VA Class:RE102

AHFS Class:

• Selective beta-2-Adrenergic Agonists 12:12.08.12

Generic Name(s):

• Formoterol Fumarate

Chemical Name:

• (±)-2'-Hydroxy-5'-[( R *)-1-hydroxy-2-[[( R *)- p -methoxy-α-methylphenethyl]amino]ethyl]formanilide fumarate

Molecular Formula:

• C₁₉H₂₄N₂O₄)₂•C₄H₄O₄

Formoterol fumarate, a synthetic sympathomimetic amine, is a relatively selective, long-acting β₂-agonist.1

Bronchospasm

Formoterol fumarate is used alone or in fixed combination with budesonide or glycopyrrolate for long-term maintenance treatment of bronchospasm or airflow obstruction associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.1,51,55 Formoterol fumarate also is used concomitantly with long-term asthma controller therapy, such as inhaled corticosteroids, as a long-acting bronchodilator for the prevention of bronchospasm in patients with reversible obstructive airway disease (e.g., asthma).7,15,16,18,19,51 Monotherapy with long-acting β₂-adrenergic agonists, such as formoterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.1,41,51,54,55 (See Asthma-related Death and Serious Asthma-related Events under Warnings/Precautions: Warnings, in Cautions.) Because of these risks, the use of formoterol alone for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated .1,41 (See Cautions: Contraindications.) The fixed combination of formoterol fumarate and budesonide (formoterol/budesonide; Symbicort^®) and fixed combination of formoterol fumarate and mometasone furoate (formoterol/mometasone; Dulera^®) are used only in patients with asthma who have not responded adequately to long-term asthma controller therapy, such as inhaled corticosteroids, or whose disease severity warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist.51,54 Once asthma control is achieved and maintained, the patient should be assessed at regular intervals and therapy should be stepped down (e.g., discontinuance of formoterol or formoterol in fixed combination with budesonide), if possible without loss of asthma control, and the patient should be maintained on long-term asthma controller therapy, such as inhaled corticosteroids.41,48 Formoterol in fixed combination with budesonide should not be used in patients whose asthma is adequately controlled on a low or medium dosage of inhaled corticosteroids.48

Formoterol fumarate alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate is not indicated for the relief of acute bronchospasm and should not be initiated in patients with rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.1,48,54,55 Use of long-acting β₂-adrenergic agonists with or without inhaled corticosteroids for acute exacerbations of COPD has not been evaluated.35 A short-acting inhaled β₂-adrenergic agonist should be used intermittently (as needed) for acute symptoms of asthma or COPD.18,31,33,34 (See Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease under Warnings/Precautions: Warnings, in Cautions.)

Asthma

Considerations in Initiating Antiasthma Therapy

In the stepped-care approach to antiasthmatic drug therapy, asthma is classified according to severity upon initial presentation (intermittent asthma or mild, moderate, or severe persistent asthma)47 and also by response to treatment (i.e., asthma control).18,47 While classification of asthma severity is useful for determining initial treatment, disease severity may vary over time and with treatment; therefore, after therapy is initiated, periodic assessment of asthma control is emphasized for guiding treatment decisions.18,47 Asthma management guidelines state that initial therapy for asthma should correspond to disease severity, with subsequent monitoring and adjustments in therapy to achieve and maintain control of asthma according to the goals of treatment.18,47 Asthma therapy is aimed at achieving and maintaining control of asthma by reducing ongoing impairment (e.g., prevention of chronic and troublesome symptoms, reducing use of reliever drugs, maintaining normal or near-normal lung function and activity levels) and risk of future events (e.g., exacerbations requiring systemic corticosteroids, treatment-related adverse effects).47 These 2 components of asthma control (i.e., current impairment and future risk) may respond differently to treatment.47

The National Asthma Education and Prevention Program (NAEPP) classifies the levels of asthma control as well controlled, not well controlled, or very poorly controlled.47 In the stepped-care approach, the treatment step selected for asthma control in patients already receiving asthma therapy is based on the patient's current treatment and level of asthma control.18,47 Stepwise therapy is meant to assist, not replace, the clinical decision-making process in selecting therapy for individual patients.47 Once initiated, treatment is adjusted continuously according to changes in asthma control.47 Patients should be monitored every 2-6 weeks following initiation of therapy to ensure that asthma control is achieved.47 If asthma symptoms are not controlled with the current treatment regimen, treatment is stepped up until control is achieved.47 If an alternative treatment was used and produced an inadequate response, the preferred treatment should be used before stepping up to the next level of therapy.47 Regular monitoring at 1- to 6-month intervals, depending on the level of control, is recommended to ensure that control of asthma is maintained and that appropriate adjustments in therapy are made.47 When control has been maintained for at least 3 months, treatment intensity may be stepped down to find the lowest dosage and/or number of drugs required to maintain asthma control, with continued follow-up at 3-month intervals.47

Intermittent Asthma

Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).18,47 A reliever drug such as a selective short-acting inhaled β₂-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol) is recommended on an as-needed basis to control occasional acute symptoms (e.g., cough, wheezing, dyspnea) of short duration; such use of an inhaled short-acting β₂-agonist alone generally is sufficient as initial treatment for newly diagnosed patients whose asthma severity is initially classified as intermittent (e.g., patients with daytime symptoms of asthma not more than twice weekly and nocturnal symptoms not more than twice a month).18,26,27,28,47 Most experts consider short-acting inhaled β₂-adrenergic agonists to be drugs of choice for treating acute asthma symptoms and exacerbations and for preventing exercise-induced bronchospasm.18,47 Alternatives to short-acting inhaled β₂-agonists recommended by some clinicians for relief of acute asthma symptoms include an inhaled anticholinergic agent (e.g., ipratropium), a short-acting oral β₂-agonist, or a short-acting theophylline (provided extended-release theophylline is not already used), but these alternatives have a slower onset of action and/or a higher risk for adverse effects.18 Oral β₂-adrenergic agonist therapy is suggested for use principally in patients unable to use inhaled bronchodilators (e.g., young children).18 Other experts do not recommend oral β₂-agonists for relief of acute asthma symptoms.47 Use of short-acting inhaled β₂-agonists in asymptomatic asthma should be limited to pretreatment prior to exercise and, in intermittent asthma, should be limited to providing relief as symptoms develop; some clinicians state that patients requiring symptomatic relief more than twice weekly or repeatedly over 1 or 2 days should be evaluated for possible initiation of long-term controller therapy.18,47

Mild Persistent Asthma

When control of symptoms deteriorates in mild intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), asthma management guidelines and most clinicians recommend initiation of a controller drug such as an anti-inflammatory agent, preferably a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered dose inhaler in adults and adolescents, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma supplemented by as-needed use of a short-acting, inhaled β₂-agonist.18,26,27,28,47 Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include certain leukotriene modifiers (i.e., montelukast, zafirlukast), extended-release theophylline, or mast-cell stabilizers (i.e., cromolyn, nedocromil [preparations for oral inhalation no longer commercially available in the US]), but these therapies are less effective18,31,47 and generally not preferred as initial therapy.18,31,47 Some experts recommend that long-term control therapy be considered in infants and young children who have identifiable risk factors for asthma and who in the previous year have had 4 or more episodes of wheezing that lasted more than 1 day and symptoms that affected sleep.47 Low-dose inhaled corticosteroids also are recommended as the preferred initial therapy in such children.18,47 Cromolyn sodium is suggested (based on extrapolation of data from studies in older children) or montelukast is recommended by some experts as alternative, but not preferred, therapy in children 4 years of age or younger with mild persistent asthma.47 Other experts do not consider mast cell stabilizers or extended-release theophylline to be acceptable alternatives to inhaled corticosteroids for routine use as initial long-term therapy in such patients.18

Moderate Persistent Asthma

According to asthma management guidelines, therapy with a long-acting inhaled β₂-agonist, such as formoterol or salmeterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed short-acting inhaled β₂-agonist treatment.18,47 However, NAEPP recommends that the beneficial effects of long-acting inhaled β₂-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.47 (See Uses: Bronchospasm and also see Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.) Asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid31 is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents).18,31,47 Alternative less effective therapies that may be added to a low dosage of inhaled corticosteroid include an oral extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast).18,31,47

Limited data are available in infants and children 11 years of age or younger with moderate persistent asthma, and recommendations of care are based on expert opinion and extrapolation from studies in adults.18,47 According to asthma management guidelines, a long-acting inhaled β₂-agonist (e.g., formoterol, salmeterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy in children 5-11 years of age.18,47 Because comparative data establishing relative efficacy of these agents in this age group are lacking, there is no clearly preferred agent for use as adjunctive therapy with a low-dose inhaled corticosteroid for treatment of asthma in these children.47 In children 5-11 years of age with moderate persistent asthma that is not controlled with a low dosage of an inhaled corticosteroid, another preferred option according to asthma management guidelines is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).18,47 In infants and children 4 years of age or younger with moderate persistent asthma that is not controlled by a low dosage of an inhaled corticosteroid, the only preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 mcg but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).47

Severe Persistent Asthma

Maintenance therapy with an inhaled corticosteroid at medium dosages or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg in children 5-11 years of age [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β₂-agonist is the preferred treatment according to asthma management guidelines in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week).18,47 Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in adolescents and adults.47 Alternatives to a long-acting inhaled β₂-agonist for severe persistent asthma in adults and children 5 years of age or older receiving medium-dose inhaled corticosteroids include extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast), but these therapies are generally not preferred.18,47 Omalizumab may be considered in adults and adolescents with severe asthma with an allergic component who are inadequately controlled with high-dose inhaled corticosteroids and a long-acting β₂-agonist.47 In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β₂-agonist or montelukast is the only preferred treatment according to asthma management guidelines.47 Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in older children.47

Poorly Controlled Asthma

If asthma symptoms in adults and children 5 years of age or older with moderate to severe asthma are very poorly controlled (i.e., at least 2 exacerbations per year requiring oral corticosteroids) with low to high maintenance dosages of an inhaled corticosteroid and a long-acting inhaled bronchodilator,19 a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma.18,47 In infants and children 4 years of age or younger with moderate to severe asthma who are very poorly controlled (more than 3 exacerbations per year requiring oral corticosteroids) with medium to high maintenance dosages of an inhaled corticosteroid with or without adjunctive therapy (i.e., a long-acting inhaled β₂-agonist, montelukast), a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma.47

While clinical efficacy of oral corticosteroids as add-on therapy in adults and children 5 years of age or older with very severe asthma that is inadequately controlled with a high-dose inhaled corticosteroid, intermittent oral corticosteroid therapy, and a long-acting inhaled β₂-agonist bronchodilator has not been established in randomized controlled studies, some experts suggest regular use of oral corticosteroids in such patients, based on consensus and clinical experience.47 Similarly, some experts, based on consensus and clinical experience, suggest regular use of oral corticosteroid therapy in infants and children 4 years of age or younger with very severe asthma who are not controlled with high-dose inhaled corticosteroid and either a long-acting inhaled β₂-agonist or montelukast and intermittent oral corticosteroid therapy.47 However, other experts do not consider regular use of oral corticosteroid therapy to be appropriate therapy in children with severely uncontrolled asthma.18 (See Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.)

When asthma symptoms at any stage are not controlled with maintenance therapy (e.g., inhaled corticosteroids) plus supplemental short-acting inhaled β₂-agonist bronchodilator therapy as needed (e.g., if there is a need to increase the dose or frequency of administration of the short-acting sympathomimetic agent), prompt reevaluation is required to adjust dosage of the maintenance regimen or institute an alternative maintenance regimen.18,27,28,31 For additional details on the stepped-care approach to drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12 and also see Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.

Clinical Experience with Formoterol Fumarate

While formoterol has a more rapid onset of action than salmeterol,6,7,15,18 the clinical importance of this difference in the treatment of asthma has not been established,15,16 and neither formoterol nor salmeterol should be used to relieve symptoms of acute asthma.1,8,15,16 (See Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease under Warnings/Precautions: Warnings, in Cautions and also see Supplemental Therapy in Acute Asthma under Bronchospasm: Asthma, in Uses in Salmeterol 12:12.08.12.)

Results of several controlled, comparative studies in adolescents and adults with mild to moderate asthma (i.e., requiring daily use of short-acting inhaled β₂-adrenergic bronchodilators with or without orally inhaled corticosteroids or theophylline) indicate that therapy with orally inhaled formoterol fumarate (12 or 24 mcg twice daily) is more effective than therapy with orally inhaled albuterol (180 mcg 4 times daily) or placebo in controlling asthma symptoms (e.g., as determined by days free of asthma symptoms, presence of nocturnal asthma symptoms, nights without nocturnal awakenings), reducing the need for rescue medication (e.g., intermittent use of a short-acting, β₂-agonist bronchodilator to control asthma exacerbations), and improving lung function (e.g., as determined by mean peak expiratory flow rate [PEFR], forced expiratory volume in 1 second [FEV₁]).12 In a large clinical study in children (5-12 years of age) with persistent asthma who required concomitant therapy with an anti-inflammatory agent (i.e., cromolyn sodium, inhaled corticosteroid) and a daily inhaled bronchodilator (e.g., albuterol) at study entry, usual dosages of orally inhaled formoterol fumarate (12 mcg twice daily) were consistently more effective than placebo in improving pulmonary function (as measured by FEV₁ area under the curve [AUC]) on day 1 of treatment and at 12 weeks and 1 year.17 Anti-inflammatory agents were continued throughout the study.17 While regular use of bronchodilators was not permitted during the study, orally inhaled albuterol was used as supplemental therapy for acute symptoms of asthma.17 While comparative clinical data for formoterol and salmeterol are limited, the drugs appeared to have similar efficacy (in terms of PEFR values, use of rescue medication, and symptom control) and safety in a 6-month, randomized, open-label study in adults with reversible obstructive airways disease who received orally inhaled formoterol fumarate 12 mcg or salmeterol 50 mcg twice daily.16

Clinical Experience with Fixed Combination of Formoterol Fumarate and Budesonide

In 2 randomized, double-blind, placebo-controlled clinical studies in patients 12 years of age or older with mild to severe asthma, orally inhaled formoterol/budesonide (9 mcg of formoterol fumarate and 160 or 320 mcg of budesonide twice daily) produced greater improvement in most indices of pulmonary function (e.g., mean percent change from baseline in FEV₁ or morning and evening PEFR) than either drug alone and similar efficacy as concurrent therapy with both drugs given as single-entity preparations.48

In one randomized, double-blind, multicenter study, 184 pediatric patients 6 to younger than 12 years of age with asthma received orally inhaled formoterol/budesonide (9 mcg of formoterol fumarate and 160 mcg of budesonide twice daily) or orally inhaled single-entity budesonide 160 mcg twice daily.51 In patients receiving formoterol/budesonide, there was a substantial change in 1-hour post-dose FEV₁ at 12 weeks, which improved by 0.28 L from baseline in those receiving the fixed combination compared with 0.17 L in those receiving single-entity budesonide.51

Clinical Experience with Fixed Combination of Formoterol Fumarate and Mometasone Furoate

In one randomized, double-blind, placebo-controlled, 26-week study in patients with asthma 12 years of age or older, orally inhaled formoterol/mometasone (2 inhalations of preparation containing 5 mcg of formoterol fumarate and 100 mcg of mometasone furoate twice daily) was compared with either mometasone furoate 100 mcg, formoterol fumarate 5 mcg, or placebo (2 inhalations administered twice daily).54 A co-primary efficacy end point in this study was the change from baseline in FEV₁ AUC from 0-12 hours.54 In this study, patients receiving formoterol/mometasone had substantially greater increases in FEV₁ AUC 0-12 hours at 12 weeks compared with those receiving single-entity mometasone furoate or placebo; such improvements were maintained over the 26-week study period.54 Another primary end point in this study was deterioration in asthma or reduction in lung function.54 Patients who received formoterol/mometasone had fewer reports of asthma deterioration compared with patients receiving single-entity formoterol fumarate.54

In a randomized, double-blind, 12-week study in patients with asthma 12 years of age or older, orally inhaled formoterol/mometasone (2 inhalations of preparation containing 5 mcg of formoterol fumarate and 100 or 200 mcg of mometasone furoate administered twice daily) was compared with mometasone furoate 200 mcg (2 inhalations administered twice daily).54 Patients who received either dosage of the formoterol/mometasone fixed combination had substantially greater increases in mean FEV₁ from baseline and over 12 weeks compared with those receiving single-entity mometasone furoate.54

Chronic Obstructive Pulmonary Disease

Orally inhaled formoterol is used alone or in fixed combination with budesonide or glycopyrrolate as a bronchodilator for the long-term symptomatic treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.1,19,23,24,51,55

In the stepped-care approach to drug therapy for COPD, mild, intermittent symptoms and minimal lung impairment (FEV₁ at least 80% of predicted) can be treated with a short-acting, selective inhaled β₂-adrenergic agonist (e.g., albuterol) as needed for acute symptoms.19,20,21,32,35,46 For the treatment of moderate to severe COPD (e.g., FEV₁ 30 to less than 80% of predicted value) who have persistent symptoms despite as-needed therapy with ipratropium or a selective inhaled β₂-agonist, maintenance treatment with one or more long-acting bronchodilators (e.g., orally inhaled formoterol, salmeterol, tiotropium) can be added, and a short-acting, selective inhaled β₂-agonist used as needed for immediate symptom relief.32,33,34,35 Maintenance therapy with long-acting bronchodilators in patients with moderate to severe COPD is more effective and more convenient than regular use of short-acting bronchodilators.32,33,34,35

Maintenance therapy (e.g., 4 times daily) with a short-acting, selective inhaled β₂-agonist is not preferred but may be used in patients with persistent symptoms of COPD; such therapy should not exceed 6-12 inhalations daily.32,35,46 Guidelines for the management of COPD state that low- to high-dose ipratropium (6-16 inhalations daily) can be added to therapy with a short-acting, selective β₂-agonist19,20,21,32,34,46 (as separate inhalations or in fixed combination) in patients with mild to moderate persistent symptoms of COPD, with the frequency of inhalation dosing with either agent not to exceed 4 times daily;20,21,25,32,33,34 the highest dosage of ipratropium included in some guidelines for COPD32,34,46 exceeds the manufacturer's maximum recommended daily dosage (12 inhalations).25,46 Combining bronchodilators from different classes and with differing durations of action may increase the degree of bronchodilation with a similar or lower frequency of adverse effects.34,35

For patients not responding adequately to treatment with a long-acting bronchodilator, a combination of several long-acting bronchodilators, such as tiotropium and a long-acting β-adrenergic agonist, may be used.33,34,35 A short-acting bronchodilator may be used as needed for relief of acute symptoms that occur despite regular use of long-acting bronchodilators.35 For treatment of severe to very severe COPD (e.g., FEV₁ less than 30 to less than 50% of predicted, history of exacerbations), the addition of an inhaled corticosteroid to one or more long-acting bronchodilators given separately or in fixed combination may be needed.33,34,35 If symptoms are not adequately controlled with inhaled corticosteroids and a long-acting bronchodilator or if limiting adverse effects occur, oral extended-release theophylline may be added or substituted.32,35 For additional information on the stepped-care approach to drug therapy in COPD, see Chronic Obstructive Pulmonary Disease under Uses: Bronchospasm, in Ipratropium Bromide 12:08.08.

Clinical Experience with Formoterol Fumarate

In a long-term (12-month) controlled comparative study in patients with COPD, orally inhaled formoterol fumarate (12 mcg twice daily) produced greater bronchodilation (as measured by increases in area under the forced expiratory volume in 1 second [FEV₁]-time curve) than dose-adjusted oral extended-release theophylline (dosage adjusted to maintain plasma drug concentrations within the range of 8-20 mcg/mL) or placebo for a period of 12 hours following the morning dose.23 Approximately half of the patients in each group were receiving inhaled corticosteroids, which were continued during the study along with as-needed rescue therapy with inhaled albuterol.23 Therapy with formoterol also decreased mild exacerbations of COPD (defined as the number of days with at least 2 symptom scores of 2 or greater and/or a reduction in peak expiratory flow [PEF] exceeding 20%) and the use of supplemental (rescue) medication compared with oral extended-release theophylline or placebo.23

In a similar short-term (12-week) controlled study in patients with COPD, orally inhaled formoterol fumarate (12 mcg twice daily), produced greater improvement in FEV₁ (for 12 hours following the dose), symptoms, and quality of life than inhaled ipratropium bromide (36 mcg 4 times daily) or placebo.24 Therapy with orally inhaled formoterol also decreased mild exacerbations of COPD (defined as the number of days with at least 2 symptom scores of 2 or greater and/or a reduction in peak expiratory flow [PEF] exceeding 20%) and the need for rescue therapy with a short-acting β₂-agonist (albuterol) compared with orally inhaled ipratropium or placebo.24 Compared with formoterol fumarate 12 mcg twice daily, a dosage of 24 mcg twice daily did not provide additional benefits on FEV₁ and other end points in these studies.23

Clinical Experience with Fixed Combination of Formoterol Fumarate and Budesonide

In 2 randomized, double-blind, placebo-controlled studies of 6 or 12 months' duration in patients with COPD, orally inhaled formoterol/budesonide (9 mcg of formoterol fumarate and 320 mcg of budesonide twice daily) produced greater improvements in the mean percent change from baseline in predose FEV₁ compared with formoterol fumarate alone or placebo and in 1-hour postdose FEV₁ compared with budesonide alone or placebo.48 The formoterol/budesonide fixed combination given in a dosage of 9 mcg of formoterol fumarate and 160 mcg of budesonide twice daily did not produce greater improvements from baseline in predose FEV₁ than formoterol alone or placebo.48 Therefore, the higher dosage of formoterol/budesonide is the only recommended dosage for the treatment of airflow obstruction in COPD.48

Clinical Experience with Fixed Combination of Formoterol Fumarate and Glycopyrrolate

In 2 randomized, double-blind, placebo-controlled, parallel group studies of 24 weeks' duration in 3699 adults 40 years of age or older with moderate to very severe COPD, orally inhaled formoterol/glycopyrrolate (9.6 mcg of formoterol fumarate and 18 mcg of glycopyrrolate twice daily) resulted in a larger increase in mean change from baseline in trough FEV₁ after 24 weeks compared with either drug alone or placebo.55 The mean peak FEV₁ improvement from baseline with the formoterol/glycopyrrolate fixed combination compared with placebo after 24 weeks was 291 and 267 mL, respectively.55 Overall, the need for rescue medication with orally inhaled albuterol also was reduced in patients treated with formoterol/glycopyrrolate compared with those receiving placebo.55

Administration

Oral Inhalation

Formoterol Fumarate

Formoterol fumarate oral inhalation solution (Perforomist^®) is administered by oral inhalation using a standard jet nebulizer connected to an air compressor and equipped with a mouthpiece or face mask.1 Formoterol fumarate oral inhalation solution is available in single-dose vials that should be stored in the foil pouch provided by the manufacturer and removed immediately before use.1

For administration of formoterol fumarate oral inhalation solution for nebulization, the entire contents of the 20-mcg vial should be squeezed into the nebulizer reservoir.1 The nebulizer reservoir should be connected to the mouthpiece or face mask, and then the nebulizer should be connected to the compressor.1 The patient should be seated in an upright, comfortable position and should inhale the medication as calmly, deeply, and evenly as possible through the mouth using the mouthpiece or face mask of the nebulizer until the nebulizer stops producing mist in the reservoir (average nebulization time is 9 minutes).1 The nebulizer should be cleaned after use according to the manufacturer's instructions.1 The safety and efficacy of formoterol fumarate oral inhalation solution delivered from a nebulizer other than the Pari-LC Plus^® nebulizer or a compressor other than the PRONEB^® Ultra compressor have not been established.1 Formoterol fumarate oral inhalation solution should not be mixed with other inhalation solutions or ingested.1

Fixed Combination of Formoterol Fumarate and Budesonide

Formoterol fumarate dihydrate in fixed combination with budesonide (formoterol/budesonide; Symbicort^®) is administered by oral inhalation using an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant.48 Formoterol/budesonide inhalation aerosol should only be used with the actuator supplied with the product.48

Before each inhalation of formoterol/budesonide, the inhaler must be shaken well for 5 seconds.48 The aerosol inhaler should be test sprayed twice into the air (away from the face) before initial use, and shaken well for 5 seconds before each spray.48 If the inhaler has not been used for more than 7 days or if the inhaler was dropped, the inhaler should be test sprayed twice into the air (away from the face) and shaken well for 5 seconds before each spray.48 Rinsing the mouth after inhalation of formoterol/budesonide inhalation aerosol and spitting out the water are advised.48 The mouthpiece of the inhaler should be wiped clean with a dry cloth every 7 days.48 The inhaler should be discarded when the labeled number of inhalations has been used or within 3 months after removal from the foil pouch.48 The canister should never be immersed in water to determine the amount of drug remaining in the canister (“float test”).48

Fixed Combination of Formoterol Fumarate and Glycopyrrolate

Formoterol fumarate in fixed combination with glycopyrrolate (formoterol/glycopyrrolate; Bevespi^® Aerosphere^®) is administered by oral inhalation using an oral aerosol inhaler with HFA propellant.55 Formoterol/glycopyrrolate inhalation aerosol should only be used with the actuator supplied with the product.55

The aerosol inhaler should be primed by releasing 4 test sprays into the air (away from the face) before initial use, and shaken well before each spray.55 If the inhaler has not been used for more than 7 days, the priming process should be repeated (using only 2 sprays rather than 4).55

To administer a dose of formoterol/glycopyrrolate, the cap should be removed from the mouthpiece.55 Before each inhalation, the inhaler must be shaken well.55 The inhaler should be held with the mouthpiece pointing towards the face while the patient exhales through the mouth as fully and comfortably as possible.55 The lips should be closed around the mouthpiece and the head tilted back, keeping the tongue below the mouthpiece.55 While inhaling slowly and deeply, the center of the dose indicator should be pressed down until the canister stops moving in the actuator and a spray has been released, then the dose indicator should be released.55 At the end of inhalation, the mouthpiece should be removed from the mouth and the breath held as long as comfortably possible (up to 10 seconds) then the patient should exhale gently.55 The process should be repeated for the second inhalation.55 The cap should be replaced on the mouthpiece immediately after use.55

The Bevespi^® Aerosphere^® inhaler should be cleaned once weekly by removing the canister from the actuator; the canister should not be cleaned or allowed to get wet.55 The actuator should be held under warm running water for about 30 seconds.55 The actuator should then be turned upside down and water rinsed through the actuator again for about 30 seconds.55 The actuator should be allowed to dry overnight.55 When the actuator is dry, the canister should be pressed gently down into the actuator; the canister should not be pressed down too hard since this may cause drug to be released.55 Priming of the inhaler should be repeated after each cleaning by shaking well and releasing 2 test sprays into the air away from the face.55 The inhaler should be discarded 3 months after removal from the foil pouch or when the dose indicator reads “0,” whichever comes first.55 The canister should never be immersed in water to determine the amount of drug remaining in the canister (“float test”).55

Fixed Combination of Formoterol Fumarate and Mometasone Furoate

Formoterol fumarate dihydrate in fixed combination with mometasone furoate (formoterol/mometasone; Dulera^®) is administered by oral inhalation as an oral inhalation suspension using a metered-dose aerosol inhaler with HFA propellant.54 Formoterol/mometasone inhalation aerosol should only be used with the actuator supplied with the product.54

The aerosol inhaler should be primed by releasing 4 test sprays into the air (away from the face) before initial use, and shaken well before each spray.54 If the inhaler has not been used for more than 5 days, it should be primed again by test spraying 4 times into the air (away from the face) and shaken well before each spray.54 Before each inhalation, the inhaler must be shaken well.54 Following each dose, the mouth should be rinsed thoroughly without swallowing.54 The mouthpiece of the inhaler should be wiped clean with a dry cloth every 7 days; water should not be used to clean the inhaler.54

Dosage

Each 2-mL single-dose vial of formoterol fumarate oral inhalation solution contains 20 mcg of formoterol fumarate.1 The oral inhalation solution does not require dilution prior to administration by nebulization.1 The actual amount of drug delivered to the lungs will depend on patient factors and the type of nebulization system used and its performance.1

Each actuation of the oral aerosol inhaler containing the fixed combination of formoterol fumarate dihydrate and budesonide delivers 5.1 mcg of formoterol fumarate dihydrate and 91 or 181 mcg of budesonide from the valve and delivers 4.5 mcg of formoterol fumarate dihydrate and 80 or 160 mcg of budesonide from the actuator per metered spray, depending on the preparation used.51 The strength of formoterol/budesonide preparations and dosage of the fixed combination are expressed in terms of drug delivered from the mouthpiece of the actuator.51 The actual amount of drug delivered to the lungs depends on factors such as the patient's coordination between the actuation of the inhaler and inspiration through the delivery system.51 The commercially available formoterol/budesonide aerosol inhaler delivers 60 metered sprays per 6- or 6.9-g canister and 120 metered sprays per 10.2-g canister.51

After priming of the oral aerosol inhaler containing the fixed combination of formoterol fumarate and glycopyrrolate, each actuation of the oral aerosol inhaler (Bevespi^® Aerosphere^®) delivers 5.5 mcg of formoterol fumarate and 10.4 mcg of glycopyrrolate (equivalent to 8.3 mcg of glycopyrronium) from the valve.55 Dosage is expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 4.8 mcg of formoterol fumarate and 9 mcg of glycopyrrolate (equivalent to 7.2 mcg of glycopyrronium) from the actuator.55 The actual amount of drug delivered to the lungs depends on factors such as the patient's coordination between actuation of the device and inspiration through the delivery system.55 Commercially available formoterol/glycopyrrolate aerosol inhaler delivers 28 or 120 metered sprays per 5.9- or 10.7-g canister, respectively.55

Each actuation of the oral aerosol inhaler containing the fixed combination of formoterol fumarate dihydrate and mometasone furoate delivers 5.5 mcg of formoterol fumarate dihydrate and 115 or 225 mcg of mometasone furoate from the valve and delivers 5 mcg of formoterol fumarate dihydrate and 100 or 200 mcg of mometasone furoate from the actuator per metered spray, depending on the preparation used.54 The strength of formoterol/mometasone preparations and dosage of the fixed combination are expressed in terms of drug delivered from the mouthpiece of the actuator.54 The actual amount of drug delivered to the lungs may depend on factors such as the patient's coordination between actuation of the device and inspiration through the delivery system.54 Commercially available formoterol/mometasone aerosol inhaler delivers 60 or 120 metered sprays per 8.8- or 13-g canister, respectively.54

Asthma

Fixed Combination of Formoterol Fumarate and Budesonide

In asthmatic patients 12 years of age or older, the recommended initial dosage of the oral inhalation aerosol containing formoterol fumarate dihydrate in fixed combination with budesonide is based on the patient's asthma severity.51 The dosage of the formoterol/budesonide fixed combination in this age group is 9 mcg of formoterol fumarate dihydrate and 160 or 320 mcg of budesonide (2 inhalations of preparation containing 4.5 mcg of formoterol fumarate dihydrate and 80 or 160 mcg of budesonide) twice daily, given approximately 12 hours apart (morning and evening).51 In asthmatic patients 6 to younger than 12 years of age, the recommended initial dosage of formoterol/budesonide is 9 mcg of formoterol fumarate dihydrate and 160 mcg of budesonide (2 inhalations of preparation containing 4.5 mcg of formoterol fumarate dihydrate and 80 mcg of budesonide) twice daily, given approximately 12 hours apart (morning and evening).51 The maximum recommended dosage of formoterol/budesonide in asthmatic patients 12 years of age or older is 9 mcg of formoterol fumarate dihydrate and 320 mcg of budesonide (2 inhalations of preparation containing 4.5 mcg of formoterol fumarate dihydrate and 160 mcg of budesonide) twice daily.49,51 The maximum recommended dosage in asthmatic children 6 to younger than 12 years of age is 9 mcg of formoterol fumarate dihydrate and 160 mcg of budesonide (2 inhalations of preparation containing 4.5 mcg of formoterol fumarate dihydrate and 80 mcg of budesonide) twice daily.51 The manufacturer states that administration of formoterol/budesonide oral inhalation aerosol more frequently than twice daily or in excess of 2 inhalations twice daily is not recommended.51 Patients receiving formoterol/budesonide should not use additional long-acting β₂-agonists for any reason.51

Improvement in asthma control following oral inhalation of formoterol/budesonide may occur within 15 minutes of initiating treatment, although maximum benefit may not be achieved for 2 weeks or longer after therapy initiation.51 Individual patients will experience a variable time to onset and degree of symptom relief.51 If control of asthma is inadequate after 1-2 weeks of therapy at the lower dosage, switching to a higher strength of the fixed combination (higher strengths contain higher dosages of budesonide only) may provide additional asthma control.51 If acute asthmatic symptoms arise despite therapy with formoterol in fixed combination with budesonide, a short-acting inhaled β₂-adrenergic agonist should be taken for immediate relief.51 Patients should be advised not to discontinue formoterol/budesonide without medical supervision, as symptoms may recur after treatment discontinuance.51 If a previously effective dosage of formoterol/budesonide fails to provide adequate asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options should be considered (e.g., switching to a higher strength of the fixed combination [higher strengths contain higher dosages of budesonide only], adding additional inhaled corticosteroids, initiating systemic corticosteroids).51 (See Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease under Warnings/Precautions: Warnings, in Cautions.)

Fixed Combination of Formoterol Fumarate and Mometasone Furoate

In asthmatic patients 12 years of age or older, the recommended initial dosage of the oral inhalation aerosol containing formoterol fumarate dihydrate in fixed combination with mometasone furoate is based on the patient's asthma severity, previous asthma therapy (including previous inhaled corticosteroid dosage), current control of asthma symptoms, and risk of future asthma exacerbations.54

In adults and adolescents 12 years of age or older, the dosage of the formoterol/mometasone fixed combination is 10 mcg of formoterol fumarate dihydrate and 200 or 400 mcg of mometasone furoate (2 inhalations of preparation containing 5 mcg of formoterol fumarate dihydrate and 100 or 200 mcg of mometasone furoate) twice daily.54 If control of asthma is inadequate after 2 weeks of formoterol/mometasone therapy at the lower dosage, switching to a higher strength of the fixed combination (higher strengths contain higher dosages of mometasone only) may provide additional asthma control.54 The maximum recommended dosage of formoterol/mometasone in asthmatic adults and adolescents 12 years of age or older is 10 mcg of formoterol fumarate dihydrate and 400 mcg of mometasone furoate twice daily.54

Chronic Obstructive Pulmonary Disease

Formoterol Fumarate

For maintenance therapy of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), the recommended dosage of formoterol fumarate oral inhalation solution is 20 mcg (entire contents of a single-dose vial) every 12 hours (morning and evening) by nebulization.1 The total daily dosage of formoterol fumarate oral inhalation solution should not exceed 40 mcg.1 If shortness of breath occurs despite therapy with formoterol oral inhalation solution, a short-acting inhaled β₂-adrenergic agonist should be taken for immediate relief.1

Fixed Combination of Formoterol Fumarate and Budesonide

For maintenance therapy of airflow obstruction in patients with COPD, the recommended dosage of the oral inhalation aerosol containing formoterol fumarate dihydrate in fixed combination with budesonide in adults is 9 mcg of formoterol fumarate dihydrate and 320 mcg of budesonide (2 inhalations of preparation containing 4.5 mcg of formoterol fumarate dihydrate and 160 mcg of budesonide) twice daily (morning and evening).51 In clinical studies, lower dosages of formoterol/budesonide (i.e., 2 inhalations of preparation containing 4.5 mcg of formoterol fumarate dihydrate and 80 mcg of budesonide twice daily) did not produce greater improvements from baseline in predose FEV₁ than formoterol alone or placebo; therefore, such dosages are not recommended for the treatment of airflow obstruction in COPD.51

If shortness of breath occurs despite therapy with the recommended dosage of formoterol/budesonide, a short-acting inhaled β₂-adrenergic agonist should be taken for immediate relief.51 Patients should be advised not to discontinue formoterol/budesonide without medical supervision, as symptoms may recur after treatment discontinuance.51 The manufacturer states that administration of formoterol/budesonide inhalation aerosol more frequently than twice daily or in excess of 2 inhalations twice daily is not recommended.51 Patients receiving formoterol/budesonide should not use additional long-acting β₂-agonists for any reason.51

Fixed Combination of Formoterol Fumarate and Glycopyrrolate

For the long-term management of airflow obstruction associated with COPD, the usual dosage of formoterol fumarate in fixed combination with glycopyrrolate in adults is 9.6 mcg of formoterol fumarate and 18 mcg of glycopyrrolate (2 inhalations of preparation containing 4.8 mcg of formoterol fumarate and 9 mcg of glycopyrrolate) twice daily via the Aerosphere^® device.55 More frequent administration or higher dosages are not recommended.55 Orally inhaled formoterol/glycopyrrolate should not be used for the treatment of acute episodes of bronchospasm.55

Special Populations

Hepatic Impairment

The manufacturers of formoterol fumarate and formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate make no specific dosage recommendations for patients with hepatic impairment at this time.1,48,54,55 However, since formoterol fumarate, budesonide, and mometasone are cleared predominantly by the liver, impaired liver function theoretically may lead to accumulation of the drugs in plasma.48,54,55 Therefore, the manufacturers of formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate state that patients with hepatic disease should be closely monitored for signs of increased drug exposure.48,54,55

Renal Impairment

The manufacturers of formoterol fumarate and formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate make no specific dosage recommendations for patients with renal impairment at this time.1,48,54,55

The manufacturer of formoterol fumarate in fixed combination with glycopyrrolate states that the preparation should be used in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute) or end-stage renal disease requiring dialysis only if expected benefits outweigh potential risks.55

Geriatric Patients

The manufacturers of formoterol fumarate and formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate state that dosage adjustment is not required in geriatric patients.1,48,54,55

Contraindications

Formoterol fumarate1 and fixed combinations containing formoterol fumarate51,54,55 are contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.1,51,54,55

Because of the risk of asthma-related death and hospitalization, use of formoterol for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated.1,55 (See Asthma-related Death and Serious Asthma-related Events under Warnings/Precautions: Warnings, in Cautions and also see Uses: Bronchospasm.)

Formoterol fumarate in fixed combination with budesonide (formoterol/budesonide; Symbicort^®) and formoterol fumarate in fixed combination with mometasone furoate (formoterol/mometasone; Dulera^®) are contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) when intensive measures are required.48,54

Formoterol fumarate in fixed combination with glycopyrrolate (formoterol/glycopyrrolate; Bevespi^® Aerosphere^®) is not indicated for the treatment of asthma.55

Warnings/Precautions

Warnings

Use of Fixed Combinations

When formoterol fumarate is used in fixed combination with budesonide, glycopyrrolate, or mometasone furoate, the usual cautions, precautions, contraindications, and interactions associated with budesonide, glycopyrrolate, or mometasone furoate must be considered.48,54,55

Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.48,54,55

Asthma-related Death and Serious Asthma-related Events

Monotherapy with long-acting β₂-adrenergic agonists, such as formoterol, increases the risk of asthma-related death.1,41,48,50,51,54,55 In addition, available data from controlled clinical trials suggest that use of long-acting β₂-adrenergic agonists as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients.41,51,54 Because of these risks, the use of long-acting 2-adrenergic agonists, including formoterol, alone for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated .1,41,55 (See Cautions: Contraindications.) However, FDA has concluded that there is no clinically important increased risk of serious asthma-related events, including hospitalization, intubation, or death, associated with concomitant use of long-acting β₂-adrenergic agonists (e.g., formoterol) and inhaled corticosteroids compared with inhaled corticosteroids alone based on the results of several large clinical studies.50,51,52,53,54 In addition, these studies showed that combination therapy with long-acting β₂-adrenergic agonists and inhaled corticosteroids was more effective in reducing the incidence of asthma exacerbations (i.e., events requiring use of systemic corticosteroids for at least 3 outpatient days or an asthma-related hospitalization or emergency department visit requiring use of systemic corticosteroids) compared with use of inhaled corticosteroids alone.50,52,53

The formoterol/budesonide and formoterol/mometasone fixed combinations should be used only in patients with asthma who have not responded adequately to long-term asthma controller therapy, such as inhaled corticosteroids, or whose disease severity warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist.51,54 Once asthma control is achieved and maintained, the patient should be assessed at regular intervals and therapy should be stepped down (e.g., discontinuance of the long-acting β₂-adrenergic agonist), if possible without loss of asthma control, and the patient should be maintained on long-term asthma controller therapy, such as inhaled corticosteroids.1,41,48 Long-acting β₂-adrenergic agonists, including formoterol alone or in fixed combination with budesonide, should not be used in patients whose asthma is adequately controlled on a low or medium dosage of inhaled corticosteroids.41,48 In pediatric and adolescent patients with asthma who require the addition of a long-acting β₂-adrenergic agonist to inhaled corticosteroid therapy, a fixed-combination preparation containing both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist generally should be used to ensure compliance with both drugs.41 (See Uses: Bronchospasm.)

Data from a large placebo-controlled study (Salmeterol Multi-center Asthma Research Trial ([SMART]) evaluating the safety of another long-acting β₂-adrenergic agonist, salmeterol, in patients with asthma showed an increase in asthma-related deaths in patients receiving salmeterol.1,29,30,36,37,38,48,54,55 (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.) The increased risk of asthma-related death with salmeterol is considered a class effect of the long-acting β₂-adrenergic agonists, including formoterol.1,48,54,55 However, no adequate studies have been conducted to determine whether the rate of asthma-related death is increased with formoterol.1,48 Clinical studies with inhalation of formoterol as a dry powder suggest that the incidence of serious asthma exacerbations is increased in patients receiving formoterol compared with those receiving placebo, although the sample sizes in these studies were not adequate to quantify the precise differences between treatment groups.1,48,54

In 4 randomized, double-blind, active-controlled clinical trials mandated by FDA, the risk of serious asthma-related events from use of inhaled corticosteroids alone compared with combined use of long-acting β₂-adrenergic agonists and inhaled corticosteroids was evaluated over 26 weeks in 41,297 patients with asthma (3 trials in adults and adolescents 12 years of age or older and one trial in children 4-11 years of age).50,51,52,54 The primary safety end point in all of these trials was serious asthma-related events, including hospitalization, intubation, and death; these events were reviewed by a blinded committee to determine if the events were asthma related.50,51,52,54 The 3 trials performed in adults and adolescents were designed to rule out a hazard ratio of 2, and the pediatric trial was designed to rule out a hazard ratio of 2.7; this objective was met in all 4 individual trials.50,51,52,54 The trials were not designed to rule out all risk for serious asthma-related events associated with long-acting β₂-adrenergic agonists in combination with inhaled corticosteroids compared with inhaled corticosteroids alone.50,51,54

The safety studies in adults and adolescents included one trial comparing salmeterol and fluticasone propionate in fixed combination as the inhalation powder with fluticasone propionate oral inhalation powder alone, one trial comparing formoterol and mometasone furoate in fixed combination with mometasone furoate alone, and one trial comparing formoterol and budesonide in fixed combination with budesonide alone.50,51,52,53,54 In a meta-analysis combining data from these 3 trials, a hazard ratio of 1.1 for first serious asthma-related event in patients receiving fixed-combination therapy with long-acting β₂-adrenergic agonists and inhaled corticosteroids compared with patients receiving inhaled corticosteroids alone was reported.50,51,54 Subgroup analyses for gender, adolescents 12-17 years of age, Asian and African-American patients, and obese patients also showed no substantial increase in the risk of serious asthma-related events or asthma exacerbations in these populations.50,52

The safety study in children 4-11 years of age included 6208 patients who were randomized to receive salmeterol and fluticasone propionate in fixed combination as the inhalation powder or fluticasone propionate inhalation powder alone.50,51,54 Serious asthma-related events were reported in 0.9% of patients receiving salmeterol and fluticasone in fixed combination and in 0.7% of patients receiving fluticasone alone, with an estimated hazard ratio for first event of 1.29 for the combination therapy compared with fluticasone alone.50,51,54 No asthma-related deaths or intubations were reported in either group of pediatric patients.50,51,54

No adequate studies have been conducted to determine whether the rate of death is increased in patients with COPD receiving long-acting β₂-adrenergic agonists.1

Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease

Substantially worsening or acutely deteriorating asthma may be a life-threatening condition.1,7 Formoterol oral inhalation therapy should not be initiated in patients with substantially worsening or acutely deteriorating asthma.1,7 Formoterol in fixed combination with budesonide, glycopyrrolate, or mometasone furoate should not be initiated in patients with rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.48,54,55

Failure to respond to a previously effective dosage of formoterol may indicate substantially worsening asthma or destabilization of COPD that requires prompt reevaluation.1,18,48,54,55 If inadequate control of symptoms persists with supplemental β₂-agonist bronchodilator therapy (i.e., if there is a need to increase the dose or frequency of administration of the short-acting, inhaled bronchodilator), prompt reevaluation of asthma or COPD therapy is required, with special consideration given to the possible need for anti-inflammatory treatment (e.g., corticosteroids); however, extra or increased doses of formoterol should not be used in such situations.1,6,10,54,55 If asthma deteriorates in patients receiving formoterol in fixed combination with budesonide or mometasone furoate, prompt reevaluation of asthma therapy is required, with special consideration given to the possible need for increasing the strength of the fixed combination (higher strengths contain higher dosages of budesonide or mometasone only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids; patients should not increase the frequency of administration of formoterol/budesonide or formoterol/mometasone.48,54 If COPD deteriorates in patients receiving formoterol/glycopyrrolate, prompt reevaluation of COPD therapy is required.55

Concomitant Anti-Inflammatory Therapy

The manufacturer states that there are no data demonstrating clinical anti-inflammatory effects of formoterol that could be expected to substitute for or allow reduction in the dosage of corticosteroids.6,13,15 Particular care is needed for patients who have been transferred from systemically active corticosteroids to orally inhaled corticosteroids since death resulting from adrenal insufficiency has occurred in some asthmatic patients during and after such transfer.48,54 (See Withdrawal of Systemic Corticosteroid Therapy under Warnings/Precautions: Warnings, in Cautions in Budesonide 68:04.)

Concomitant Short-Acting Bronchodilators

The manufacturer states that if patients are taking a short-acting, inhaled β₂-agonist bronchodilator on a regular basis (e.g., 4 times daily) at the time formoterol or formoterol in fixed combination with budesonide, glycopyrrolate, or mometasone is initiated, these patients should be instructed to discontinue the regular use of the short-acting agent and use it only for relief of acute asthma symptoms.1,48,54,55 Regular (e.g., daily) use of inhaled β₂-agonists does not adequately control asthma symptoms or airway hyperresponsiveness on a long-term basis and is not recommended by current asthma management experts.18,26,27

Cardiovascular Effects

Formoterol, like other sympathomimetic amines, may increase heart rate or blood pressure.1,7,48,54,55 Although such effects are uncommon at recommended dosages, the drug may need to be discontinued if such cardiovascular effects occur.1,48,54,55

Excessive Doses

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.1,48,54,55 (See Cautions, in Albuterol 12:12.08.12.)

Patients receiving formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate should not use additional formoterol or other long-acting β₂-agonists for any reason.1,48,54,55

Sensitivity Reactions

Immediate Hypersensitivity Reactions

Anaphylactic reactions, urticaria, angioedema, rash, flushing, allergic dermatitis, and bronchospasm have been reported with oral inhalation therapy with formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone.1,48,54,55 Orally inhaled formoterol/glycopyrrolate should be discontinued immediately if such allergic reactions occur, particularly angioedema (e.g., difficulties with breathing or swallowing; swelling of the tongue, lips, or face), urticaria, or rash, and alternative therapy considered.55

Major Toxicities

Paradoxical Bronchospasm

As with other inhaled β₂-receptor agonists, a patient may develop acute bronchospasm, which may be life-threatening, immediately upon inhalation of formoterol.1,48,54,55 If paradoxical bronchospasm occurs, formoterol should be discontinued immediately and alternative therapy instituted.1,48,54,55

General Precautions

Acute or Worsening Asthma or COPD

Formoterol, alone or in fixed combination with budesonide or mometasone furoate, or other long-acting β₂-adrenergic agonists (e.g., salmeterol) should not be used to relieve symptoms of acute asthma.1,5,6,8,48,54 Formoterol alone or in fixed combination with glycopyrrolate should not be used to relieve symptoms of acutely deteriorating COPD.55

Failure to respond to a previously effective dosage of formoterol may indicate substantially worsening asthma or destabilization of COPD that requires prompt reevaluation.1 If inadequate control of symptoms persists with supplemental β₂-agonist bronchodilator therapy (i.e., if there is a need to increase the dose or frequency of administration of the short-acting inhaled bronchodilator or if a substantial decrease in peak expiratory flow or other index of lung function occurs), immediate reevaluation of asthma therapy is required (e.g., adjusting the inhaled corticosteroid dosage or initiating systemic corticosteroids); however, extra or increased doses of formoterol should not be used in such situations.1,6,10 If asthma deteriorates in patients receiving formoterol in fixed combination with budesonide or mometasone furoate, prompt reevaluation of asthma therapy is required, with special consideration given to the possible need for increasing the strength of the fixed combination (higher strengths contain higher dosages of budesonide or mometasone only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids; patients should not increase the frequency of administration of formoterol in fixed combination with budesonide or mometasone furoate.48,54

Cardiovascular Effects

Although uncommon at recommended dosages, clinically important changes in systolic and/or diastolic blood pressure, heart rate, and ECG (e.g., flattening of the T wave, prolongation of the QT_c interval, ST-segment depression) have been associated with formoterol oral inhalation therapy and may necessitate discontinuance of the drug.1,17,48,54,55 Cardiovascular effects generally have resolved within a few hours.17

Like other sympathomimetic amines, formoterol should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, or hypertension; in patients with seizure disorders or thyrotoxicosis; and in those who are unusually responsive to sympathomimetic amines.1,48,54,55

Metabolic and Electrolyte Effects

Clinically important changes in blood glucose and serum potassium have occurred infrequently during clinical studies with formoterol at recommended dosage.1,48,54,55

Specific Populations

Pregnancy

Category C.48,55 (See Users Guide.) Formoterol may interfere with uterine contractility; carefully weigh benefit versus risk in labor.1

There is an increased risk of adverse perinatal outcomes (e.g., preeclampsia, premature birth, low birth weight, and neonates small for gestational age) in women with poorly or moderately controlled asthma.54 Pregnant women with asthma should be closely monitored and therapy adjusted as necessary to maintain optimal asthma control.54

The effects of formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate during labor and delivery are not known.51,54,55 Because of the potential for β-agonist interference with uterine contractility, use of formoterol in fixed combination with budesonide, glycopyrrolate, or mometasone during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.51,54,55

Lactation

Formoterol is distributed into milk in rats; it is not known whether formoterol is distributed into human milk.1,51,54,55 Effects of formoterol fumarate on breast-fed infants or milk production also are not known.1,51,54

The benefits of breast-feeding and the woman's clinical need for formoterol fumarate alone or in fixed combination with budesonide or mometasone should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1,51,54

Because many drugs are distributed into human milk, caution should be exercised when formoterol fumarate in fixed combination with glycopyrrolate is administered to nursing women.55 Since there are no data from controlled clinical studies, the manufacturer of formoterol/glycopyrrolate states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.55

Pediatric Use

Formoterol fumarate oral inhalation solution (Perforomist^®) and formoterol fumarate in fixed combination with glycopyrrolate (Bevespi^® Aerosphere^®) are not indicated for use in children.1,55 Safety and efficacy of these preparations in children have not been established.1,55

Safety and efficacy of formoterol fumarate in fixed combination with budesonide (Symbicort^®) in pediatric patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration.51 Safety and efficacy of formoterol/budesonide in pediatric patients 6 to less than 12 years of age with asthma have been established in studies of up to 12 weeks' duration;51 however, the manufacturer states that safety and efficacy of the fixed-combination preparation in children younger than 6 years of age with asthma have not been established.51

Safety and efficacy of formoterol fumarate in fixed combination with mometasone furoate (Dulera^®) in pediatric patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration.54

Available data from controlled clinical trials suggest that monotherapy with long-acting β₂-adrenergic agonists increases the risk of asthma-related hospitalization in pediatric and adolescent patients.51,54 (See Asthma-related Death and Serious Asthma-related Events under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

No substantial differences in safety and efficacy of formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate have been observed in geriatric patients relative to younger adults.1,48,54,55 However, the manufacturers state that the possibility that some geriatric patients may exhibit increased sensitivity to formoterol or fixed combinations containing formoterol cannot be ruled out.1,54,55 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 2% or more of adults in clinical trials receiving formoterol fumarate oral inhalation solution for the treatment of COPD include diarrhea,1 nausea,1 vomiting,1 nasopharyngitis,1 dry mouth,1 dizziness,1 and insomnia.1

Adverse effects occurring in 3% or more of patients receiving formoterol fumarate in fixed combination with budesonide for the treatment of asthma include nasopharyngitis,51 headache,51 upper respiratory tract infection,51 pharyngolaryngeal pain,51 sinusitis,51 influenza,51 back pain,51 nasal congestion,51 stomach discomfort,51 vomiting,51 and oral candidiasis.51

Adverse effects occurring in 3% or more of patients receiving formoterol fumarate in fixed combination with budesonide for the treatment of COPD include nasopharyngitis,51 oral candidiasis,51 bronchitis,51 sinusitis,51 and upper respiratory tract infection.51

Adverse effects occurring in 2% or more of patients receiving formoterol fumarate in fixed combination with glycopyrrolate for the treatment of COPD and more frequently than in those receiving placebo include urinary tract infection55 and cough.55

Adverse effects occurring in 3% or more of patients receiving formoterol fumarate in fixed combination with mometasone furoate for the treatment of asthma and more frequently than in those receiving placebo include nasopharyngitis,54 sinusitis,54 and headache.54

The following information addresses potential interactions with formoterol fumarate.1 When formoterol fumarate is used in fixed combination with budesonide, glycopyrrolate, or mometasone furoate, interactions associated with budesonide, glycopyrrolate, and mometasone also should be considered.48,54,55 No formal drug interaction studies have been performed to date with the fixed-combination preparations containing formoterol fumarate and budesonide, glycopyrrolate, or mometasone.48,54,55

Drugs that Prolong QT Interval

Potential pharmacologic interaction (increased risk of ventricular arrhythmias and effects of formoterol on the cardiovascular system may be potentiated).1 Drugs that prolong the QT interval should be used concomitantly with formoterol with extreme caution.1

Sympathomimetic Agents

Potential additive pharmacologic and adverse effects.1 Additional sympathomimetic agents administered by any route should be used with caution.1

Xanthine Derivatives/Corticosteroids

Potential pharmacologic interaction (increased risk of hypokalemia).1

Non-potassium-sparing Diuretics

Potential additive ECG and/or hypokalemic effects, especially when the recommended dosage of the β-agonist is exceeded; the clinical importance is unknown.1,48 Concomitant administration of β-agonists and non-potassium-sparing diuretics should be used with caution.1,48

Monoamine Oxidase Inhibitors/Tricyclic Antidepressants

Potential pharmacologic interaction (effects of formoterol on the cardiovascular system may be potentiated).1,48 Formoterol should be used with extreme caution during concomitant therapy1,48 or within 2 weeks following discontinuance of a monoamine oxidase (MAO) inhibitor or tricyclic antidepressant.48

Beta-Adrenergic Blocking Agents

Potential pharmacologic interaction (antagonism).1,48 Cardioselective β-adrenergic blocking agents should be considered if concomitant therapy with formoterol is necessary.1,48

Description

Formoterol fumarate is a synthetic sympathomimetic amine.6,7,15 Like salmeterol,8 formoterol is a long-acting, selective β₂-receptor agonist,1,6,7,15,48 and is structurally and pharmacologically similar to other selective β₂-adrenergic receptor agonists (e.g., albuterol, salmeterol).6,7 Formoterol occurs as a racemic mixture;1,7 only the R,R -enantiomer is active.7,14,17

Formoterol stimulates β₂-adrenergic receptors and apparently has little or no effect on β₁-1,6,7,48 or α-adrenergic receptors.7 The drug's β-adrenergic effects appear to result from stimulation of the production of cyclic adenosine-3',5'-monophosphate (cAMP) by activation of adenyl cyclase.1,48 Cyclic AMP mediates numerous cellular responses, and increased concentrations of cAMP are associated with relaxation of bronchial smooth muscle and suppression of some aspects of inflammation, such as inhibition of release of proinflammatory mast-cell mediators (e.g., histamine, leukotrienes).1,48 Some studies in patients with mild asthma and in animals suggest that formoterol inhibits allergen-induced infiltration of eosinophils into airways, and reduces extravasation of plasma proteins (e.g., albumin).1,2,7,13,48 However, current evidence indicates that formoterol, like salmeterol,8 does not possess clinically important anti-inflammatory effects.6,13,15

Tolerance to the bronchoprotective effects of formoterol (diminished effect on FEV1) has been reported after prolonged (2 weeks) dosing at twice the recommended dose (24 mcg), with loss of protection at the end of the 12-hour dosing period.17,48

Limited data suggest that formoterol has a more rapid onset of action than salmeterol but a similar duration of action and similar bronchodilatory effects.6,7,15

Advice to Patients

When formoterol fumarate is used in fixed combination with budesonide, glycopyrrolate, or mometasone furoate, importance of informing patients of important cautionary information about budesonide, glycopyrrolate, or mometasone furoate.48,54,55

A copy of the manufacturer's patient information (medication guide) for formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate must be provided to all patients each time the drug is dispensed.1,40,42,48,54,55 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time the prescription is refilled.1,42,48,54,55

Importance of informing patients that monotherapy with long-acting β₂-adrenergic agonists, including formoterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.1,48,51,54,55 Importance of informing patients that long-term asthma controller drugs must be continued when formoterol is added to the treatment regimen.51

Importance of pediatric patients receiving therapy under adult supervision.51

Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the oral inhalation delivery system.1,48,54,55

Importance of correct procedure for administering formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate and any concomitant therapy (e.g., a short-acting β₂-adrenergic agonist).1,48,54,55 Importance of not breathing into the inhaler.51

Importance of adherence to dosing schedules of formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate and any concomitant therapy, including not altering the dose or frequency of use of such drugs unless otherwise instructed by a clinician.1,48,54,55 Importance of advising patient that if a dose of formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.1,48,54,55

Importance of informing patients of adverse effects associated with β₂-adrenergic agonists such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.1,48,54,55

Importance of understanding that formoterol-containing therapy does not relieve acute symptoms of asthma or COPD.1,48,54,55 Importance of all patients being provided with and instructed in the use of a short-acting, inhaled β₂-adrenergic bronchodilator as supplemental therapy for acute asthma or COPD symptoms.1,48,54,55

Importance of discontinuing regular use of a short-acting, inhaled β-adrenergic bronchodilator when initiating therapy with formoterol and instituting intermittent use of a short-acting bronchodilator ( not formoterol) to relieve acute symptoms of asthma.1,48,54,55 Importance of contacting a clinician if respiratory symptoms worsen or are not relieved by usual dosage of formoterol fumarate.1,48 Importance of contacting a clinician or obtaining medical care right away if 4 or more inhalations of a short-acting β₂-agonist are required daily for 2 or more consecutive days, an entire canister of the short-acting β₂-agonist is used in 8 weeks, peak flow meter results decrease, or asthma symptoms do not improve after 1 week of formoterol therapy.48

Importance of instructing patients to seek emergency medical care if breathing problems worsen rapidly and usual doses of a short-acting bronchodilator do not relieve acute asthma or COPD symptoms.1,48,54,55

Importance of advising patients who are receiving formoterol-containing preparations not to use additional formoterol or other long-acting inhaled β₂-adrenergic agonists for any reason.1,48,54,55

Importance of patients not discontinuing formoterol-containing therapy and not discontinuing or reducing concomitant asthma therapy without medical supervision, since symptoms may worsen.48,54,55

Importance of promptly contacting clinicians or seeking emergency medical care if symptoms of a serious allergic reaction (e.g., rash, hives, breathing problems, swelling of the face, tongue, or mouth) develop.1,54,55

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses (e.g., heart disease, high blood pressure, seizures, thyroid problems, diabetes mellitus, drug or food allergies).1,48,54,55

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,48,54,55

Importance of informing patients of other important precautionary information.1,48,54,55 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Mylan. Perforomist^® (formoterol fumarate) inhalation solution prescribing information. Morgantown, WV; 2018 Mar.

2. Wallin A, Sandstrom T, Soderberg M et al. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Am J Respir Crit Care Med . 1999; 159:79-86. [PubMed 9872822]

3. National Asthma Education and Prevention Program. Expert panel report II: guidelines for the diagnosis and management of asthma. 1997 Feb.

4. Palmqvist M, Persson G, Lazer L et al. Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J . 1997; 10:2484-9. [PubMed 9426083]

5. Boulet LP, Becker A, Berube D et al. Summaryof recommendations from the Canadian Asthma Consensus Report, 1999. CMAJ . 1999; 161(Suppl.11):S1-S12.

6. Moore RH, Khan A, Dickey BF et al. Long-acting inhaled β₂-agonists in asthma therapy. Chest . 1998; 113:1095-1108. [PubMed 9554653]

7. Bartow RA, Brogden RN. Formoterol. An update of its pharmacological properties and therapeutic efficacy in the management of asthma. Drugs . 1998; 55:303-22. [PubMed 9506248]

8. GlaxoWellcome. Serevent^® Diskus^® (salmeterol xinafoate inhalation powder) prescribing information. Research Triangle Park, NC; 2008 Mar.

9. Beasley R, Pearce N, Crane J et al. β-agonists: what is the evidence that their use increases the risk of asthma morbidity and mortality? J Allergy Clin Immunol . 1999; 103:S18-30. (IDIS 435471)

10. Tattersfield AE, Postma DS, Barnes PJ et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. Am J Respir Crit Care Med . 1999; 160:594-9. [PubMed 10430734]

12. Bensch G, Lapidus RJ, Levine BE et al. A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler. Ann Allergy Asthma Immunol . 2001; 86L19-27. (IDIS 458307)

13. Pauwels RA, Lofdahl CG, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med . 1997; 337:1405-11. [PubMed 9358137]

14. Zhang M, Fawcett JP, Kennedy JM et al. Stereoselective glucuronidation of formoterol by human liver microsomes. Br J Clin Pharmacol . 2000; 49:152-7. [PubMedCentral][PubMed 10671910]

15. Anon. Formoterol (Foradil Aerolizer) for asthma. Med Lett Drugs Ther . 2001; 43:39-40. [PubMed 11353924]

16. Vervloet D, Ekstrom T, Pela R et al. A 6-month comparison between formoterol and salmeterol in patients with reversible obstructive airways disease. Respir Med . 1998; 92:836-42. [PubMed 9850367]

17. Novartis, East Hanover, NJ: Personal communication

18. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative for asthma: global strategy for asthma management and prevention. Bethesda, MD: National Institutes of Health. 2009 Dec. Available at: [Web]. Accessed 2010 Sep 23. [Web]

19. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart, Lung, and Blood Institute, Global Initiative for Chronic Obstructive Lung Disease, World Health Organization; 2001. Available at NIH website. Accessed Sep. 26, 2002. [Web]

20. American Thoracic Society. ATS Statement: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 1995; 152(Suppl):S78-120.

21. Veterans' Health Administration Department of Veteran Affairs. The pharmacologic management of chronic obstructive pulmonary disease. Washington, DC: Veterans' Health Administration; 1999 June. Pharmacy Benefits Management No. 99-0012. Available at VA PBM website. Accessed Sep. 30, 2002. [Web]

22. Veterans' Health Administration, Department of Veterans' Affairs. VHA/DOD clinical practice guideline for the management of chronic obstructive pulmonary disease: complete summary. Washington, DC: Veterans' Health Administration; 1999 Aug.

23. Rossi A, Kristufek P, Levine BE et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest . 2002; 121:1058-9. [PubMed 11948033]

24. Dahl R, Greefhorst LA, Nowak D. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2001; 164:778-84. [PubMed 11549532]

25. Boehringer Ingelheim. Atrovent^® (ipratropium bromide) inhalation aerosol prescribing information. Ridgefield, CT; 1999 Mar.

26. British Thoracic Society/Scottish Intercollegiate Guidelines Network. Guidelines on the management of asthma: a national clinical guideline. London, Eng; British Thoracic Society. 2008 May. Available at BTS/SIGN website. Accessed 2008 Oct 10. [Web]

27. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 1995 Jan:77-100. NIH/NHLBI Publication No. 95-3659.

28. National Asthma Education and Prevention Program. Expert panel report II: guidelines for the diagnosis and management of asthma. 1997 Feb.

29. Rickard KA. Dear healthcare professional letter regarding important safety information on the use of Serevent^® in patients with asthma. Rockville, MD: US Food and Drug Administration; 2003 Jan 23.

30. Food and Drug Administration. Study of asthma-drug halted. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2003 Jan 23.

31. National Asthma Education Program Expert Panel Report. Executive summary: guidelines for the diagnosis and management of asthma—update on selected topics 2002. J Allergy Clin Immunol . 2002; 110(Suppl.5):S141-219.

32. American Thoracic Society and European Respiratory Society. Standards for the diagnosis and management of patients with COPD. New York, NY: American Thoracic Society, European Respiratory Society; 2005 Sep 8. Available at ATS website. Accessed Aug 10, 2007. [Web]

33. O'Donnell DE, Aaron S, Bourbeau J et al. State of the art compendium: Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease. Can Respir J . 2004; 11(Suppl. B):7B-59B. [PubMed 15340581]

34. Celli BR, Macnee W. Standard for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J . 2004; 23:932-46. [PubMed 15219010]

35. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart, Lung, and Blood Institute, Global Initiative for Chronic Obstructive Lung Disease, World Health Organization; 2007 Dec. Available at NIH website. Accessed Jul 27, 2008. [Web]

36. GlaxoSmithKline. Advair^® Diskus^® (fluticasone propionate/salmeterol xinafoate) inhalation powder prescribing information. Research Triangle Park, NC; 2008 Aug.

37. Lurie P, Wolfe SM. Misleading data analyses in salmeterol (SMART) study. Lancet . 2005; 366:1261-2. [PubMed 16214589]

38. GlaxoSmith Kline. GlaxoSmithKline clinical trial register: salmeterol studies. SLGA5011: a double-blind, randomized, placebo-controlled surveillance study of asthma event outcomes in subjects receiving either usual pharmacotherapy of asthma or usual pharmacotherapy plus salmeterol 42 mcg twice daily. Research Triangle Park, NC. Available at GSK website. Accessed Oct. 11, 2005. [Web]

39. Fontana PG, LeClerc JM. Dear healthcare professional letter regarding Foradil^® (formoterol fumurate) Aerolizer^® dry powder capsules for inhalation safety update. Dorval, QC: Novartis Pharmaceuticals Canada; 2005 Sep. 7. Available at Health Canada website. Accessed Oct. 14, 2005. [Web]

40. Food and Drug Administration. FDA drug safety communication: New safety requirements for long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Feb 18. Available from FDA website ([Web]). Accessed 2010 Jul 7.

41. Food and Drug Administration. FDA drug safety communication: Drug labels now contain updated recommendations on the appropriate use of long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Jun 2. Available from FDA website ([Web]). Accessed 2010 Jul 7.

42. Symbicort^® (budesonide/formoterol fumarate dihydrate) inhalation aerosol risk evaluation and mitigation strategy (i). Initial approval 2009 Feb. Revised 2011 Feb. Reference ID: 2906451. Available from FDA website ([Web]). Accessed 2011 May 24.

43. Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS). Available from FDA website ([Web]). Accessed 2011 Apr 20.

46. American Thoracic Society and European Respiratory Society. Standards for the diagnosis and management of patients with COPD: patient version. New York, NY: American Thoracic Society, European Respiratory Society; 2004. Available at ATS website. Accessed Aug 20, 2007. [Web]

47. National Asthma Education and Prevention Program. Expert panel report III: guidelines for the diagnosis and management of asthma. 2007 Jul. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute. Available at NIH website. Accessed Jul 27, 2008. [Web]

48. AstraZeneca L.P. Symbicort^® (budesonide and formoterol fumarate dihydrate) inhalation aerosol prescribing information. Wilmington, DE; 2010 Jun.

49. AstraZeneca L.P,Wilmington, DE: Personal communication

50. Food and Drug Administration. FDA drug safety communication: FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS). Silver Spring, MD; 2017 Dec 20. Available from FDA website. Accessed 2018 May 8. [Web]

51. AstraZeneca L.P. Symbicort^® (budesonide and formoterol fumarate dihydrate) inhalation aerosol prescribing information. Wilmington, DE; 2017 Dec.

52. Busse WW, Bateman ED, Caplan AL et al. Combined analysis of asthma safety trials of long-acting β₂-agonists. N Engl J Med. 2018; 378:2497-505. [PubMed 29949492]

53. Peters SP, Bleecker ER, Canonica GW et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med. 2016; 375:850-60. [PubMed 27579635]

54. Merck. Dulera^® (mometasone furoate and formoterol fumarate dihydrate) inhalation aerosol prescribing information. Whitehouse Station, NJ; 2019 Apr.

55. AstraZeneca Pharmaceuticals. Bevespi^® Aerosphere^® (glycopyrrolate and formoterol fumarate) inhalation aerosol prescribing information. Wilmington, DE; 2017 Jun.