism results in excessive cardiac stimulation and arrhythmias. There is no use for β 1 agonists in asthma. 5 The β 2-agonists are divided into two categories: SABAs and LABAs. Peak effects of SABA administration is about 30 minutes post-inhalation, whereas the onset of LABAs is slightly longer. The duration of action is approximately 3 to 4 hours for SABAs and 12 hours for LABAs. 6,7 Chronic administration of β 2 agonists leads to decreased response due to downregulation and desensitization of β 2 receptors. 2,5 This tolerance Class Agent Contraindications and Black Box Warnings (BBW) 7 SABAs Albuterol Hypersensitivity Pro-Air LABAs Ventolin Pirbuterol Maxair Levalbuterol Xopenex Terbutaline Formoterol Foradil Salmeterol Serevent Table 3: Beta-adrenergic Agonists Pregnancy Category (P)/Breast Feeding Hypersensitivity, Cardiac arrhythmias, Tachycardia from digitalis intoxication Hypersensitivity BBW: LABAs increase the risk of asthma-related deaths. BBW: LABAs may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Short-Acting Beta-adrenergic agonists: SABAs are indicated for all asthma patients to be used as needed for intermittent bronchospasm. 1 SABAs display varying potencies for β 2 receptors. However, when administered in equipotent doses, all SABAs produce a similar level of response. All SABAs produce a better response when administered by inhalation route as compared to the oral route. 2 Oral administration also increases systemic adverse drug reactions (ADRs) such as tachycardia and nervousness, which occur in up to 5% and 20%, respectively, of patients on oral albuterol as compared to rates of 1% and 4%, respectively, of patients on albuterol by inhalation. 6 SABAs are usually delivered by a metered-dose inhaler (MDI). (BF) 7,10 P: C-- compatible BF: probably compatible P: C probably compatible BF: probably compatible P: C--probably compatible BF: probably compatible P: B low risk per animal data BF: Probably compatible P: C probably compatible BF: probably compatible P: C probably compatible BF: probably compatible 4 Asthma Maintenance Alabama Pharmacy Association Normal Dose 7 MDI: 2 puffs q4-6 hours as needed MDI: 2 inhalations at a 1-3 minute interval, followed by a third inhalation MDI: 2 puffs q4-6 hours Tablet: 5 mg PO q6 hours DPI: Inhale the contents of 1 capsule q12 hours DPI: 1 inhalation BID

6 Long-Acting Beta-adrenergic agonists: LABAs are more lipid soluble than the SABAs, causing them to more readily partition and remain in lung tissue. 2 Adverse drug reactions are similar to those seen with SABAs. 7 Due to the lack of antiinflammatory activity, LABAs should not be used as monotherapy and should only be used in combination with ICS. Patients on LABAs without ICS therapy are at Table 4: Dosing: Inhaled Corticosteroids for Treatment of Asthma 2,12 Inhaled Corticosteroids Daily Low Dose (mcg) Daily Medium Dose (mcg) Daily High Dose (mcg) Beclomethasone Dipropionate HFA MDI Budesonide DPI Budesonide Nebules used in s Ciclesonide Fluticasone propionate HFA MDI Fluticasone propionate DPI Mometasone furoate DPI > > > >540-1,080 1,000 used in s > > >320 >480 >720 >1,080 2,000 used in s >320 >640 >352 >440 >400 >500 >440 >440 an increased risk of life-threatening exacerbations and asthma-related death. 2,8,9 Because LABAs in combination with ICS can provide greater asthma control than simply increasing ICS doses, the addition of a LABA is preferred therapy in step 3 for children aged 12 and older and adults and steps 4 and 5 in children aged 5 to 11. 1,9 The combinations of LABAs with ICS therapy has not been studied for reducing risk of exacerbations in children age 4 to 11 and has not been studied at all in children 0 to 4 years old. 1,5 LABAs are usually delivered by dry powder inhalers (DPI). MDI: Metered Dose Inhalers DPI: Dry Powder Inhalers Inhaled Corticosteroids The inhaled corticosteroids (ICSs) are considered to be the preferred long-term control therapy in children and adults. The ICSs play an antiinflammatory role in asthma by reducing the number of inflammatory mediators in the circulation and airways of patients. Mediators affected include: eosinophils, mast cells, macrophages, and T lymphocytes found in the epithelium and submucosa of the bronchioles. They may also decrease mucous secretion and plasma exudation in airways while also minimizing the potential for narrowing of the airway. These effects are usually seen after 1 to 3 months of therapy, although an improvement in symptoms can be seen in 1 to 2 weeks with maximum improvement in 4 to 8 weeks. Additionally, long-term therapy can lower a patient s sensitivity to cold air, exercise, allergens, and irritants. 11 ICSs should not be used for the relief of acute bronchospasm, the primary treatment of status asthmaticus, or if hypersensitive to any ingredients. Mometasone is contraindicated in patients with hypersensitivity to milk proteins. 11 The most common adverse effects seen in the class were headache, myalgia, coughing, congestion, pharyngitis, rhinitis, upper respiratory tract infections (URTI), and influenza-like syndrome. Flunisolide shows a greater incidence of adverse effects overall, and compared to others in the class. The ICSs have also been shown to decrease bone mineral density, impair growth rates in children, increase rate of oral fungal infections, and may cause hypothalamic-pituitary-adrenal axis (HPA) suppression (HPA suppression with systemic corticosteroids occurs to a greater degree than with ICSs). Instruct patients to rinse their mouths, without swallowing, following use to limit oral fungal infections. Use caution in patients with compromised 5 Asthma Maintenance Alabama Pharmacy Association

7 immune systems, when transferring from systemic corticosteroids, and if combining therapy with systemic corticosteroids due to increased risk of HPA suppression. Flunisolide may have more systemic absorption than other agents in this class and should be monitored for evidence of systemic corticosteroid effects. When discontinuing flunisolide because of systemic effects, discontinue slowly in accordance with accepted procedures associated with the discontinuation of oral corticosteroids. The ICSs are pregnancy category C, except for budesonide which is category B. 11 Combination Products: Since LABAs should not be used as monotherapy for asthma, several formulations are available that combine LABAs with ICSs in a single inhaler, which may benefit patient compliance. 13,14 Table 5: LABA/ICS Combinations Product Dosing 7 Advair Diskus DPI: One inhalation (fluticasone & salmeterol) twice daily, 12 hours Advair HFA (fluticasone & salmeterol) Symbicort (budesonide & formoterol) Dulera (mometasone & formoterol) apart MDI: Two inhalations twice daily, 12 hours apart MDI: Two inhalations twice daily MDI: Two inhalations twice daily Leukotriene Modifiers (Zafirlukast, Montelukast, Zileuton) The leukotriene modifiers are not as effective as LABAs when added to ICSs for moderate persistent asthma and thus, serve as alternatives in mild persistent asthma or as alternative add-on therapy for moderate persistent asthma. 1,2,15 The leukotriene modifiers inhibit the leukotriene associated effects of inflammation in asthma such as: airway edema, smooth muscle constriction, and inflammatory cell activity. Zafirlukast and montelukast are two cysteinyl leukotriene receptor antagonists and have inhibitory activity on leukotrienes LTC 4, LTD 4, and LTE 4. The cysteinyl leukotriene receptor is located in smooth muscle and macrophages found in the airway, and on other inflammatory cells, such as eosinophils. Zileuton inhibits 5-lipoxygenase, which inhibits leukotriene formation, specifically LTB 4, LTC 4, LTD 4, and LTE 4. These leukotrienes play a role in inflammation and the anaphylactic response and include altering the migration of neutrophils and eosinophils, the aggregation of monocytes and neutrophils, increased capillary permeability, the adhesion of leukocytes, and the constriction of smooth muscle contributing to edema, increased mucous secretion, and airway bronchoconstriction in asthma patients. 11 All three class members are contraindicated if hypersensitive to any component of the formulation. Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis. Zileuton is contraindicated in active liver disease, or if transaminase levels are at least 3 times the upper limit of normal (ULN) consistently. 11 The leukotriene modifiers should not be used to treat an acute asthma attack, but they can be continued during acute exacerbations. Neuropsychiatric disturbances such as sleep disorders and behavioral changes have occurred and should be brought to the attention of the prescriber. The common ADRs for the class include: headache, abdominal pain, nausea, pain, and myalgia. The other most common ADRs specific for zafirlukast are: fever, diarrhea, and elevation of alanine aminotransferase enzymes (ALTs). The other most common ADRs specific for montelukast include: URTI, fever, pharyngitis, cough, diarrhea, otitis media, influenza, rhinorrhea, and sinusitis. Phenylketonuric patients should be made aware that the 4 mg and 5 mg chewable tablets contain aspartame. The other most common ADRs for zileuton are elevation of ALTs and dyspepsia. ALTs may become elevated while on zileuton or zafirlukast, so monitor for clinical signs and symptoms of liver dysfunction such as fatigue, jaundice, lethargy, nausea, or right upper quadrant pain. Discontinue zileuton or zafirlukast and monitor transaminase levels until normal if signs and symptoms of liver dysfunction are present, or discontinue zileuton if transaminase levels reach 5 times over the ULN. Caution should be emphasized in patients who consume alcohol or who have a history of liver disease due to zileuton or zafirlukast s effects on hepatic transaminases and the potential for liver injury. Zileuton is pregnancy category C. Zafirlukast and Montelukast are pregnancy category B Asthma Maintenance Alabama Pharmacy Association

8 Table 6: Dosing: Leukotriene Modifiers for Treating Asthma 11 Age Zileuton (Zyflo ) Montelukast (Singulair ) Zafirlukast (Accolate ) s IR: One 600 mg tablet 4 times/day (2,400 mg/day) ER: Two 600 mg tablets twice/day (2,400 mg/day) 10 mg once/day *EIB: 10 mg/day 2 hours before exercise 20 mg twice/day 15 years old 6-14 years old 2-5 years old months old 6-12 months old ( 12 yo) See adult ( 12 yo) See adult 10 mg/day *EIB: 10 mg/day 2 hours before exercise 5 mg/day (chewable) 4 mg/day (chewable tablet or packet of oral granules) 4 mg/day (packet of oral granules) Off Label: 4mg/day at bedtime (chewable tablet or packet of oral granules) ( 12 yo) See adult ( 12 yo) See adult (5-11 yo) 10 mg twice/day *EIB = Exercise induced bronchospasms; montelukast is approved for EIB, but is significantly less effective than short-acting inhaled β 2-agonists Cromolyn: Cromolyn is a mast cell stabilizer and the only drug in its class to be approved for use in asthma. Cromolyn is a direct antagonist at histamine-1 receptors and inhibitor of histamine release from mast cells; it also inhibits neurally mediated bronchoconstriction through stimulation of group-c nerve fibers, but does not cause bronchodilation. 2,7 Cromolyn is only effective in asthma through the inhalation route. ADRs with cromolyn are rare and are reported as: cough, wheezing, sneezing, and nasal congestion. No significant drug interactions have been documented with this drug. 2,7 Cromolyn has a Pregnancy Category B rating. 7 It is compatible with pregnancy and probably compatible with breastfeeding. 10 Cromolyn is no more effective than theophylline or the leukotriene antagonists in asthma, and is less effective than ICSs and β2-agonists and is therefore only appropriate to be used as an alternative in Step 2 treatment for all age groups. 1,2 Cromolyn may be used as a preventative treatment for unavoidable exposure to allergens. 1 Clinical improvement should be expected in 1 to 2 weeks for most patients. Initial dosing is 20 mg by inhalation four times daily, tapered down to 20 mg three times daily or twice daily upon symptom improvement. Unlike the β-agonists, tolerance has not been documented with cromolyn. 2 Methylxanthines: The use of methylxanthines in asthma has declined significantly in recent years due to toxicities, numerous drug interactions, and decreased efficacy compared with ICSs and LABAs. Theophylline is the primary methylxanthine, as other drugs such as aminophylline are converted to theophylline in the body. Theophylline non-selectively inhibits phosphodiesterase enzymes (PDE III and PDE IV), causing an increase in camp and cyclic guanosine monophosphate (cgmp) which results in bronchodilation; the drug also displays mild antiinflammatory properties. 2,16 Theophylline is a pregnancy category C drug which is rated compatible with pregnancy and breastfeeding. 10,16 Theophylline has a narrow therapeutic index which requires vigilant serum monitoring to prevent toxicities. Normal limits of theophylline serum levels range from 5-15 mcg/ml. For serum levels 15 mcg/ml or for the presence of 7 Asthma Maintenance Alabama Pharmacy Association

9 toxicities, dose adjustments may be required. 7 ADRs associated with theophylline overdose range from nausea, jitteriness, vomiting, and difficulty sleeping to cardiac tachyarrhythmias and seizures. Theophylline is eliminated primarily by CYP1A2 and CYP3A3 hepatic enzymes with about 10% of the dose being excreted unchanged in the kidney. Drug and disease interactions exist which may alter the clearance of theophylline and contribute to a lack of efficacy or significant ADRs. Some common interactions include smoking, as well as cytochrome (CYP) inducers such as rifampin, carbamazepine, and phenobarbital that increase the clearance of theophylline. Viral infections, propranolol, macrolide antibiotics, and fluoroquinolone antibiotics decrease clearance of theophylline. 2,16 Theophylline is less effective than ICSs and not more effective than oral β agonists, cromolyn, or leukotriene antagonists; it is more toxic than any of these agents. Adding theophylline to ICSs is less effective than adding LABAs. A 2007 randomized, double blind, placebo-controlled 24 week clinical trial showed the addition of theophylline to patients poorly controlled on combination ICS and LABA therapy does not improve episodes of poor control including decreased peak flow, increased β agonist use, increased oral corticosteroid use, or unscheduled healthcare visits. 17 Due to the toxicities and interactions of theophylline and the efficacy of other drugs in asthma, theophylline is only recommended as an alternative in the guidelines if other therapies are contraindicated. 1 Omalizumab (recombinant anti-ige antibody) Omalizumab (Xolair ) is approved for use in chronic asthma in patients >12 years old not well controlled on oral corticosteroids or ICSs. 11 Omalizumab is a recombinant anti-ige antibody that binds the Fc portion of the IgE antibody which prevents it from binding to its receptor found on mast cells and basophils resulting in a decrease in mediator release provoked by allergens. In 8-12 weeks, omalizumab also decreases the expression of the IgE receptor found on airway submucosal mast cells and basophils. 2,18 Omalizumab therapy is contraindicated in patients with a hypersensitivity to omalizumab. 11 The most common ADRs include injection site reaction, viral infection, upper respiratory tract infections, sinusitis, headaches, pharyngitis, and arthralgias. Some severe ADRs observed were anaphylaxis and malignancies but incidences were rare. Anaphylaxis is a Black Box Warning and patients should be cautioned on the warning signs and symptoms of anaphylaxis as they have been known to occur up to 24 hours after an injection and beyond one year of regular administration. 11 Omalizumab is pregnancy category B. 10 Omalizumab is dosed every 2 or 4 weeks and varies in patients based on their weight and their pretreatment serum IgE levels. It s important to utilize pretreatment levels for dosing because the levels are elevated during treatment and will remain elevated for up to one year after discontinuation of treatment. Therefore, retesting of IgE levels for the purpose of dosage adjustment is not recommended during therapy or up to one year following discontinuation of therapy. 2,11,18 Dosage adjustments are recommended for significant changes in weight during therapy. 7 Counseling Patients should be counseled on medication use and non-pharmacologic approaches. Training for asthma inhalers varies by inhaler and may require some patient individualization. Some patients have difficulty using inhalers and require holding chambers to deliver adequate doses of inhaled drugs. Maintenance therapy such as daily use of ICSs improves control and may reduce the need for SABAs. Avoiding environmental triggers such as known allergens and tobacco smoke may relieve symptoms and minimize medication use. Annual vaccination with inactivated influenza virus is recommended for all asthma patients without contraindications. 2,4 Conclusion Asthma is a complicated disease with a wide variety of clinical presentations. Asthma is defined and characterized by excessive reactivity of the lungs to a wide variety of allergens, airflow limitation, and chronic inflammation. The goal of asthma therapy is to normalize, as much as possible, the patient s life and prevent chronic irreversible lung changes. Drugs are the mainstay of asthma therapy. The goal of drug therapy is to use the minimum amount of medications possible to completely control the disease. In chronic asthma, therapy should be aimed at both bronchospasm and inflammation so as to produce the best results. In patients with intermittent asthma, a SABA can be used when symptoms are present. Next, patients who have mild asthma should be placed on low dose ICS to help control symptoms before they happen and continue use of the SABAs for relief of symptoms. Patients with moderate to severe asthma should be placed on a medium to high dose ICS and a SABA to help control symptoms. For patients who still 8 Asthma Maintenance Alabama Pharmacy Association

10 are not controlled on their medications, LABAs can be added to help prevent the asthma symptoms before they cause a problem. 13 Patients should be followed and monitored thoroughly for evidence of adverse events. A foundation of any therapy and very important in asthma is thorough patient education and the recognition that most asthma deaths are preventable. References: 1. Busse WW, Boushey HA, Camargo CA, Evans D, Foggs MB, Jansen SL, et al. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute.[October 2007, cited Feb ]. Available from: 2. Kelly HW, Sorkness CA. Asthma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill Medical; c.2011 p Beasley R. The global burden of asthma report. In: Global Initiative for Asthma (GINA). Chest 2006;130:4S-12S. 4. Pascual RM, Peters SP. Asthma. Med Clin N Am Nov;95(6): Kelly HW. Risk versus benefit considerations for the beta(2)-agonists. Pharmacotherapy. 2006;26: S. 6. Albuterol Sulfate Inhalation, Oral. In: Drug Facts and Comparisons (Facts and Comparisons eanswers) [AUHSOP Intranet]. St. Louis: Wolters Kluwer Health [updated Jan 2011, cited 2012 Feb 2]. [about 10 p.]. Available from: 7. Albuterol, Levalbuterol, Pirbuterol, Terbutaline, Formoterol, Salmeterol, Cromolyn, Advair, Symbicort, Dulera, Omalizumab, Theophylline. In Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Lexi-Comp, Inc. [updated Dec 2011, cited 2012 Feb 2]. [about 10 p. each] Available from 8. Nelson HS, Weiss ST, Bleecker ER, et al. The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest Jan;129: Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax. 2005;60: Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9 th ed. Philadelphia: Lippincott Williams & Wilkins; c Corticosteroids, Leukotriene Formation Inhibitors, Leukotriene Receptor Antagonists, Omalizumab. In: Drug Facts and Comparisons (Facts and Comparisons eanswers) [AUHSOP Intranet]. St. Louis: Wolters Kluwer Health [updated 2012, cited 2012 Feb 3]. [about 20p.]. Available from: Kelly HW. Comparison of inhaled corticosteroids: An update. Ann Pharmacother. 2009;43: Abramowicz M, ed. Drugs for Asthma. Treatment Guidelines Med Lett Feb;10(114): Fanta CH. Asthma. N Engl J Med Mar 5;360: O Byrne PM, Gauvreau GM, Murphy DM. Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma. J Allergy Clin Immunol. 2009;124: Theophylline. In: Clinical Pharmacology [AUHSOP Intranet]. Tampa, FL: Goldstandard/Elsevier. [updated Feb , cited Feb ]. [about 10 p.] Available from: The American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med. 2007;175: Ledford DK. Omalizumab: Overview of pharmacology and efficacy in asthma. Expert Opin Drug Saf. 2009;8: Asthma Maintenance Alabama Pharmacy Association