Therapeutics

Management of

Asthma

Dr Sura Al Zoubi

PhD,

MClinPharm

Lecture 13

References

• Pharmacotherapy: A Pathophysiologic Approach, 10e. Chapter 26: Asthma

• GLOBAL INITIATIVE FOR ASTHMA, Global Strategy for Asthma Management and Prevention. 2019 update. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf

DEFINITION

• Asthma is a heterogeneous disease, usually

characterized by chronic airway inflammation.

It is defined by the history of respiratory

symptoms such as wheeze, shortness of breath,

chest tightness, and cough that vary over time

and in intensity, together with variable

expiratory airflow limitation

EPIDEMIOLOGY

• An estimated 25.7 million persons in the United States have asthma (about 8.4% of the population).

• Asthma is the most common chronic disease among children in the United States

• It is a leading cause of preventable hospitalization in the United States

ETIOLOGY

• Epidemiologic studies strongly support the concept of a genetic predisposition plus environmental interaction to the development of asthma, yet the picture remains complex and incomplete

• Environmental risk factors for the development of asthma include socioeconomic status, family size, exposure to second hand tobacco smoke in infancy and in utero, allergen exposure, ambient air pollution, urbanization, viral respiratory infections including respiratory syncytial virus (RSV) and rhinovirus, and decreased exposure to common childhood infectious agents

PATHOPHYSIOLOGY

• Major characteristics of asthma include a variable degree of airflow obstruction (related to bronchospasm, edema, and mucous hypersecretion), BHR, and airway inflammation

Acute Inflammation • Inhaled allergen challenge models contribute most to our understanding

of acute inflammation in asthma.

• Inhaled allergen challenge in allergic patients leads to an early phase reaction that, in some cases, may be followed by a late-phase reaction.

• The activation of cells bearing allergen-specific immunoglobulin E (IgE) initiates the early phase reaction.

• It is characterized by the rapid activation of airway mast cells and macrophages leading to the rapid release of pro-inflammatory mediators such as histamine, eicosanoids, and reactive oxygen (O2) species that induce contraction of airway smooth muscle, mucous secretion, and vasodilation

• The late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation and involves the recruitment and activation of eosinophils, CD4+ thymically derived lymphocytes (T cells), basophils, neutrophils, and macrophages

Chronic Inflammation

• In asthma, all cells of the airways are involved and become activated.

• Included are eosinophils, neutrophils, T cells, mast cells, alveolar macrophages and dendritic cells, epithelial cells, fibroblasts, and bronchial smooth muscle cells.

• These cells also regulate airway inflammation and initiate the process of remodeling by the release of cytokines and growth factors

CLINICAL PRESENTATION

• Chronic Ambulatory Asthma

• General

• Asthma is a disease of exacerbation and remission, so the patient may not have any signs or symptoms at the time of examination.

• Symptoms

• The patient may complain of episodes of shortness of breath, chest tightness, coughing (particularly at night), wheezing, or a whistling sound when breathing.

• These often occur in association with exercise, but also occur spontaneously or in association with known allergens.

• Signs

• Expiratory wheezing (rhonchi) on auscultation, dry hacking cough, or signs of atopy (allergic rhinitis and/or atopic dermatitis) may occur.

CLINICAL PRESENTATION

• Laboratory

• Spirometry demonstrates obstruction (reduced FEV1/forced vital capacity [FVC]) with reversibility following inhaled β2-agonist administration (FEV1 increases by more than 12% and 200 mL).

• The FEV1/FVC ratio is normally more than 0.75 to 0.80 in adults, and more than 0.90 in children.

• Other Diagnostic Tests

• Excessive variability in twice daily peak expiratory flow (PEF) over 2 weeks (greater than 10% in adults and greater than 13% in children).

• A fall in FEV1 of at least 10% following 6 minutes of near maximal exercise.

• Elevated eosinophil count and IgE concentration in blood.

• Elevated FeNO (greater than 20 ppb in children younger than 12 years of age and greater than 25 ppb in adults).

• Positive methacholine challenge (PC20 FEV1 less than 12.5 mg/mL) or mannitol challenge (FEV1 decrease of at least 15% from baseline after 635 mg or less).

CLINICAL PRESENTATION

• Acute Severe Asthma

• General

• An episode can progress over several days or hours (usual scenario) or progresses rapidly over 1 to 2 hours.

• Symptoms

• The patient is anxious in acute distress and complains of severe dyspnea, shortness of breath, chest tightness, or burning.

• The patient is only able to say a few words with each breath.

• Symptoms are unresponsive to usual measures (short-acting inhaled β2-agonist administration).

• Signs

• Signs include expiratory and inspiratory wheezing on auscultation (breath sounds may be diminished with very severe obstruction), dry hacking cough, tachypnea, tachycardia, pale or cyanotic skin, hyper-inflated chest with intercostal and supraclavicular retractions, and hypoxic seizures if very severe.

CLINICAL PRESENTATION

• Laboratory

• Peak expiratory flow and/or FEV1 less than 40% of normal predicted values.

• Decreased arterial O2 (PaO2), and O2 saturations by pulse oximetry (SaO2 less than 90% [0.90] on room air is severe).

• Decreased arterial or capillary CO2 if mild, but in the normal range or increased in moderate to severe obstruction.

• Other Diagnostic Tests

• Blood gases to assess metabolic acidosis (lactic acidosis) in severe obstruction.

• Complete blood count if there are signs of infection (fever and purulent sputum).

• Serum electrolytes as therapy with β2-agonist and corticosteroids can lower serum potassium, magnesium, and phosphate, and increase glucose.

• Chest radiograph if signs of consolidation on auscultation.

Nocturnal Asthma

• Worsening of asthma during sleep is referred to as nocturnal asthma.

• Patients with nocturnal asthma exhibit significant falls in pulmonary function between bedtime and awakening.

• Typically, their lung function reaches a nadir at 3 to 4 am.

• Although the pathogenesis of this phenomenon is unknown, it has been associated with diurnal patterns of endogenous cortisol secretion and circulating epinephrine.

• Direct evidence for an inflammatory component to nocturnal asthma includes increased circulating histamine and activated eosinophils and LT excretion at night associated with increased BHR to methacholine

FACTORS CONTRIBUTING TO

ASTHMA SEVERITY

1. Viral Respiratory Infections

2. Environmental and Occupational Factors

3. Stress, Depression, and Psychosocial Factors

4. Chronic Rhinosinusitis

5. Gastroesophageal Reflux Disease

6. Female Hormones

7. Food, Drugs and Vitamins

8. Obesity

9. Smoking History

Diagnosis

Management of Asthma

• General principles

• The long term goals of asthma management are risk reduction and symptoms control

• The aim is to reduce the burden to the patient and to reduce their risk of

1. Asthma related death,

2. Exacerbations,

3. Airway damage, and

4. Medication side-effects.

Non-pharmacological strategies and

interventions

• Smoking cessation advice

• Physical activity

• Occupational asthma; identify and remove

occupational sensitizers as soon as possible

• NSAIDs including aspirin

Pharmacological strategies

Starting asthma treatment

• For the best outcomes, ICS-containing treatment should be inhaled as soon as possible after the diagnosis of asthma is made because;

1. Patients with even mild asthma can have severe exacerbations

2. Low dose ICS markedly reduces asthma hospitalisation and death

3. Low dose ICS is very effective in preventing severe exacerbations, reducing symptoms, improving lung function and preventing exercise induced bronchoconstriction, even in patients with mild asthma

Starting asthma treatment

4. Early treatment with low dose ICS leads to better lung function than if symptoms have been present for more than 2-4 years

5. Patients not taking ICS who experience a severe exacerbation have lower long-term lung function than those who have started ICS

6. In occupational asthma, early removal from exposure and early treatment increase the probability of recovery

• For most asthma patients, controller treatment can be started with either as-needed low dose ICS-formoterol (or, if not available, low dose ICS whenever SABA is taken) or with regular daily low dose ICS

• Consider starting at a higher step (e.g. medium/high dose ICS, or low-dose ICS-LABA) if on most days the patient has troublesome asthma symptoms; or waking from asthma once or more a week)

• If initial asthma presentation is with severely uncontrolled asthma, or with acute exacerbation, give a short course of OCS and start regular controller treatment (e.g. medium dose ICS-LABA)

• Consider stepping down after asthma has been well controlled for 3 months. However, in adults and adolescents, ICS should not be completely stopped.

Starting asthma treatment

Why are there concerns about

SABA-only treatment?

• Many guidelines recommend that patients with mild asthma should be treated with as-needed SABA reliever alone. This dates back more than 50 years, to when asthma was thought of primarily as a disease of bronchoconstriction. However, airway inflammation is found in most patients with asthma, even in those with intermittent or infrequent symptoms.

• Although SABA provides quick relief of symptoms, SABA-only treatment is associated with increased risk of exacerbations and lower lung function. Regular use increases allergic responses and airway inflammation. Over-use of SABA (e.g. >= 3 canisters dispensed in a year) is associated with an increased risk of severe exacerbation, and dispensing of >= 12 canisters in a year is associated with increased risk of asthma related death.

STEPWISE APPROACH FOR

ADJUSTING TREATEMENT FOR

INDIVIDUAT PATIENT NEEDS

• There are preferred controller treatments at each step for adults and adolescents.

• However, at each step, other controller options are also available, that are not as effective as the ‘preferred controller’, but that may be considered for patients with particular risk factors or if the preferred controller is not available.

• For patients whose asthma is not well-controlled on a particular treatment, adherence, inhaler technique and comorbidities should be checked before considering a different medication in the same step, or before stepping up.

STEP 1

• Preferred controller: As-needed low dose ICS-formoterol

• Step 1 recommendations are for patients with symptoms less than twice a month and no exacerbation risk factors

• Other controller options: Low dose ICS taken whenever SABA is taken.

STEP 2

• Preferred controllers: Daily low dose ICS plus as needed SABA, OR as-needed low dose ICS-formoterol

• Daily low dose ICS plus as needed SABA: The most important consideration was reducing the risk of severe exacerbation

• As-needed low dose ICS-formoterol: the most important consideration were to prevent severe exacerbation and to avoid the need for daily ICS in patients with mild asthma

STEP 2

• Other controller options:

1. Low dose ICS taken whenever SABA is taken

2. Leukotriene receptor antagonists (LTRA): less effective than regular ICS particularly for preventing exacerbation

3. Daily low dose ICS-LABA as initial therapy: this leads to faster improvement in symptoms and FEV1 than ICS alone but is more costly and the exacerbation rate is similar

STEP 3

• Preferred controllers: Low dose ICS-LABA plus as-needed SABA, OR low dose ICS-formoterol maintenance and reliever therapy

• Other controller options:

1. Medium dose ICS

2. Low dose ICS plus LTRA

3. Add-on sublingual immunotherapy (SLIT), for adult patients with rhinitis provided FEV1 is >70% predicted

STEP 4

• Preferred controllers: Low dose ICS-formoterol as maintenance and reliever therapy, OR medium dose ICS-LABA maintenance plus as-needed SABA

• Other controller options:

1. Add-on tiotropium for patients >= 6 years with history of exacerbations

2. Add-on LTRA

3. Increase to high dose ICS-LABA: consider the potential increase in ICS side effects

4. Add-on sublingual immunotherapy (SLIT), for adult patients with rhinitis provided FEV1 is >70% predicted

STEP 5 • Refer for phenotypic investigation +/- add-on treatment

• Add-on treatments include;

1. Tiotropium: patients >= 6 years with a history of exacerbations

2. Anti-IgE (omalizumab): for severe allergic asthma and patients >= 6 years

3. Anti-IL5 (mepolizumab): for severe eosinophilic asthma and patients >= 6 years

4. Anti-ILR (benralizumab): patients >= 12 years

5. Anti-IL4R (dupilumab): patients >= 12 years

• Other controller options:

1. Low dose OCS but long-term systemic side effects are common and burdensome

How is asthma severity assessed

• Currently, asthma severity is assessed retrospectively from the level of treatment required to control symptoms and exacerbations.

• Mild asthma is asthma that can be controlled with Step 1 or 2 treatment.

• Severe asthma is asthma that requires Step 5 treatment. It may appear similar to asthma that is uncontrolled due to lack of treatment.

Reviewing response and adjusting

treatment

• Patient should preferably be seen 1-3 months

after starting treatment and every 3-12 month

after that (every 4-6 weeks during pregnancy).

• After exacerbation, a review visit within 1 week

should be scheduled.

• Every patient should be trained in essential skills and guided asthma self-management, including;

1. Asthma information

2. Inhaler skills

3. Adherence

4. Written asthma action plan

5. Self-monitoring of symptoms and/or peak flow

6. Regular medical review

• The patient response should be evaluated whenever treatment is changed.

• Assess symptom control, exacerbations, side effects, lung function and patient satisfaction

Stepping up

• Periodic adjustment of controller treatment by clinician and/or patient may be needed.

• Sustained step up (for at least 2-3 months): if symptoms and/or exacerbation persist despite 2-3 month of controller treatment.

• Short-term step-up (for 1-2 weeks): during viral infection or allergen exposure

• Day to day adjustment by patient for prescribed as-needed low dose ICS-formoterol for mild asthma, or low dose ICS-formoterol as maintenance and reliever therapy

Stepping down

• Consider stepping down treatment once good

control has been achieved and maintained for 3

months, to find the lowest treatment that

control both symptoms and exacerbations, and

minimizes side-effects.

Identifying patients at risk of

asthma-related death

• Patients with features indicating increased risk of asthma-related death should be flagged for more frequent review.

• These features include:

1. History: of near-fatal asthma (ever) requiring intubation and ventilation; hospitalization or emergency care for asthma in the last year

2. Medications: not currently using ICS, or with poor adherence with ICS; currently using or recently stopped OCS, over-use of SABA especially more than 1 canister/month

3. Comorbidities: history of psychiatric disease or psychological problems; confirmed food allergy in patients with asthma

4. Lack of a written asthma action plan

Written asthma action plan

• All patients should be provided with a written action plan appropriate for their level of asthma control and health literacy, so they know how to recognise and respond to worsening asthma.

• The written asthma action plan should include:

1. The patient’s usual asthma medications

2. When and how to increase medication, and start OCS

3. How to access medical care if symptoms fail to respond

ASTHMA FLARE-UPS

(EXACERBATIONS)

• A flare-up or exacerbations is an acute or sub-

acute worsening in symptoms and lung

function from the patient’s usual status;

occasionally it may be the initial presentation

of asthma

Managing exacerbations in primary

or acute care

• Assess exacerbation severity while starting SABA and oxygen. Assess;

1. dyspnoea (e.g. is the patient able to speak sentences or only words),

2. respiratory rate,

3. pulse rate,

4. oxygen saturation and

5. lung function.

• Check for anaphylaxis.

• Consider alternative causes of acute breathlessness (e.g. heart failure, upper airway dysfunction, inhaled foreign body or pulmonary embolism)

Managing exacerbations in primary or acute

care

• Arrange immediate transfer to;

1. Acute care facility if there are signs of severe exacerbation,

2. Intensive care if the patient is drowsy, confused, or has a silent chest.

• For these patients, immediately give;

1. Inhaled SABA (repeated doses),

2. Inhaled ipratropium bromide,

3. Oxygen

4. Systemic corticosteroids.

• Check response of symptoms and saturation frequently, and measure lung

function after 1 hour.

• Titrate oxygen to maintain saturation of 93-95% in adults and adolescents

• For severe exacerbations, add ipratropium

bromide, and consider giving SABA by

nebulizer.

• In case of acute care facilities, intravenous

magnesium sulfate may be considered for

inadequate response to intensive initial

treatment

Reviewing response

• Monitor patient closely and frequently during treatment, and titrate treatment according to response.

• Transfer to higher level care if worsening of failing to respond.

• Decide on need for hospitalization based on clinical status, symptoms and lung function, response to treatment, recent and past history of exacerbation, and ability to manage at home

• Before discharge, arrange ongoing treatment. For most patients, prescribe regular controller therapy (or increase current dose) to reduce the risk of further exacerbations.

• Continue increased controller doses for 2-4 weeks, and reduce reliever to as needed dosing.

• Check inhaler technique and adherence.

• Provide an interim written asthma action plan

• Arrange early follow-up after any exacerbation within 2-7 days

Follow-up after exacerbation

• Exacerbation often represent failures in

chronic asthma care, and they provide

opportunities to review the patient’s asthma

management.

• All patients must followed up regularly by

health care provider until symptoms and lung

function return to normal.

Monitoring

• A complete blood count may be appropriate for patients with fever or purulent sputum

• Serum electrolytes should be monitored in patients who take diuretics regularly and in patients with coexistent cardiovascular disease as short-acting inhaled β2-agonists can produce transient decreases in potassium, magnesium, and phosphate

• The combination of high-dose β2-agonists and systemic corticosteroids occasionally may result in excessive elevations of glucose and lactic acid

β2-Agonists

• Short-acting β2-agonists are the most effective bronchodilators.

• Aerosol administration enhances bronchoselectivity and provides more rapid response and greater protection against provocations (eg, exercise, allergen challenges) than systemic administration.

• In adults, administration as either continuous or intermittent (every 20 minutes for 3 doses) administration over 1 hour results in equivalent improvement.

• In acute severe asthma, continuous nebulization of short-acting β2-agonists (eg, albuterol) is recommended for patients having unsatisfactory response after three doses (every 20 min) of aerosolized β2-agonists and potentially for patients presenting initially with PEF or FEV1 values less than 30% of predicted normal.

• Albuterol and other inhaled short-acting selective β2-agonists are indicated for intermittent episodes of bronchospasm

• Two long-acting β2-agonists LABA, formoterol and salmeterol, provide bronchodilation for at least 12 hours.

• Three ultra-LABA (indacaterol, olodaterol, and vilanterol) have a 24-hour bronchodilator duration of effect.

• Vilanterol in combination with fluticasone furoate is available for once-daily dosing for asthma in adults aged 18 and older in the United States and for children and adults aged 12 and older in Europe.

• Products containing indacaterol and olodaterol are currently only indicated for COPD but are being evaluated for asthma.

Corticosteroids

• Inhaled corticosteroids (ICS) are the preferred long-term control therapy for asthma because of potency and consistent effectiveness; they are the only therapy shown to reduce risk of dying from asthma.

• Most patients with moderate disease can be controlled with twice-daily dosing; some products have once-daily dosing indications. Patients with more severe disease require multiple daily dosing.

• Because inflammation inhibits steroid receptor binding, patients should be started on higher and more frequent doses and then tapered down once control has been achieved.

• Response to inhaled corticosteroids is delayed; symptoms improve in most patients within the first 1 to 2 weeks and reach maximum improvement in 4 to 8 weeks.

• Maximum improvement in FEV1 and PEF rates may require 3 to 6 weeks.

• Systemic toxicity of inhaled corticosteroids is minimal with low to moderate doses, but risk of systemic effects increases with high doses. Local adverse effects include dose-dependent oropharyngeal candidiasis and dysphonia, which can be reduced by using a spacer device.

• Systemic corticosteroids are indicated in all patients with acute severe asthma not responding completely to initial inhaled β2-agonist administration (every 20 min for 3 or 4 doses) and should be administered within one hour of presentation.

• IV therapy offers no advantage over oral administration except in patients unable to take oral medications. Adults are treated effectively with a 5 to 7 day course of prednisone (or equivalent)

• Full doses should be continued until the PEF reaches 70% of predicted normal or personal best. Tapering the dose after discharge is unnecessary if patients are prescribed an ICS for outpatient therapy.

• In patients who require chronic systemic corticosteroids for asthma control, the lowest possible dose should be used. Toxicities may be decreased by alternate-day therapy or high-dose inhaled corticosteroids.

Methylxanthines • Theophylline appears to produce bronchodilation through nonselective

phosphodiesterase inhibition. Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV).

• Sustained-release theophylline is the preferred oral preparation, whereas its complex with ethylenediamine (aminophylline) is the preferred parenteral product due to increased solubility. IV theophylline is also available.

• Theophylline is eliminated primarily by metabolism via hepatic CYP P450 enzymes (primarily CYP1A2 and CYP3A4) with 10% or less excreted unchanged in urine. CYP P450 enzymes are susceptible to induction and inhibition by environmental factors and drugs. Significant reductions in clearance can result from cotherapy with cimetidine, erythromycin, clarithromycin, allopurinol, propranolol, ciprofloxacin, interferon, ticlopidine, zileuton, and other drugs. Some substances that enhance clearance are rifampin, carbamazepine, phenobarbital, phenytoin, charcoal-broiled meat, and cigarette smoking.

• Because of large interpatient variability in theophylline clearance, routine monitoring of serum theophylline concentrations is essential for safe and effective use. A steady-state range of 5 to 15 mcg/mL (27.75–83.25 μmol/L) is effective and safe for most patients.

Methylxanthines • Sustained-release oral preparations are preferred for outpatients,

but each product has different release characteristics. Preparations unaffected by food that can be administered every 12 or 24 hours are preferable.

• Adverse effects include nausea, vomiting, tachycardia, jitteriness, and difficulty sleeping; more severe toxicities include cardiac tachyarrhythmias and seizures.

• Sustained-release theophylline is less effective than inhaled corticosteroids and no more effective than oral sustained-release β2-agonists, cromolyn, or leukotriene antagonists.

• Addition of theophylline to optimal inhaled corticosteroids is similar to doubling the dose of the inhaled corticosteroid and is less effective overall than long-acting β2-agonists as adjunctive therapy.

Anticholinergics • Ipratropium bromide and tiotropium bromide produce bronchodilation only

in cholinergic-mediated bronchoconstriction. Anticholinergics are effective bronchodilators but are not as effective as β2-agonists. They attenuate but do not block allergen- or exercise-induced asthma in a dose-dependent fashion.

• Time to reach maximum bronchodilation from aerosolized ipratropium is longer than from aerosolized short-acting β2-agonists (30–60 min vs 5–10 min). However, some bronchodilation is seen within 30 seconds, and 50% of maximum response occurs within 3 minutes.

• Ipratropium bromide has a duration of action of 4 to 8 hours; tiotropium bromide has a duration of 24 hours.

• In acute exacerbations, inhaled ipratropium bromide produces a further improvement in lung function of 10% to 15% over inhaled β2-agonists alone. When added to initial therapy, ipratropium bromide reduces the hospitalization rate in patients with moderate to severe exacerbations.

• Inhaled ipratropium bromide is only indicated as adjunctive therapy in severe acute asthma not completely responsive to β2-agonists alone.

Magnesium Sulfate

• Magnesium sulfate is a moderately potent bronchodilator, producing relaxation of smooth muscle by blocking calcium ion influx into smooth muscles; it may also have antiinflammatory effects.

• For patients with severe asthma exacerbations, a single 2-gram IV infusion may reduce hospital admissions in adults who have an FEV1 <25% to 30% predicted upon arrival in the emergency department, children and adults who have persistent hypoxemia after standard treatment, and children whose FEV1 remains below 60% predicted after 1 hour of standard treatment.

• Adverse effects include hypotension, facial flushing, sweating, depressed deep tendon reflexes, hypothermia, and CNS and respiratory depression.

Leukotriene Modifiers • Zafirlukast (Accolate) and montelukast (Singulair) are oral leukotriene receptor

antagonists that reduce the proinflammatory (increased microvascular permeability and airway edema) and bronchoconstriction effects of leukotriene D4. They improve pulmonary function tests, decrease nocturnal awakenings and β2-agonist use, and improve symptoms. However, they are less effective than low-dose inhaled corticosteroids.

• They are not used to treat acute exacerbations and must be taken on a regular basis, even during symptom-free periods.

• Adult zafirlukast dose is 20 mg twice daily, taken at least 1 hour before or 2 hours after meals. Montelukast adult dose is 10 mg once daily, taken in the evening without regard to food.

• Rare elevations in serum aminotransferase concentrations and clinical hepatitis have been reported. An idiosyncratic syndrome similar to the Churg–Strauss syndrome, with marked circulating eosinophilia, heart failure, and associated eosinophilic vasculitis, has been reported rarely; a direct causal association has not been established.

• Zileuton (Zyflo) is a 5-lipoxygenase inhibitor; use is limited due to potential for elevated hepatic enzymes, especially in first 3 months of therapy, and inhibition of metabolism of some drugs metabolized by CYP3A4 (eg, theophylline and warfarin). Dose of zileuton tablets is 600 mg four times daily with meals and at bedtime. Dose of zileuton extended-release tablets is two 600-mg tablets twice daily, within 1 hour after morning and evening meals (total daily dose 2400 mg).

Omalizumab

• Omalizumab (Xolair) is an anti-IgE antibody approved for treatment of allergic asthma not well controlled by oral or inhaled corticosteroids. Dosage is determined by baseline total serum IgE (international units/mL) and body weight (kg). Doses range from 150 to 375 mg subcutaneously at either 2- or 4-week intervals.

• Because of high cost, omalizumab is only indicated as step 5 or 6 care for patients with allergies and severe persistent asthma inadequately controlled with combination of high-dose inhaled corticosteroids and long-acting β2-agonists and at risk for severe exacerbations.

• Because of 0.2% incidence of anaphylaxis, observe patients for a reasonable period after injection because 70% of reactions occur within 2 hours. Some reactions have occurred up to 24 hours after injection.

Thank You